1. Acute Coronary Syndromes (ACS)

ACS encompasses unstable angina, NSTEMI, and STEMI. This section covers pathophysiology, diagnosis, reperfusion, antithrombotic therapy, mechanical complications, cardiogenic shock, and secondary prevention at fellowship level — integrating the 2023 ESC and 2025 ACC/AHA guidelines.

▼1.1 Epidemiology & Pathophysiology

ACS remains the leading cause of cardiovascular mortality worldwide. In Southeast Asia, ischaemic heart disease accounts for ~17% of all deaths. The pathophysiology of most ACS (>90%) is atherosclerotic plaque rupture or erosion with superimposed thrombosis.

Plaque rupture (65–75%) occurs at the shoulder of a thin-cap fibroatheroma (TCFA, fibrous cap <65 µm), where macrophage-derived matrix metalloproteinases (MMP-1, -8, -13) weaken the cap. Plaque erosion (25–35%) involves superficial endothelial loss over a proteoglycan-rich matrix — commoner in younger women, smokers, and those with metabolic syndrome, without frank rupture.

Thrombus forms via: platelet adhesion (GPIb–vWF), activation (ADP, TXA2, thrombin via PAR-1/4), and aggregation (GPIIb/IIIa crosslinked by fibrinogen), in concert with the extrinsic coagulation cascade activated by tissue factor on exposed adventitia.

⭐ ACS Spectrum

UA: ischaemia without myonecrosis — hs-troponin < 99th percentile URL
NSTEMI: troponin rise/fall >99th percentile URL; no persistent STE; partial or transient occlusion
STEMI: persistent STE ≥1 mm (limb) or ≥2 mm (precordial) in ≥2 leads; complete occlusion
Type 2 MI: supply-demand mismatch (tachyarrhythmia, shock, anaemia, PE, hypertension) — not ACS

🔑 Non-obstructive Culprit Plaques: ~50% of culprit lesions causing STEMI cause <70% stenosis before rupture. Stress testing identifies flow-limiting disease but cannot predict plaque rupture — hence most MIs occur without prior symptoms. Plaque stabilisation (high-intensity statin, aspirin, lifestyle) is the foundation of primary prevention.

📚 Pathophysiology

2023 ESC ACS Guidelines — Byrne RA et al., Eur Heart J 2023;44:3720
PROSPECT — Stone GW et al., NEJM 2011 — Plaque vulnerability & MACE

▼1.2 STEMI — Diagnosis & ECG Localization

STEMI requires: (1) symptoms of myocardial ischaemia AND (2) new STE ≥1 mm in ≥2 contiguous limb leads OR ≥2 mm in ≥2 contiguous precordial leads OR new LBBB + troponin rise/fall. Hs-troponin rises 1–3 h from onset.

Territory	Leads	Culprit	Reciprocal	Pearl
Anterior	V1–V4	LAD	II, III, aVF ↓	De Winter T-waves = LAD occlusion without STE
Extensive anterior	V1–V6, I, aVL	Proximal LAD (pre-D1)	II, III, aVF ↓	Wellens syndrome: biphasic or deep T inversions V2–V3 = reperfused LAD
Inferior	II, III, aVF	RCA 80%, LCx 20%	I, aVL ↓	Always obtain V4R; RVI in 30–50% of inferior STEMI
Lateral	I, aVL, V5–V6	LCx, OM, Diagonal	V1–V2 ↓	Isolated high lateral (I, aVL) = D1 or OM1
Posterior	V7–V9 STE; V1–V3 tall R + STD	LCx or RCA-PDA	V1–V3 STD	Get posterior leads whenever V1–V3 show STD + tall R
RV	V4R ≥1 mm STE	Proximal RCA	—	Avoid nitrates & diuretics — give IV fluid
Left main / prox LAD	aVR STE + diffuse STD ≥6 leads	LM or proximal LAD	Diffuse lateral–inferior ↓	Immediate cath-lab activation; very high mortality

🔑 Wellens Syndrome — Never Stress Test: Type A: biphasic T-waves V2–V3. Type B: deep symmetric T inversions V2–V3. Both = critical proximal LAD after spontaneous reperfusion. Patient is pain-free with near-normal troponin at presentation. Stress testing is absolutely contraindicated — risk of massive anterior STEMI. Urgent coronary angiography is mandatory.

📚 STEMI Diagnosis

2023 ESC ACS Guidelines — STE definitions & STEMI equivalents
APEX-AMI — Smith SW, JACC 2012 — Modified Sgarbossa criteria
Wellens HJ — Am Heart J 1982 — Original description

▼1.3 STEMI — Reperfusion Strategy

Primary PCI is the preferred reperfusion strategy when achievable within 120 minutes of first medical contact. Target door-to-balloon <90 minutes from hospital arrival. Fibrinolysis is used when timely PCI is not feasible.

Strategy	Indication	Time Target	Key Details
Primary PCI	All STEMI; preferred if within 120 min FMC	D2B <90 min; FMC-device <120 min	Superior to lysis for death/reinfarction/stroke (GUSTO IIb, PRAGUE-2, DANAMI-2)
Fibrinolysis + pharmacoinvasive	PCI not achievable within 120 min; symptoms <12 h	Door-to-needle <30 min	Routine angiography within 3–24 h after lysis regardless of reperfusion status
Rescue PCI	Failed lysis (ST resolution <50% at 60–90 min)	Immediate transfer	Emergency PCI of infarct-related artery

Tenecteplase (TNK) dosing (single IV bolus): <60 kg → 30 mg; 60–70 kg → 35 mg; 70–80 kg → 40 mg; 80–90 kg → 45 mg; >90 kg → 50 mg. Halve dose in patients ≥75 years (STREAM trial).

Complete revascularisation: COMPLETE trial (STEMI) — staged PCI of non-culprit lesions reduced CV death/MI vs. culprit-only (HR 0.74, NNT 23). Class I, 2023 ESC. For cardiogenic shock: CULPRIT-SHOCK — culprit-only PCI reduces 30-day mortality vs. immediate multivessel PCI.

🔑 Pharmacoinvasive Strategy: When primary PCI is not available within 120 minutes, administer fibrinolysis and transfer immediately. Even with apparent reperfusion success (>50% ST resolution), coronary angiography within 3–24 hours is Class I (2023 ESC) — the pharmacoinvasive approach. Angiography <2 h post-lysis is not recommended (higher bleeding without added benefit).

📚 STEMI Reperfusion

COMPLETE — Mehta SR et al., NEJM 2019
CULPRIT-SHOCK — Thiele H et al., NEJM 2017
STREAM — Armstrong PW et al., NEJM 2013

▼1.4 NSTE-ACS — Risk Stratification

NSTE-ACS (NSTEMI + unstable angina) risk stratification guides invasive timing and intensity of therapy. The GRACE score is the most validated predictor of in-hospital and 6-month mortality.

Score	Variables	High Risk Threshold	Strength
GRACE 2.0	Age, HR, SBP, Creatinine, Killip, cardiac arrest, ST deviation, troponin	>140 (in-hospital mortality)	Best validated; use routinely
TIMI NSTE-ACS (0–7)	Age ≥65, ≥3 CAD risk factors, known CAD, ASA use, ≥2 anginal episodes/24h, ST deviation, +troponin	Score ≥5	Simple; less discriminating than GRACE
HEART (0–10)	History, ECG, Age, Risk factors, Troponin	≥7 (50% MACE rate)	Excellent for ED triage; safe discharge if ≤3 (1.7% MACE)

hs-Troponin 0h/1h ESC algorithm: Rule-out if hs-cTnT <5 ng/L at 0h AND Δ <3 ng/L at 1h. Rule-in if hs-cTnT ≥52 ng/L at 0h OR Δ ≥5 ng/L at 1h. NPV >99.5%.

🔑 Type 2 MI — Always Distinguish: Not all elevated hs-troponin = ACS. Type 2 MI results from supply-demand mismatch: tachyarrhythmia, severe hypertension, hypotension, sepsis, PE, anaemia. Treatment is of the underlying cause — NOT antithrombotic loading. The distinction determines whether the patient needs angiography or treatment of a precipitating condition.

📚 NSTE-ACS Risk Stratification

TIMACS — Mehta SR et al., NEJM 2009
VERDICT — Kofoed KF et al., JAMA Cardiol 2018
2023 ESC ACS Guidelines — Risk stratification

▼1.5 NSTE-ACS — Invasive Strategy & Timing

⭐ Invasive Strategy Timing (2023 ESC)

Immediate <2h: cardiogenic shock, haemodynamic instability, refractory ischaemia, new diffuse STD + STE in aVR/V1 (LM suspect), life-threatening arrhythmia
Early <24h: GRACE >140, significant hs-troponin rise, dynamic ST/T changes, DM, CKD (eGFR <60), LVEF <40%, prior PCI <6 months, prior CABG
Selective <72h: intermediate-risk without high-risk features; non-invasive evaluation acceptable
Conservative: low GRACE (<109), negative serial troponins, stable ECG, no recurrent symptoms

Complete revascularisation in NSTEMI: BIOVASC trial (2022) — immediate complete PCI non-inferior to staged PCI for composite MACE at 1 year. Both strategies acceptable; staged within 45 days preferred for complex anatomy.

📚 NSTE-ACS Invasive Strategy

TACTICS-TIMI 18 — Cannon CP et al., NEJM 2001
BIOVASC — Diletti R et al., Lancet 2022
FRISC II — Lancet 1999

▼1.6 Antiplatelet Therapy — DAPT Protocols

Drug	Loading / Maintenance	Key Trial	Advantage	Key Limitation
Ticagrelor	180 mg / 90 mg BD	PLATO: ↓CV death/MI/stroke 16% vs. clopidogrel	Reversible; fast onset 30 min; works regardless of CYP2C19 genotype	Dyspnoea 15% (benign, adenosine-mediated); avoid if prior haemorrhagic stroke
Prasugrel	60 mg / 10 mg OD (5 mg if <60 kg or ≥75 yr)	TRITON-TIMI 38: ↓MI 24% vs. clopidogrel in PCI; ↑major bleeding	Most potent P2Y12; fastest onset	Contraindicated if prior stroke/TIA; no benefit with pretreatment (ACCOAST)
Clopidogrel	600 mg / 75 mg OD	CURE: ↓CV events 20% vs. ASA alone	Low cost; safe with OAC (preferred in triple therapy)	CYP2C19 poor metabolisers (15–25% Asians): ↓efficacy, ↑stent thrombosis

DAPT duration: standard 12 months post-ACS. Shorten to 3–6 months in high bleeding risk (ARC-HBR criteria). Extend >12 months with ticagrelor 60 mg BD (PEGASUS-TIMI 54) or prasugrel 10 mg OD in high ischaemic risk (DAPT score ≥2). AF+ACS: dual therapy (DOAC + clopidogrel, stop ASA after ≤1 week) per AUGUSTUS trial.

🔑 CYP2C19 and Asian Patients: 15–25% of South-East Asians carry CYP2C19 loss-of-function alleles (*2, *3), reducing clopidogrel active metabolite formation by 60–80%. Poor metabolisers have 3× stent thrombosis risk. TAILOR-PCI showed genotype-guided ticagrelor in poor/intermediate metabolisers reduces MACE by 34%. Consider CYP2C19 testing in all Asian patients treated with clopidogrel post-PCI.

📚 Antiplatelet Therapy

PLATO — Wallentin L et al., NEJM 2009
TRITON-TIMI 38 — Wiviott SD et al., NEJM 2007
CURE — Yusuf S et al., NEJM 2001
AUGUSTUS — Lopes RD et al., NEJM 2019
PEGASUS-TIMI 54 — Bonaca MP et al., NEJM 2015
TAILOR-PCI — Pereira NL et al., NEJM 2020

▼1.7 Anticoagulation in ACS

Agent	Dose	Key Trials	Special Considerations
UFH	60–100 U/kg IV bolus; PCI target ACT 250–350 s (or 200–250 s with GPIIb/IIIa)	Standard PCI anticoagulant	Safe in renal failure; reversible with protamine; monitor ACT
Enoxaparin	PCI: 0.5 mg/kg IV; NSTE-ACS medical: 1 mg/kg SC BD; 1 mg/kg SC OD if CrCl <30	EXTRACT-TIMI 25, SYNERGY	Reduce dose in CKD; switch to UFH if CrCl <15 or if PCI planned with CrCl <30
Bivalirudin	0.75 mg/kg bolus → 1.75 mg/kg/h infusion (during PCI)	HORIZONS-AMI, EUROMAX	Lower major bleeding vs. UFH+GPIIb/IIIa; good choice if HIT history; adjust for renal function (GFR <30: reduce infusion to 1 mg/kg/h)
Fondaparinux	2.5 mg SC OD	OASIS-5, OASIS-6	Preferred for medically managed NSTE-ACS (50% less bleeding vs. enoxaparin); add UFH 85 U/kg before PCI to prevent catheter thrombosis — Class I 2023 ESC

🔑 Fondaparinux and PCI — The Catheter Thrombosis Risk: Fondaparinux selectively inhibits factor Xa but has NO anti-IIa activity. At the catheter–blood interface during PCI, insufficient thrombin inhibition allows catheter clot formation. OASIS-5 confirmed this excess risk. Solution: always add a standard UFH bolus (85 U/kg IV, or 60 U/kg if GPIIb/IIIa planned) before PCI when fondaparinux was used as pre-procedure anticoagulant.

📚 ACS Anticoagulation

OASIS-5 — Yusuf S et al., NEJM 2006
HORIZONS-AMI — Stone GW et al., NEJM 2008
EXTRACT-TIMI 25 — Antman EM et al., NEJM 2006

▼1.8 Adjunctive Medical Therapy

Drug	Dose	Indication	Evidence / Target
Metoprolol succinate Carvedilol	25→200 mg OD 3.125→25 mg BD	All ACS (HR >60, SBP >90, no acute LV failure); indefinitely if LVEF ≤40%	COMMIT/CCS-2, CAPRICORN; HR target 55–60 bpm
Ramipril / Enalapril or Sacubitril/valsartan	5–10 mg OD / 10–20 mg BD 24/26 → 97/103 mg BD	All ACS; especially LVEF ≤40%, HF, HTN, DM; ARNI if HFrEF post-MI	SAVE, ISIS-4; PARADISE-MI: ARNI ↓CV death/HF-hosp vs. ramipril (HR 0.90)
Atorvastatin 80 mg Rosuvastatin 20–40 mg	High intensity — start immediately	All ACS patients; target LDL <55 mg/dL	PROVE-IT TIMI 22, MIRACL; add ezetimibe → PCSK9i if needed
Eplerenone	25→50 mg OD	LVEF ≤40% + HF or DM; K+ <5.0, Cr ≤2.5	EPHESUS: 15% ↓mortality
Empagliflozin / Dapagliflozin	10 mg OD	Post-ACS with HFrEF or DM; start before discharge	EMPACT-MI, DAPA-MI 2024
Colchicine	0.5 mg OD	Post-MI secondary prevention (add to GDMT)	COLCOT: 23% ↓CV events; 2023 ESC Class IIa

🔑 REDUCE-AMI — Long-term Beta-Blocker in Preserved EF: The 2024 REDUCE-AMI RCT (N=5,020; post-STEMI/NSTEMI, mean LVEF 58.5%) showed NO reduction in death or MI with long-term metoprolol vs. no treatment (HR 0.96). Revised guidance: continue indefinitely only if LVEF ≤40% or symptomatic arrhythmia. In patients with preserved EF post-MI, the benefit of long-term beta-blocker is uncertain — individualise based on HR, symptoms, and comorbidities.

📚 Adjunctive Therapy

EPHESUS — Pitt B et al., NEJM 2003
PARADISE-MI — Pfeffer MA et al., NEJM 2021
REDUCE-AMI — Yndigegn T et al., NEJM 2024
COLCOT — Tardif JC et al., NEJM 2019
EMPACT-MI — Butler J et al., NEJM 2024

▼1.9 Post-MI Mechanical Complications

Complication	Timing	Presentation	Echo Finding	Management
Free wall rupture	1–5 days	Sudden haemodynamic collapse, PEA, tamponade; Beck's triad (hypotension, JVD, muffled heart sounds)	Pericardial effusion + diastolic collapse of RA/RV	Emergency pericardiocentesis (bridge) → urgent cardiac surgery; mortality >50%
Ventricular septal rupture (VSR)	3–7 days	New harsh holosystolic murmur (LLSB), biventricular failure, O₂ step-up RA→RV on RHC	Colour-flow jet LV→RV through IVS	IABP or Impella bridge → surgical repair (preferred) or percutaneous closure; 30-day mortality ~40%
Papillary muscle rupture (PMR)	2–7 days	Acute severe MR, acute pulmonary oedema; systolic murmur may be soft (equalised pressures)	Flail leaflet; severe eccentric MR; preserved LVEF despite low CO	IABP + nitroprusside → emergent MVR (repair rarely feasible acutely); mortality 30–50%
LV aneurysm	Weeks–months	Persistent STE >2 weeks; HF; ventricular arrhythmias; mural thrombus	Dyskinetic thin-walled anterior segment; possible thrombus	GDMT; anticoagulate if thrombus (warfarin 3–6 months); consider aneurysmectomy if refractory
RV infarction	Acute	Inferior STEMI + hypotension + JVD + clear lungs (Kussmaul sign); V4R STE ≥1 mm	RV dilation; ↓TAPSE; preserved LVEF	Avoid nitrates & diuretics; IV NS 500 mL bolus; dobutamine 2.5–10 µg/kg/min; temporary pacing for complete AVB

🔑 VSR vs. Papillary Muscle Rupture — Diagnostic Differentiation: Both present with haemodynamic collapse + new murmur post-MI. VSR: harsh LLSB murmur, biventricular failure, O₂ step-up RA→RV on right heart cath, commoner in anterior/inferior MI. PMR: apical radiating murmur (may be absent), acute pulmonary oedema dominating, predominantly inferior MI (posteromedial PM supplied solely by RCA). Echo colour-flow Doppler is diagnostic.

▼1.10 Cardiogenic Shock

Cardiogenic shock (CS) complicates 5–8% of STEMI. In-hospital mortality remains 40–50%. Definition: SBP <90 mmHg ≥30 min (or vasopressors required) + CI <2.2 L/min/m² + PCWP >15 mmHg + end-organ hypoperfusion.

⭐ SCAI CS Staging (2019)

Stage A — At Risk: large MI, history of HF; no CS signs
Stage B — Beginning: hypotension/tachycardia; no hypoperfusion; lactate normal
Stage C — Classic CS: vasopressors OR SBP <90; cold/clammy; oliguria; lactate >2 mmol/L
Stage D — Deteriorating: worsening on initial support; ≥2 pressors or escalating MCS
Stage E — Extremis: cardiac arrest; CPR; refractory VT/VF; pH <7.2; lactate >8

Reperfusion: Early PCI reduces 6-month mortality (SHOCK trial: 50% vs. 63% — the only intervention with mortality benefit in RCTs). Culprit-only PCI at index procedure (CULPRIT-SHOCK): reduces 30-day mortality vs. immediate multivessel PCI in CS.

MCS devices: IABP-SHOCK II — IABP no mortality benefit (39% vs. 41%); IMPRESS — Impella CP not superior to IABP; ECMO-CS — VA-ECMO no benefit in unselected CS. Evidence does NOT support routine MCS — use multidisciplinary shock team approach, phenotype the CS, and escalate individualised therapy.

🔑 Vasopressors in Cardiogenic Shock: First-line: dobutamine 5–20 µg/kg/min (dopaminergic + β1/β2 + α1 effects; preferred inotrope). Pure vasopressors (norepinephrine) increase afterload and worsen cardiac output in CS — use ONLY if distributive component (mixed shock) or as bridge. OPTICS trial: dopamine showed no benefit over dobutamine in CS. Avoid high-dose dopamine unless refractory hypotension with vasodilatory component.

📚 Cardiogenic Shock

SHOCK — Hochman JS et al., NEJM 1999
IABP-SHOCK II — Thiele H et al., NEJM 2012
CULPRIT-SHOCK — Thiele H et al., NEJM 2017
ECMO-CS — Combes A et al., NEJM 2023
SCAI CS Staging — Baran DA et al., JACC Heart Fail 2019

▼1.11 ACS in Special Populations

Women: Atypical symptoms (dyspnoea, nausea, fatigue, back/jaw pain) in up to 40%. Higher rate of plaque erosion vs. rupture. SCAD accounts for 35% of ACS in women <50 years — suspect in young women without traditional risk factors. Long smooth tapering stenosis or double-lumen appearance on angiography; IVUS/OCT confirms intramural haematoma. Conservative management preferred (avoid PCI unless haemodynamic compromise); β-blockers reduce recurrence.

Elderly (>75 years): Benefit of invasive strategy maintained (AFTER EIGHTY trial — early invasive vs. conservative in ≥80 years: ↓MACE). Higher bleeding and contrast nephropathy risk — adjust anticoagulant doses, use radial access, minimise contrast. Halve TNK dose if fibrinolysis used.

CKD: Troponin elevated at baseline (↓renal clearance). eGFR <30: use UFH (not enoxaparin) for PCI; avoid fondaparinux if eGFR <20. Hydrate with NS; minimise contrast volume; avoid NSAIDs. Invasive strategy beneficial despite higher procedural risk.

Diabetes: Higher rate of silent MI, multivessel CAD, restenosis. Add SGLT2i/GLP-1RA to GDMT. Withhold metformin 48 h before/after contrast. CYP2C19 testing especially important (higher prevalence of poor metabolisers). SGLT2 inhibitors: CV mortality benefit independent of glycaemia.

🔑 SCAD — Key Recognition Points: Young woman + ACS without traditional risk factors = consider SCAD until proven otherwise. Associations: fibromuscular dysplasia (FMD), Marfan/EDS, peripartum state, emotional/physical stress, exogenous hormones. Angiography: long smooth tapered stenosis, intramural haematoma (may look like normal lumen if bilateral). OCT/IVUS confirms. Avoid PCI (propagation risk) — medical therapy: β-blockers, aspirin. Screen renal/iliac arteries for FMD.

▼1.12 Long-term Secondary Prevention

⭐ Post-ACS Secondary Prevention — Evidence Checklist

Antiplatelet: DAPT 12 months; ASA indefinitely; consider de-escalation (ticagrelor→clopidogrel) in HBR (HOST-EXAM)
Statin: High-intensity — target LDL <55 mg/dL; if not achieved: add ezetimibe then PCSK9i (FOURIER, ODYSSEY-OUTCOMES)
ACEi/ARB or ARNI: indefinitely if LVEF ≤40%, HF, HTN, DM
Beta-blocker: indefinitely if LVEF ≤40%; reassess at 1 year if EF preserved (REDUCE-AMI 2024: no benefit in preserved EF)
MRA (eplerenone 25–50 mg): if LVEF ≤40% + HF or DM (EPHESUS)
SGLT2i (dapagliflozin/empagliflozin 10 mg OD): if HFrEF or DM (DAPA-MI, EMPACT-MI)
Colchicine 0.5 mg OD: post-MI (COLCOT: 23% ↓MACE; 2023 ESC Class IIa)
BP target <130/80 mmHg; Glucose: HbA1c <7% (avoiding hypoglycaemia)
Smoking cessation: reduces mortality 36% — most impactful single intervention
Cardiac rehabilitation: ↓mortality 26% (ExTraMATCH II meta-analysis); exercise 30–60 min moderate intensity ≥5 days/week

📚 Secondary Prevention

FOURIER — Sabatine MS et al., NEJM 2017
ODYSSEY-OUTCOMES — Schwartz GG et al., NEJM 2018
COLCOT — Tardif JC et al., NEJM 2019
REDUCE-AMI — Yndigegn T et al., NEJM 2024
2023 ESC ACS Guidelines — Long-term management chapter

▼1.13 Practice Questions — ACS

Q1. A 58-year-old man presents with 2 hours of chest pain. ECG shows ST depression in V1–V3 with tall R waves and upright T waves. What is the most appropriate next step?

Obtain posterior leads V7–V9.

ST depression in V1–V3 with tall R waves = reciprocal changes of a posterior STEMI (LCx or RCA-PDA occlusion). Posterior leads showing STE ≥0.5 mm in V7–V9 confirm posterior MI → activate cath-lab for primary PCI, not manage as NSTE-ACS.

Q2. A patient with inferior STEMI received TNK fibrinolysis and has >50% ST resolution at 90 min. She has transferred to your PCI centre. What is next?

Coronary angiography within 3–24 hours (pharmacoinvasive strategy).

2023 ESC Class I: after successful fibrinolysis, routine coronary angiography within 3–24 h is recommended — even if clinical reperfusion appeared successful. Angiography <2 h post-lysis is NOT recommended (↑bleeding without benefit). This is the pharmacoinvasive approach.

Q3. An NSTEMI patient is started on fondaparinux 2.5 mg SC. PCI is planned next morning. What must be given before PCI begins?

UFH 85 U/kg IV bolus.

Fondaparinux alone during PCI causes catheter thrombosis due to absent anti-IIa activity. A standard UFH bolus must be added before PCI (Class I, 2023 ESC). This is one of the highest-yield pharmacology points in cardiology board examinations.

Q4. A 43-year-old woman without traditional CV risk factors presents with NSTEMI. Angiography shows a long smooth tapered stenosis in the LAD with a double-lumen appearance. Diagnosis?

Spontaneous Coronary Artery Dissection (SCAD).

Long smooth tapered stenosis + double-lumen = SCAD. Management: conservative (avoid PCI — propagation risk); β-blockers; screen for FMD (CTA of renal/iliac arteries). OCT/IVUS confirms intramural haematoma. SCAD accounts for 35% of MI in women <50 years.

2Heart Failure & Cardiomyopathy

▶2.1 HF Epidemiology & Pathophysiology

Heart failure (HF) affects 64 million people worldwide; prevalence is increasing as the population ages. In Thailand, HF represents a major cause of hospitalisation, with 30-day re-admission rates of 20–25%. Lifetime risk at age 40 is ~20%. Five-year mortality for HFrEF remains ~50%.

Pathophysiology: HF is a clinical syndrome of impaired cardiac output or elevated filling pressures that leads to symptomatic dyspnoea, fatigue, and fluid retention. Three fundamental mechanisms: (1) Systolic dysfunction — loss of contractile myocytes → ↓stroke volume; (2) Diastolic dysfunction — impaired relaxation/increased stiffness → ↑filling pressures; (3) Neurohormonal activation — SNS, RAAS, ADH, endothelin → initially compensatory, chronically maladaptive.

Maladaptive remodelling cascade: Reduced cardiac output → baroreceptor activation → SNS ↑ (↑HR, ↑contractility, ↑SVR) → RAAS ↑ → angiotensin II + aldosterone → Na/H₂O retention + vasoconstriction → ↑preload/afterload → myocyte hypertrophy, fibrosis, apoptosis → eccentric remodelling → progressive chamber dilation → worsening EF. This is the target of ACEi/ARB, beta-blockers, MRAs, and sacubitril/valsartan.

⚡ Neurohormonal Targets in HFrEF

RAAS: ACEi/ARB/ARNI — reduce angiotensin II, aldosterone; vasodilation + anti-fibrotic
SNS: Beta-blockers (BB) — block catecholamine excess; reverse remodelling
Aldosterone: MRA (eplerenone/spironolactone) — anti-fibrotic, anti-hypokalaemic
SGLT2: SGLT2i (empagliflozin/dapagliflozin) — osmotic diuresis, cardiac energy substrate shift
Combined RAAS+neprilysin: ARNI (sacubitril/valsartan) — ↑ANP/BNP, ↓maladaptive remodelling

🔶 Starling Curve in HF

On a depressed Starling curve, increasing preload (fluid) produces little additional stroke volume but greatly increases filling pressures → pulmonary congestion. Conversely, diuresis improves symptoms without reducing CO significantly — this explains why decongestion is the central acute HF strategy.

▶2.2 HF Classification & Phenotypes

Classification by EF (2021 ESC):

Phenotype	LVEF	Additional Criteria	Prevalence
HFrEF (Reduced EF)	≤40%	—	~40% of all HF
HFmrEF (Mildly reduced EF)	41–49%	Elevated filling pressures OR structural disease	~20%
HFpEF (Preserved EF)	≥50%	Elevated NPs + diastolic dysfunction on echo	~40%
HFimpEF (Improved EF)	Previously ≤40%, now >40%	Don't withdraw GDMT	Variable

NYHA Functional Classification:

Class	Symptoms	Clinical Significance
I	No symptoms at ordinary activity	Asymptomatic LV dysfunction
II	Mild symptoms with ordinary activity; comfortable at rest	Mild HF
III	Symptoms with less-than-ordinary activity; comfortable only at rest	Moderate HF
IV	Symptoms at rest or with any physical activity	Severe/advanced HF

ACC/AHA Stages: Stage A (risk factors, no structural disease) → Stage B (structural disease, no symptoms) → Stage C (structural + symptoms) → Stage D (refractory, advanced HF).

🔶 HFpEF — The Diagnosis Challenge

HFpEF requires: (1) symptoms/signs of HF, (2) LVEF ≥50%, (3) objective evidence of elevated filling pressures. H₂FPEF score and HFA-PEFF algorithm are validated tools. Key: raised NTproBNP (≥125 pg/mL ambulatory, ≥365 pg/mL acute) + diastolic dysfunction on echo (e prime <7 cm/s, E/e ratio >14, LAVi >34 mL/m²) + structural criteria.

▶2.3 HFrEF — Foundational GDMT (The Four Pillars)

Pillar	Drug	Starting Dose	Target Dose	Mortality Benefit
ARNI (preferred) / ACEi	Sacubitril/valsartan Enalapril (if ARNI not tolerated)	24/26 mg BD 2.5 mg BD	97/103 mg BD 10 mg BD	PARADIGM-HF: 20% ↓CV death vs. enalapril CONSENSUS, SOLVD
Beta-blocker	Carvedilol Metoprolol succinate Bisoprolol	3.125 mg BD 12.5–25 mg OD 1.25 mg OD	25 mg BD 200 mg OD 10 mg OD	CARVEDILOL, COPERNICUS, MERIT-HF, CIBIS-II: 34% ↓mortality
MRA	Eplerenone (preferred post-MI) Spironolactone	25 mg OD 25 mg OD	50 mg OD 25–50 mg OD	EPHESUS: 15% ↓mortality; RALES: 30% ↓mortality (spiro)
SGLT2 inhibitor	Dapagliflozin Empagliflozin	10 mg OD 10 mg OD	10 mg OD 10 mg OD	DAPA-HF: 26% ↓HF events/CV death; EMPEROR-Reduced: 25% ↓CV death/HF-hosp

Sequencing (2022 AHA/2021 ESC guidance): Start all 4 pillars simultaneously or in rapid sequence (weeks not months). Do NOT wait to maximise one before adding another. SGLT2i can be started first in unstable patients (no hypotension risk, no upward titration needed). Titrate to target doses as tolerated. Loop diuretics for decongestion — use lowest effective dose.

⚡ Class I Recommendations — HFrEF

ARNI preferred over ACEi (or ARB if not tolerated) — PARADIGM-HF; switch ACEi→ARNI if tolerated
3 evidence-based BBs only: carvedilol, bisoprolol, metoprolol succinate (extended-release)
MRA: spironolactone or eplerenone — eGFR >30, K+ <5.0
SGLT2i: dapagliflozin or empagliflozin — even without DM
ICD if LVEF ≤35% on GDMT ≥3 months, NYHA II–III, life expectancy >1 year
CRT if LVEF ≤35%, LBBB, QRS ≥150 ms, NYHA II–IV on GDMT

🔶 PARADIGM-HF — Why ARNI Over ACEi

Sacubitril/valsartan inhibits both RAAS (valsartan) and neprilysin (sacubitril). Neprilysin inhibition prevents breakdown of natriuretic peptides (ANP, BNP) → enhanced natriuresis, vasodilation, anti-fibrotic. PARADIGM-HF: 20% ↓CV death+HF hospitalisation vs. enalapril (HR 0.80). Caution: 36h washout required when switching from ACEi (angioedema risk). Contraindicated in history of angioedema.

Key References — HFrEF GDMT

PARADIGM-HF — McMurray JJ et al., NEJM 2014
DAPA-HF — McMurray JJV et al., NEJM 2019
EMPEROR-Reduced — Packer M et al., NEJM 2020
RALES — Pitt B et al., NEJM 1999
EPHESUS — Pitt B et al., NEJM 2003
MERIT-HF — MERIT-HF Study Group, Lancet 1999

▶2.4 HFrEF — Device Therapy (ICD & CRT)

Implantable Cardioverter-Defibrillator (ICD):

Indication	LVEF Threshold	Key Trial	Class
Secondary prevention (survived SCD/VT)	Any EF	AVID, CASH, CIDS	I
Primary prevention — ischaemic CM	≤35%, NYHA II–III, on GDMT ≥3 months, LVEF not improved	MADIT-II, SCD-HeFT	I
Primary prevention — non-ischaemic CM	≤35%, NYHA II–III, on GDMT ≥3 months	SCD-HeFT, DANISH	I (2022 AHA); IIa if no LBBB/CRT candidate

DANISH trial caveat: ICD in non-ischaemic CM reduced SCD but not all-cause mortality (possibly because many received CRT and died of non-cardiac causes). ICD benefit strongest if: younger, no CRT, higher co-morbidity burden.

Cardiac Resynchronisation Therapy (CRT):

Criterion	Threshold	Evidence	Class
LVEF + LBBB + QRS duration	LVEF ≤35%, LBBB, QRS ≥150 ms, NYHA II–IV	MADIT-CRT, RAFT, CARE-HF	I
LVEF + LBBB + QRS 130–149 ms	LVEF ≤35%, LBBB, QRS 130–149 ms, NYHA II–III	Meta-analysis	IIa
Non-LBBB (RBBB/IVCD) + QRS ≥150 ms	LVEF ≤35%, non-LBBB, QRS ≥150 ms	Lesser evidence	IIb
AF with high pacing burden (>40%)	LVEF ≤35% + planned AV nodal ablation	His bundle pacing alternative	IIa

🔶 CRT Response Prediction

Predictors of CRT super-response (LVEF normalisation): (1) LBBB morphology — most important; (2) QRS ≥150 ms; (3) non-ischaemic aetiology; (4) female sex; (5) sinus rhythm (not AF). RBBB with CRT: limited benefit; may even be harmful in some studies. Document true LBBB morphology (Strauss criteria: QRS ≥140 ms men/≥130 ms women + mid-QRS notching in ≥2 lateral leads).

Key References — Device Therapy

SCD-HeFT — Bardy GH et al., NEJM 2005
MADIT-II — Moss AJ et al., NEJM 2002
DANISH — Koester L et al., NEJM 2016
MADIT-CRT — Moss AJ et al., NEJM 2009
CARE-HF — Cleland JG et al., NEJM 2005

▶2.5 HFpEF — Evidence & Treatment

HFpEF accounts for ~40–50% of all HF and its prevalence is increasing with obesity and ageing. Mortality is equivalent to HFrEF. Unlike HFrEF, most landmark RCTs (perindopril, candesartan, irbesartan, spironolactone, nebivolo) failed to meet primary endpoints in HFpEF — the field has been largely negative until 2021–2023.

Positive trials in HFpEF:

Trial	Drug	Result	Class
EMPEROR-Preserved	Empagliflozin 10 mg OD	21% ↓CV death+HF hospitalisation (HR 0.79)	I (2023 ESC)
DELIVER	Dapagliflozin 10 mg OD	18% ↓CV death+HF-worsening (HR 0.82)	I (2022 AHA update)
TOPCAT	Spironolactone	Neutral overall; post-hoc: benefit in Americas subgroup; HHF ↓	IIb (can be considered)
PARAGON-HF	Sacubitril/valsartan	Borderline neutral (HR 0.87, p=0.059); possible benefit in LVEF 45–57% + women	IIb (LVEF <57%)

Management pillars in HFpEF: (1) Aggressive risk factor control: treat HTN to SBP <130 mmHg (cornerstone); control DM; weight loss (STEP-HFpEF: semaglutide improved HF outcomes); (2) Decongest with diuretics; (3) Rate control in AF (restores adequate diastolic filling time); (4) SGLT2 inhibitor — now Class I.

🔶 SGLT2 Inhibitors in HFpEF — Mechanism

SGLT2i improve HFpEF outcomes via: (1) osmotic diuresis → reduced preload; (2) cardiomyocyte energy substrate switch (glucose → ketone bodies → ↑efficiency); (3) anti-inflammatory, anti-fibrotic; (4) reduced epicardial fat; (5) erythropoietic effect. These mechanisms are independent of glycaemic control — benefit seen in non-diabetic patients (EF-agnostic effect).

Key References — HFpEF

EMPEROR-Preserved — Anker SD et al., NEJM 2021
DELIVER — Solomon SD et al., NEJM 2022
PARAGON-HF — Solomon SD et al., NEJM 2019
STEP-HFpEF — Kosiborod MN et al., NEJM 2023

▶2.6 HFmrEF

HFmrEF (LVEF 41–49%) is a heterogeneous group — some have recovered from HFrEF, others are progressing from HFpEF. Data suggest these patients respond to HFrEF GDMT, particularly SGLT2i and ARNI.

Key evidence:

Trial	Drug	HFmrEF Subgroup Result
EMPEROR-Preserved	Empagliflozin	HR 0.71 (41–49%) — consistent benefit
DELIVER	Dapagliflozin	HR 0.79 — similar to HFpEF cohort
PARAGON-HF	Sacubitril/valsartan	Trend to benefit in lower EF range and women
CHARM-Added	Candesartan	HFmrEF subgroup showed mortality signal

2023 ESC Recommendation: SGLT2i (empagliflozin or dapagliflozin) — Class IIa in HFmrEF. ACEi/ARB, BB, MRA may be considered (IIb). Treat like HFrEF if patient shows HFrEF features (prior lower EF, ischaemic aetiology).

🔶 HFimpEF — Don't Stop GDMT

Patients who recover EF from HFrEF (LVEF now >40%) still have underlying cardiomyopathy and remain at risk for deterioration. TRED-HF trial: withdrawal of GDMT in recovered DCM caused relapse in 40% at 6 months. Maintain all four pillars indefinitely unless clear contraindication.

▶2.7 Acute Decompensated HF (ADHF)

Initial Assessment: ADHF presents with acute dyspnoea, orthopnoea, peripheral oedema. Assess: precipitant (AF, dietary indiscretion, medication non-adherence, ischaemia, infection, PE), haemodynamic profile (Forrester classification), and organ perfusion.

Forrester Haemodynamic Classification:

Profile	PCWP	CI	Clinical Features	Treatment
I — Warm/Dry (normal)	<18	>2.2	Compensated	Optimise oral GDMT
II — Warm/Wet (congested)	>18	>2.2	Pulmonary congestion, adequate CO	IV loop diuretics (primary)
III — Cold/Dry (low preload)	<18	<2.2	Hypoperfusion + hypovolaemia	Cautious IV fluid; consider PA catheter
IV — Cold/Wet (cardiogenic)	>18	<2.2	Congestion + hypoperfusion	Diuretics + dobutamine ± vasopressors; MCS

Decongestion strategy:

Agent	Dose	Evidence/Notes
Furosemide IV	At least IV dose = oral daily dose; DOSE trial: 2.5× oral dose → superior decongestion	DOSE trial: high-dose preferred (more weight loss, dyspnoea relief); target UO 100–150 mL/hr
Torsemide	10–200 mg OD (more bioavailable than furosemide)	TRANSFORM-HF: no mortality difference vs. furosemide
Metolazone + loop diuretic	2.5–5 mg OD before furosemide (sequential nephron blockade)	Add for diuretic resistance; monitor K+/Mg2+ closely
Acetazolamide + loop	500 mg IV OD × 3 days	ADVOR trial: + acetazolamide → 46% more successful decongestion vs. placebo

🔶 DOSE Trial Takeaway

High-dose strategy (furosemide 2.5× daily oral dose IV q12h) vs. low-dose (1× dose): High-dose → greater weight loss, more dyspnoea relief, no significant ↑creatinine. Continuous vs. bolus: no difference. Clinical implication: do not under-diurese in ADHF — aggressive early decongestion improves outcomes.

Key References — ADHF

DOSE — Felker GM et al., NEJM 2011
ADVOR — Mullens W et al., NEJM 2022
TRANSFORM-HF — Mentz RJ et al., JAMA 2023

▶2.8 Dilated Cardiomyopathy (DCM)

DCM: LV dilation + systolic dysfunction (LVEF <50%) without sufficient CAD, hypertension, or valvular disease to explain degree of impairment. Prevalence 1:250. Causes:

⚡ DCM Aetiology Mnemonic — ABCDE

A — Alcohol (most common reversible cause; 1/3 of DCM in Western countries; abstinence → recovery)
B — Borreliosis (Lyme), Bacterial (myocarditis), B1/B3 deficiency
C — Chemotherapy (anthracyclines — dose-dependent; trastuzumab — reversible); Chagas disease
D — Drug toxicity (cocaine, methamphetamine, clozapine); Diabetes; Duchenne/Becker MD
E — Electrolyte (hypocalcaemia, hypophosphataemia); Endocrine (thyroid, phaeochromocytoma, acromegaly)
F — Familial/Genetic (25–30% of DCM; TTN variants most common — 25% of familial DCM)
G — Genetic: MYH7, LMNA, SCN5A, PLN, DSP — LMNA: conduction disease + DCM + high SCD risk

Work-up of new DCM: Echo (LV/RV function, dilation, TR), ECG (LBBB, AV block → LMNA?), BNP/NTproBNP, TSH, iron studies, viral serology (rarely helpful), CMR (LGE pattern — mid-wall fibrosis in non-ischaemic DCM vs. subendocardial in ischaemic), genetic panel (Class IIa if familial features), coronary angiography (to exclude ischaemic aetiology if pre-test probability high).

CMR in DCM: LGE pattern determines prognosis and guides ICD decision. Mid-wall/lateral LGE → ↑SCD risk → lower threshold for ICD even if LVEF not at conventional threshold. LMNA mutations: conduction disease (AV block, AF) + DCM → ICD early (even at higher EF) due to malignant arrhythmia risk.

🔶 LMNA Cardiomyopathy — High-Risk Genetics

LMNA (lamin A/C) mutations cause DCM with: (1) early conduction disease (AV block, AF) often preceding LV systolic dysfunction; (2) high SCD risk disproportionate to LVEF; (3) 3-5% of familial DCM. ICD indication: consider early (LVEF <45% or NYHA II+, or documented NSVT). Screen 1st-degree relatives. LMNA → poor response to GDMT (lower recovery rate).

▶2.9 Hypertrophic Cardiomyopathy (HCM)

HCM: LV hypertrophy (any wall ≥15 mm, or ≥13 mm with family history) without another cause (e.g., AS, HTN, athlete). Prevalence 1:200–500. Autosomal dominant; most common — MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C) — 70% of genotype-positive cases. Leading cause of SCD in young athletes.

LVOTO (LV outflow tract obstruction): Obstruction present in ~70% at rest or provocation. Gradient ≥30 mmHg at rest or ≥50 mmHg provoked = haemodynamically significant. Mechanism: ASH (asymmetric septal hypertrophy) + SAM (systolic anterior motion of MV) → dynamic LVOT gradient. Worsens with dehydration, vasodilators, digoxin, exercise.

Treatment	Agent	Mechanism	Notes
First-line (obstructive)	Disopyramide + metoprolol/atenolol	Negative inotropy → ↓SAM + ↓gradient	Disopyramide: anticholinergic SE; QT monitoring; monitor QTc
Alternative first-line	Verapamil 120–480 mg/day	↓HR, ↓inotropy; vasodilatory	Avoid if severe obstruction (risk of haemodynamic collapse)
Novel myosin inhibitor	Mavacamten 2.5–15 mg OD	Allosteric cardiac myosin inhibitor → ↓ATPase → ↓contractility	EXPLORER-HCM: 37% met primary endpoint (exercise capacity + NYHA); 2023 FDA/ESC approved
Septal reduction	Septal myectomy (gold standard) / ASA (TASH)	Remove obstructing septum	Myectomy superior long-term; TASH: higher complete AV block risk (20%); both Class III indication

SCD Risk in HCM — 5-Year Risk Calculator (HCM Risk-SCD): Variables: age, max wall thickness, LA diameter, LVOT gradient, family SCD history, NSVT on Holter, unexplained syncope. ≥6% 5-year risk → ICD Class IIa; ≥4% + additional factors → IIb.

🔶 HCM vs. Athlete Heart — Differentiation

Wall thickness 13–15 mm in an athlete: HCM vs. physiological remodelling. Features favouring HCM: (1) LV wall >15 mm; (2) LVEDd <45 mm (athletes typically dilate); (3) family history HCM or SCD; (4) E/A ratio <1 (diastolic dysfunction in HCM); (5) LVEF >65%; (6) abnormal ECG pattern (LVH criteria, negative T waves >2 leads); (7) asymmetric hypertrophy. Deconditioning over 3 months: athlete heart regresses, HCM does not.

Key References — HCM

EXPLORER-HCM — Olivotto I et al., NEJM 2020
2020 AHA/ACC HCM Guidelines
2014 ESC HCM Guidelines

▶2.10 Restrictive CM & Cardiac Amyloidosis

Restrictive cardiomyopathy (RCM): normal or reduced chamber volumes, biatrial enlargement, non-dilated ventricles, preserved or mildly reduced EF, severely impaired diastolic function (rigid myocardium). Causes: amyloidosis (most important), sarcoidosis, haemochromatosis, Fabry disease, eosinophilic CM, idiopathic.

Cardiac Amyloidosis — Two Major Types:

Type	Protein	Clinical Features	Treatment
AL (Light-chain)	Immunoglobulin light chain (monoclonal plasma cell dyscrasia)	Nephrotic syndrome, periorbital purpura, macroglossia, peripheral neuropathy; rapidly progressive; median survival 6 months untreated	Haematology referral; bortezomib-based chemotherapy; autologous SCT if eligible
ATTR (Transthyretin)	Transthyretin (wild-type or variant)	HFpEF pattern in elderly men (wtATTR); bilateral CTS; spinal stenosis; autonomic neuropathy (variant ATTR); low QRS voltage + thick walls; ECG: LBBB-like pattern in V1 (poor R progression)	Tafamidis (ATTR-ACT: 30% ↓mortality, Class I 2023 ESC); Vutrisiran (siRNA, HELIOS-B 2024); Acoramidis (ATTRibute-CM 2023)

Diagnostic Clues for Cardiac Amyloidosis:

⚡ Red Flags for Amyloid on Echo + ECG

Echo: concentric thickening, 'sparkling' myocardium (non-specific), pericardial effusion, biatrial enlargement, thickened valves, diastolic dysfunction (E/e ratio >15)
ECG: low QRS voltage DESPITE increased wall thickness on echo — classic; pseudo-infarct pattern (Q waves without MI)
Echo/ECG mismatch: high sensitivity for amyloid; calculate voltage-to-mass ratio
Clinical: HFpEF in elderly man + bilateral CTS + peripheral neuropathy = ATTR until proven otherwise
Bone scan (Tc-99m PYP/DPD/HMDP): high sensitivity for ATTR; Grade 2–3 uptake: specificity >95% if no monoclonal protein (non-biopsy diagnosis possible)

🔶 Tafamidis — ATTR-ACT Trial

Tafamidis stabilises transthyretin tetramer, preventing amyloid fibril formation. ATTR-ACT (N=441): vs. placebo over 30 months — 30% ↓all-cause mortality (HR 0.70), 32% ↓CV hospitalisation, improved 6MWT + KCCQ. Benefit greatest in NYHA I–II (start treatment early). Now Class I 2023 ESC for ATTR-CM. 2024: HELIOS-B (vutrisiran RNAi) showed 28% ↓CV death+events in ATTR-CM.

Key References — Amyloidosis

ATTR-ACT — Maurer MS et al., NEJM 2018
HELIOS-B — Solomon SD et al., NEJM 2024
ATTRibute-CM — Gillmore JD et al., NEJM 2023

▶2.11 Arrhythmogenic CM (ARVC)

ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy): progressive fibrofatty replacement of RV myocardium → RV dilation, dysfunction, VT with LBBB morphology (RV origin). Leading cause of SCD in young athletes (<35 years) in Italy/Mediterranean countries.

Genetics: Autosomal dominant; most common mutations in desmosomal proteins: PKP2 (plakophilin-2, 40–50%), DSP (desmoplakin), DSG2, DSC2, JUP. Desmosomes maintain myocyte adhesion — defective → cell death → fibrofatty replacement.

Task Force Criteria (2010, modified): Major + minor criteria from: (1) Global/regional RV dysfunction (echo/CMR), (2) Fibrofatty replacement (biopsy — rarely used), (3) Repolarisation abnormalities (T-wave inversions V1–V3), (4) Depolarisation/conduction abnormalities (epsilon wave, terminal activation delay), (5) Arrhythmias (LBBB VT, frequent PVCs >500/24h), (6) Family history. Definite ARVC: 2 major, or 1 major + 2 minor, or 4 minor from different criteria.

ECG findings: T-wave inversions V1–V3 (major criterion), epsilon wave (terminal notch in S wave, V1–V3), prolonged S-wave upstroke ≥55 ms (V1–V3), LBBB morphology VT (negative QRS in V1).

Management: Avoid competitive sport (exercise accelerates disease). Sotalol or amiodarone for VT suppression. ICD: secondary prevention (all survivors of SCA) and primary prevention (high-risk: unexplained syncope, extensive RV disease, proband with malignant family history). Catheter ablation for recurrent VT. Heart transplant for refractory disease.

🔶 ARVC Exercise Restriction — Critical Clinical Point

Exercise is the single most modifiable risk factor for disease progression and SCA in ARVC. Desmosomal stress during intense exercise → accelerated fibrofatty replacement + malignant arrhythmias. ARVC patients should be restricted from all competitive sports and high-intensity exercise — even in gene-positive, phenotype-negative individuals (preclinical). This is one of the most board-tested management pearls.

▶2.12 Practice Questions — Heart Failure & CM

Q1. A 62-year-old man with HFrEF (LVEF 32%) is on carvedilol 25mg BD, enalapril 10mg BD, furosemide 40mg OD, and spironolactone 25mg OD. He has no CKD (eGFR 65) and no angioedema. What is the single most important medication change to further reduce mortality?

Switch enalapril to sacubitril/valsartan (ARNI).

PARADIGM-HF demonstrated 20% relative risk reduction in CV death + HF hospitalisation with sacubitril/valsartan vs. enalapril. ARNI is now Class I recommendation, preferred over ACEi. Requires 36h washout from ACEi before starting to avoid angioedema risk. Add SGLT2i (dapagliflozin or empagliflozin) as well — four-pillar GDMT is the standard.

Q2. An 80-year-old man with HFpEF (LVEF 58%), hypertension, type 2 DM, and eGFR 55 mL/min presents with recurrent HF hospitalisations. Which medication has Class I evidence to reduce HF events in this patient?

Empagliflozin or dapagliflozin (SGLT2 inhibitor).

EMPEROR-Preserved and DELIVER are the first trials to demonstrate clear benefit in HFpEF. Both empagliflozin and dapagliflozin now carry Class I 2022–2023 recommendations for HFpEF. Safe with eGFR ≥20-25 mL/min. Does not require upward titration. ACEi, ARB, BB, MRA all have neutral evidence in HFpEF.

Q3. A 55-year-old woman with newly diagnosed DCM (LVEF 30%) and LBBB on ECG (QRS 158 ms) starts GDMT. At 3-month follow-up her LVEF improves to 42%. Should the ICD/CRT decision change?

Reassess at 6–12 months; maintain GDMT; if LVEF remains >40% reassess ICD need but consider CRT-D if QRS ≥150 ms and LBBB persists.

This is HFimpEF. TRED-HF shows that withdrawal of GDMT leads to relapse in 40% at 6 months — never stop GDMT. CRT-D is still indicated for LBBB + QRS ≥150 ms regardless of whether EF has improved, as it may maintain or further improve EF. ICD alone: reassess EF in 3–6 more months before deciding on primary prevention ICD.

3Cardiac Arrhythmias

▶3.1 Arrhythmia Mechanisms

Three fundamental mechanisms generate all cardiac arrhythmias:

⚡ Arrhythmia Mechanisms

1. Enhanced Automaticity: abnormal spontaneous phase 4 depolarisation in non-pacemaker cells. Examples: ATach, accelerated junctional rhythm, accelerated idioventricular rhythm (reperfusion arrhythmia). Triggered by catecholamines, ischaemia, hypokalaemia.
2. Triggered Activity: afterdepolarisations following an action potential. EAD (early after-depol, phase 2–3): LQTS → TdP; DAD (delayed after-depol, phase 4): digoxin toxicity, catecholaminergic. EADs worsen with bradycardia; DADs worsen with faster rates.
3. Re-entry: most common mechanism. Requires 2 pathways with different conduction velocities and refractory periods. Includes AVNRT, AVRT, flutter, AF, VT in scar tissue. Wavelength = conduction velocity × refractory period.

Action potential phases — clinical relevance: Phase 0 (rapid depol, Na+ current) — sodium channel blockers (flecainide, lidocaine, procainamide); Phase 2 (plateau, Ca2+ current) — calcium channel blockers (verapamil, diltiazem); Phase 3 (repolarisation, K+ current) — potassium channel blockers (amiodarone, sotalol, dofetilide) → QT prolongation; Phase 4 (automaticity, If) — ivabradine blocks funny current → ↓HR without affecting contractility.

🔶 Vaughan-Williams Classification (Simplified)

Class I: Na-channel blockers (IA — quinidine, procainamide, disopyramide; IB — lidocaine, mexiletine; IC — flecainide, propafenone). Class II: Beta-blockers. Class III: K-channel blockers, QT-prolonging (amiodarone, sotalol, dofetilide, ibutilide). Class IV: Ca-channel blockers (verapamil, diltiazem). Amiodarone is a class III but also has I/II/IV effects — 'dirty drug' with broadest spectrum.

▶3.2 AF — Classification & Pathophysiology

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia; prevalence 1–2% general population, 10% in those >80 years. AF doubles mortality risk, increases stroke risk 5-fold (20–30% of ischaemic strokes attributed to AF), and is a major cause of HF.

Classification (2020 ESC):

Type	Definition
First diagnosed	First detected episode (regardless of duration or prior episodes)
Paroxysmal	Self-terminating <7 days (usually <48 h)
Persistent	Not self-terminating or lasting >7 days
Long-standing persistent	Continuous AF >12 months; rhythm control still pursued
Permanent	Accepted by patient and physician; rate control strategy only

Pathophysiology: AF arises from electrical triggers (often rapid ectopic foci in pulmonary vein ostia) interacting with an atrial substrate (fibrosis, inflammation, remodelling). Perpetuation: structural remodelling shortens atrial ERP → re-entry. "AF begets AF" — each episode increases atrial fibrosis and makes AF more persistent. This is why early rhythm control improves outcomes (EAST-AFNET 4).

2020 ESC AF 4S-AF Schema: (1) Stroke risk (CHA₂DS₂-VASc) — anticoagulate; (2) Symptom severity (EHRA score I–IV); (3) Severity of AF burden; (4) Substrate severity. This guides integrated management decisions.

🔶 AF and Sleep Apnoea

OSA is present in 30–50% of AF patients and is a major driver of AF recurrence after cardioversion or ablation. Untreated OSA causes nocturnal hypoxia + sympathetic surges → atrial remodelling. CPAP treatment reduces AF recurrence. Always screen for OSA in AF patients (STOP-BANG questionnaire).

▶3.3 AF — Stroke Risk & Anticoagulation

CHA₂DS₂-VASc Score:

Factor	Points
Congestive HF / LVEF ≤40%	1
Hypertension	1
Age ≥75 years	2
Diabetes mellitus	1
Stroke / TIA / thromboembolism	2
Vascular disease (prior MI, PAD, aortic plaque)	1
Age 65–74 years	1
Sex category (female)	1

Anticoagulation decision (2020 ESC): Men ≥1 point, women ≥2 points → OAC recommended. Female sex alone (score = 1 in woman) does not trigger OAC — it is a risk modifier. DOACs preferred over VKA for non-valvular AF (lower ICH, lower stroke, all-cause mortality benefit in meta-analyses).

DOAC	Dose	Key Trial	Special Considerations
Dabigatran 150 mg BD	Standard dose	RE-LY	Reduce to 110 mg BD if age ≥80, high bleed risk, or on P-gp inhibitor; avoid if eGFR <30; antidote: idarucizumab
Rivaroxaban 20 mg OD	With evening meal	ROCKET-AF	15 mg OD if CrCl 15–50; avoid if CrCl <15; antidote: andexanet alfa
Apixaban 5 mg BD	2.5 mg BD if ≥2 of: age ≥80, weight ≤60 kg, Cr ≥1.5 mg/dL	ARISTOTLE	Most favourable safety profile; antidote: andexanet alfa
Edoxaban 60 mg OD	30 mg OD if CrCl 15–50, weight ≤60 kg, P-gp inhibitor	ENGAGE AF-TIMI 48	Paradoxical worse stroke rates if CrCl >95 mL/min (excessive renal clearance → subtherapeutic levels)

Valvular AF and VKA: Mechanical prosthetic valve or rheumatic mitral stenosis (moderate-severe) → VKA only (DOACs contraindicated — RE-ALIGN trial: dabigatran harmful in mechanical valves).

🔶 Left Atrial Appendage Closure (LAAC)

WATCHMAN device (Boston Scientific): indicated for AF patients with high stroke risk (CHA₂DS₂-VASc ≥2 men/≥3 women) who have contraindications to long-term anticoagulation. PROTECT-AF and PREVAIL trials: non-inferior to warfarin for stroke prevention. AMULET IDE: occlusion device (Amulet, Abbott) non-inferior to WATCHMAN 2.5. After WATCHMAN implant: 45 days of warfarin/NOAC → then DAPT → then aspirin monotherapy. Annual echocardiography to confirm occlusion.

Key References — AF Anticoagulation

RE-LY — Connolly SJ et al., NEJM 2009
ROCKET-AF — Patel MR et al., NEJM 2011
ARISTOTLE — Granger CB et al., NEJM 2011
ENGAGE AF-TIMI 48 — Giugliano RP et al., NEJM 2013
2020 ESC AF Guidelines

▶3.4 AF — Rate Control

Rate control targets: Resting HR <110 bpm is acceptable in most patients with preserved EF and few symptoms (RACE II trial: lenient ≤110 equivalent to strict ≤80 for outcomes). In symptomatic patients or HFrEF: target HR ≤80 bpm rest, ≤110 during exercise.

Agent	Dose	Preferred In	Avoid In
Bisoprolol Metoprolol tartrate	2.5–10 mg OD 25–100 mg BD/TID	HFrEF, post-MI, hypertension, exercise-induced AF	Severe reactive airway disease, sick sinus, 2°/3° AVB without pacemaker
Diltiazem Verapamil	120–360 mg/day 120–360 mg/day	Paroxysmal AF, no structural disease, COPD, symptomatic bronchospasm with BB	HFrEF (↓inotropy), pre-excitation (WPW) — risk of fast ventricular response via accessory pathway
Digoxin	0.0625–0.25 mg OD (renally adjusted)	AF + HFrEF (add-on, not first-line); sedentary elderly	Renal failure (narrow therapeutic window), hypertrophic physiology; avoid in WPW (blocks AV node → accessory pathway conduction unmasked → VF)
Amiodarone	100–200 mg OD	Only when other rate-control agents fail or contraindicated; temporary use	Avoid long-term rate control use (organ toxicity)

🔶 WPW + AF — Potentially Fatal Interaction

WPW (pre-excitation via accessory pathway) + AF: the AV node blocks impulses, but the accessory pathway (which has a shorter refractory period) can conduct very rapidly → extremely fast ventricular response (HR >200 bpm) → VF. Avoid: AV nodal blockers (adenosine, digoxin, verapamil, diltiazem, beta-blockers) — they preferentially slow AV node, unmasking accessory pathway conduction. Treatment: {d('procainamide')} IV (blocks accessory pathway) or immediate DC cardioversion.

▶3.5 AF — Rhythm Control & Cardioversion

EAST-AFNET 4 trial (2020): Early rhythm control (within 1 year of AF diagnosis) vs. rate control in patients with cardiovascular risk factors. Early rhythm control: 21% ↓CV death + stroke + HF hospitalisation (HR 0.79). Risk of adverse events similar. This landmark trial shifted management towards early rhythm control for all AF patients, not just symptomatic ones.

Pharmacological cardioversion:

Agent	Setting	Success Rate	Notes
Flecainide 200–300 mg PO (pill-in-pocket)	Paroxysmal AF, no structural disease	60–80%	Pre-load with AV nodal blocker (BB/CCB) to prevent 1:1 flutter; contraindicated in structural disease
Propafenone 450–600 mg PO	Paroxysmal AF, no structural disease	50–75%	Similar safety profile to flecainide
Ibutilide 1 mg IV (10 min)	In-hospital cardioversion	50–70%	Risk TdP 3–4%; monitor 4h post-dose; QTc monitoring essential
Amiodarone IV/PO	AF + structural disease	Slower (hours-days)	Safe in HF; most versatile but slowest cardioversion

DC Cardioversion: Biphasic shock 100–200 J (anterior-posterior pad placement preferred — lower energy requirements, higher success). Anticoagulation rule: (1) AF duration <48 hours → cardiovert without TOE (low thrombus risk); (2) AF duration >48 h or unknown → anticoagulate for ≥3 weeks before cardioversion, then ≥4 weeks after (atrial stunning), OR TOE to exclude LA/LAA thrombus then cardiovert with anticoagulation continued ≥4 weeks post.

🔶 Pill-in-Pocket for Paroxysmal AF

Flecainide or propafenone as self-administered single dose taken at symptom onset for paroxysmal AF is highly effective and safe — IF: (1) patient has previously had successful pharmacological cardioversion in hospital, (2) structurally normal heart (no CAD, no HFrEF, no LVH), (3) patient pre-loaded with AV nodal blocker (to prevent 1:1 flutter with rapid ventricular response). Educate patient: go to ED if no conversion within 6–8 hours or haemodynamic compromise.

Key References — Rhythm Control

EAST-AFNET 4 — Kirchhof P et al., NEJM 2020
AFFIRM — Wyse DG et al., NEJM 2002
2020 ESC AF Guidelines

▶3.6 AF — Catheter Ablation

Pulmonary vein isolation (PVI): Cornerstone of AF ablation. Targeting rapid ectopic foci at PV-LA junctions → electrical isolation of all 4 PVs from LA. Success rates: 70–80% paroxysmal AF, 50–65% persistent AF at 1 year (single procedure).

Key trials:

Trial	Comparison	Result
CABANA	Ablation vs. pharmacological therapy	No difference in death/stroke/serious bleeding/cardiac arrest (intention-to-treat); per-protocol analysis: 27% ↓primary endpoint with ablation
CASTLE-AF	Ablation vs. medical therapy in AF+HFrEF	38% ↓death+HF hospitalisation (HR 0.62); ↑LVEF +8% with ablation. Strong evidence for ablation in HFrEF
EARLY-AF	Cryoablation vs. antiarrhythmic drugs (first-line)	47% ↓recurrent AF; ablation superior as first-line strategy
STOP-AF FIRST	Cryoablation vs. AAD (first-line)	72% vs. 58% freedom from AF at 12 months; ablation superior

Indications (2020 ESC Class I): Symptomatic AF refractory or intolerant to ≥1 AAD, and in patients with HFrEF (CASTLE-AF data). Class IIa: as first-line therapy for paroxysmal/persistent AF if patient preference after weighing risks and benefits.

Techniques: Radiofrequency (point-by-point) vs. cryoenergy (Arctic Front balloon — circumferential). Newer: pulsed field ablation (PFA) — non-thermal, more tissue-selective (spares oesophagus, phrenic nerve), approved 2023. PULSE-AF trial: PFA superior to cryoablation for procedure efficiency and safety profile.

🔶 CASTLE-AF — Why Ablation in HFrEF Matters

In AF + HFrEF: AF is often a cause (tachycardia-induced CMP) not a consequence of HF. Restoring sinus rhythm with ablation → reversal of tachycardia-mediated CM, improved LVEF, reduced HF hospitalisation. CASTLE-AF: 38% ↓death + HF-hosp (absolute reduction meaningful). 2023 ESC: ablation is Class IIa in HFrEF — consider before assuming irreversibility of HFrEF.

▶3.7 Atrial Flutter & Macro-reentry

Typical atrial flutter (cavotricuspid isthmus-dependent): Counterclockwise macro-reentrant circuit around tricuspid annulus through the CTI (between TV and IVC). Rate: 300 bpm (typical range 250–350); ventricular rate: 2:1 block (150 bpm) is classic — HR of exactly 150 bpm should raise suspicion for flutter. Sawtooth flutter waves in inferior leads (II, III, aVF) at 300 bpm.

Clockwise flutter: Reverse typical flutter; positive flutter waves in inferior leads (inverted sawtooth). Less common; still CTI-dependent.

Atypical flutter: Non-CTI macro-reentry; post-surgical scars (post-cardiac surgery, ablation). Requires electrophysiology study for diagnosis and ablation.

Management:

⚡ Atrial Flutter Treatment

Acute rate control: IV diltiazem or metoprolol (beta-blockers less effective in flutter than in AF)
Cardioversion: DC cardioversion 50–100 J (usually easier than AF); ibutilide IV for pharmacological cardioversion
Anticoagulation: same rules as AF (treat as AF for stroke risk — CHA₂DS₂-VASc scoring)
Definitive: CTI ablation — highly effective (95% success), Class I recommendation. Flutter frequently co-exists with AF; monitor for AF post-ablation (Holter monitoring)
Anti-arrhythmic drugs: limited efficacy in flutter; risk of 1:1 conduction with Class IC drugs (flecainide/propafenone) if used without AV nodal blocker

🔶 Flutter at 150 bpm — Diagnostic Pearl

Narrow complex tachycardia at exactly 150 bpm with regular rhythm: atrial flutter with 2:1 block is the diagnosis until proven otherwise. The flutter waves are often hidden in QRS complexes or ST segments. Use vagal manoeuvres or IV adenosine to transiently increase AV block and unmask flutter waves. This is one of the highest-yield ECG recognition points in cardiology.

▶3.8 SVT — AVNRT, AVRT, & Atrial Tachycardia

Differential of narrow complex regular tachycardia (NCRT):

Arrhythmia	P wave relation to QRS	RP interval	Mechanism	Treatment
AVNRT (typical, slow-fast)	Buried in QRS or just after (pseudo-R in V1, pseudo-S in II/III/aVF)	Short RP (<70 ms)	Re-entry dual AV node pathways (slow anterograde, fast retrograde)	Adenosine; CCB/BB; EPS+ablation slow pathway (95% success)
AVRT (orthodromic, WPW)	After QRS, in ST segment	Short RP (70–100 ms); longer than AVNRT	Re-entry via accessory pathway (anterograde via AV, retrograde via AP)	Adenosine (acute); EPS+AP ablation (definitive)
Atrial tachycardia	Before QRS (P-wave morphology different from sinus)	Long RP (>half RR)	Focal automaticity or micro-reentry in atria	Beta-blockers, CCB; EPS ablation focal source
Junctional tachycardia	Retrograde P after QRS; AV dissociation	Very short or none	Enhanced junctional automaticity (post-cardiac surgery, digitalis)	Treat cause; beta-blockers; amiodarone

Adenosine for SVT — Technique: 6 mg rapid IV push + 20 mL saline flush in antecubital vein; if no response in 1–2 min: 12 mg; if no response: 12 mg again. Use with continuous ECG monitoring. Causes transient AV block — terminates AVNRT/AVRT, unmasks flutter, diagnostic (slows AV node → reveals underlying atrial activity). Contraindications: severe asthma (can cause bronchospasm), 2°/3° AVB, sick sinus without pacer, WPW with antidromic tachycardia. Use with caution in heart transplant recipients (hypersensitive to adenosine — use 1–3 mg).

🔶 AVNRT vs. AVRT — Key Differentiator

Both are short-RP tachycardias. AVNRT: P wave buried in QRS (pseudo-R' in V1) — RP <70 ms. AVRT (orthodromic): P wave just after QRS in ST segment — RP 70–100 ms (retrograde conduction takes longer as it traverses the ventricle then the accessory pathway). During sinus rhythm: delta wave in WPW (AVRT substrate), delta wave absent in AVNRT (dual AV node only). ECG during tachycardia: look for alternating bundle branch block (BBB aberrancy prolonging tachycardia cycle length in AVRT = Coumel's sign — AP is on the same side as the BBB).

▶3.9 Ventricular Tachycardia & Fibrillation

Approach to wide complex tachycardia (WCT): All WCT (>3 complexes, rate >100 bpm, QRS >120 ms) should be treated as VT until proven otherwise. Haemodynamically stable WCT can still be VT — stability does NOT differentiate VT from SVT-with-aberrancy.

⚡ Brugada Criteria for VT vs. SVT-with-aberrancy

Step 1: Any RS complex in precordial leads? No (all concordant QRS) → VT
Step 2: RS interval >100 ms in any precordial lead? → VT
Step 3: AV dissociation (independent P waves from QRS)? → VT
Step 4: Morphology criteria (RBBB-like: qR, Rs, or Rr in V1; LBBB-like: R>30ms in V1, notching in S-wave descent in V1/V2) → VT
If all criteria absent → SVT with aberrancy. Sensitivity 98%, specificity 96%

Acute management of sustained VT: Unstable (hypotension, LOC, pulmonary oedema) → immediate synchronised DC cardioversion. Stable → IV amiodarone 150 mg over 10 min then 360 mg over 6h; or procainamide IV (preferred if pre-excitation likely — 20–50 mg/min). Lidocaine: 1.5 mg/kg IV bolus — second-line especially post-MI or ischaemia-related VT.

Specific VT syndromes:

Type	Features	Treatment
Idiopathic RVOT VT	LBBB morphology, inferior axis; young patients without structural disease; triggered by exercise/catecholamines; benign prognosis	Verapamil or BB; ablation highly effective (success >90%)
Fascicular VT (Belhassen VT)	RBBB morphology, left axis deviation; relatively narrow QRS; verapamil-sensitive (terminated by verapamil — diagnostic)	Verapamil acute; ablation (posterior fascicle)
Scar-related VT (ischaemic CM)	Monomorphic sustained VT; slow-fast re-entry around MI scar; inducible at EPS	Amiodarone; ICD; VT ablation (scar substrate modification)
Polymorphic VT / TdP	Rotating QRS axis; associated with QT prolongation (acquired or congenital); precipitated by bradycardia, pause	IV magnesium sulphate 2 g; overdrive pacing/isoproterenol (↑HR → shorten QT); remove offending drug

🔶 VT Storm — Electrical Storm Management

≥3 sustained VT/VF episodes in 24h = electrical storm. Immediate management: (1) IV amiodarone 150 mg bolus + infusion; (2) deep sedation/anaesthesia (↓sympathetic tone); (3) correct electrolytes (K+ ≥4.5, Mg2+ ≥1.5); (4) if ischaemia → urgent cath; (5) consider stellate ganglion blockade (left-sided) for refractory storm; (6) if LQTS-related: IV magnesium + temporary pacing at 90–100 bpm + stop offending QT-prolonging drugs; (7) emergent VT ablation if recurrent monomorphic VT.

Key References — Ventricular Arrhythmias

2022 AHA/ACC Ventricular Arrhythmia/SCD Guidelines
CAMERAMAN — Tung R et al., JAMA 2024 (VT ablation vs. escalated AAD)

▶3.10 Bradyarrhythmias & Cardiac Pacing

Sinus Node Dysfunction (SND): Includes: sinus bradycardia (<60 bpm), sinus arrest/pause, sinoatrial exit block, sick sinus syndrome (SSS), tachy-brady syndrome. Causes: age-related fibrosis, inferior MI (RCA → SA nodal artery), hypothyroidism, drugs (BB, CCB, digoxin, amiodarone), infiltrative disease. PPM indicated for symptomatic bradycardia.

AV Block Classification:

Type	ECG Features	Level of Block	Pacing Needed?
1° AVB	PR >200 ms; all P waves conducted	AV node	No (unless symptomatic or pre-procedure)
2° Mobitz I (Wenckebach)	Progressive PR prolongation → dropped QRS; shortest PR after pause	AV node	Usually no; PPM if symptomatic or post-inferior MI with haemodynamic compromise
2° Mobitz II	Constant PR → sudden dropped QRS (no PR change); often wide QRS	His-Purkinje system (infranodal)	Yes — unpredictable complete AVB risk
2:1 AVB	2 P waves per QRS; can be Mobitz I or II — narrow QRS = likely Mobitz I; wide QRS = Mobitz II	Variable	Consider PPM; EP study if uncertain
3° (Complete) AVB	Complete AV dissociation; PP and RR intervals regular but independent; escape rhythm: junctional (40–60 bpm, narrow) or ventricular (20–40 bpm, wide)	AV node or infranodal	Yes — permanent PPM

Pacing modes (NBG code): DDD(R) — most physiological; dual chamber sensing + pacing + inhibition; rate-responsive. VVI(R) — single lead ventricular backup; simpler; used in permanent AF. VVIR — rate-responsive single chamber. Conduction system pacing (His bundle pacing, left bundle branch area pacing — LBBAP): physiological pacing, avoids RV pacing-induced dyssynchrony.

🔶 Mobitz II vs. Wenckebach — Clinical Significance

Mobitz I (Wenckebach): AV nodal block — usually benign, reversible (vagal, inferior MI), rarely progresses to complete AVB unless symptomatic. Mobitz II: infranodal block — unpredictable, can abruptly degenerate to complete AVB → syncope → sudden death. Key differentiator: Mobitz II has constant (unchanged) PR interval before the dropped beat. Mobitz II = permanent pacemaker regardless of symptoms.

▶3.11 Channelopathies (LQTS, BrS, CPVT)

Long QT Syndrome (LQTS): Prolonged cardiac repolarisation → EADs → TdP → SCD. Congenital (KCNQ1 — LQT1 most common; KCNH2 — LQT2; SCN5A — LQT3) or acquired.

Type	Gene	Trigger	Special Feature
LQT1	KCNQ1 (IKs ↓)	Exercise (swimming/exertion)	Wide-based T wave; most common; beta-blockers highly effective
LQT2	KCNH2 (IKr ↓)	Auditory stimuli, startle, emotion, post-partum	Notched T wave; avoid QT-prolonging drugs strictly; K+ >4 mEq/L
LQT3	SCN5A (INa ↑)	Sleep/bradycardia	Late-onset peaked T wave; late timing SCD; BB less effective; mexiletine (Na+ channel blocker) can shorten QTc

QTc (Bazett): QTc >460 ms in women, >450 ms in men → prolonged. >500 ms → very high TdP risk.

Brugada Syndrome (BrS): SCN5A mutation (Na-channel loss of function) → coved-type STE ≥2 mm in V1–V2 (spontaneous = Type 1 = diagnostic; fever often unmasks). SCD risk highest in men, symptomatic patients. Avoid: flecainide, procainamide, propafenone, tricyclics, cocaine, fever (all unmask BrS). Treatment: ICD for survivors of SCA or symptomatic VF/VT; quinidine (Ito-blocker) for recurrent shocks; catheter ablation of RVOT epicardial substrate.

CPVT (Catecholaminergic Polymorphic VT): RYR2 (ryanodine receptor) mutation → abnormal Ca2+ release → DADs → bidirectional VT with exercise. No structural heart disease. Normal QT. ECG: bidirectional VT (alternating QRS axis +60°/−120°). Treatment: nadolol (preferred BB); flecainide (blocks RYR2); ICD + BB; left cardiac sympathetic denervation (LCSD) for refractory cases.

🔶 Acquired LQTS — The QT Checklist

Common QT-prolonging drugs: antiarrhythmics (sotalol, amiodarone, quinidine, procainamide), antibiotics (macrolides, fluoroquinolones), antipsychotics (haloperidol, quetiapine), antiemetics (metoclopramide, ondansetron), antifungals (fluconazole). Check crediblemeds.org for risk classification. Precipitants: hypokalaemia (most common), hypomagnesaemia, bradycardia, female sex, baseline QT prolongation. Rule: maintain K+ >4.0 and Mg2+ >0.8 in at-risk patients.

▶3.12 Practice Questions — Arrhythmias

Q1. A 45-year-old woman presents with palpitations. ECG shows a regular narrow complex tachycardia at 168 bpm. You notice a pseudo-R prime in V1 and pseudo-S in inferior leads. What is the diagnosis and first-line acute treatment?

AVNRT. IV adenosine 6 mg rapid push.

Pseudo-R' in V1 and pseudo-S in inferior leads = retrograde P waves buried just after the QRS (RP <70 ms) — classic AVNRT. Adenosine 6 mg IV rapid push + 20 mL flush; repeat 12 mg × 2 if needed. Longer-term management: EPS + slow pathway ablation (success 95%).

Q2. A patient with WPW develops AF with a ventricular rate of 240 bpm and a wide, irregularly irregular QRS. What is the treatment of choice?

Immediate DC cardioversion if unstable; IV procainamide if stable.

Pre-excited AF (AF conducting via accessory pathway) with very rapid ventricular rate is life-threatening — can degenerate to VF. AV nodal blockers (adenosine, digoxin, verapamil, diltiazem, beta-blockers) are CONTRAINDICATED — they block the AV node but NOT the accessory pathway, potentially accelerating ventricular conduction → VF. Procainamide blocks the accessory pathway and is the drug of choice for stable pre-excited AF.

Q3. A 70-year-old has a regular bradycardia at 38 bpm with complete AV dissociation, a junctional escape rhythm (narrow QRS at 38 bpm), and haemodynamic instability. What is next?

Temporary transcutaneous or transvenous pacing; arrange permanent pacemaker.

Complete AV block (3° AVB) with haemodynamic compromise requires immediate pacing. Atropine 0.5–1 mg IV may be tried but usually insufficient at AV nodal or infranodal level. Transcutaneous pacing is fastest; transvenous pacing for more stable bridging. Permanent PPM is mandatory for symptomatic complete AVB regardless of reversible cause (unless clearly reversible, e.g. post-inferior MI complete AVB often resolves — observe 7–14 days before committing to PPM).

4Valvular & Congenital Heart Disease

▶4.1 Valvular Disease — General Approach

Valvular heart disease (VHD) affects ~2.5% of the general population in developed countries and is a major cause of cardiovascular morbidity. The 2021 ESC and 2020/2021 AHA/ACC guidelines form the basis of current management. Key principles: (1) Accurate assessment of severity using integrative echocardiography; (2) Timing of intervention is critical — too early risks unnecessary surgery, too late risks irreversible LV/RV dysfunction; (3) Heart valve centres / heart team decision-making for complex cases.

Severity grading (echo integration):

⚡ Valve Assessment — Integrative Echo Approach

Jet characteristics (colour Doppler) — screening only; not used to grade alone
Quantitative Doppler: EROA (effective regurgitant orifice area), RVol (regurgitant volume), RF (regurgitant fraction)
Mean gradient (stenosis): pressure half-time, continuity equation (AS)
Supportive: chamber dimensions, EF, PA pressure, wall motion
Echo pitfalls: 'discordant' AS (low-flow, low-gradient) — dobutamine stress echo or CT-Ca scoring

Indications for surgery/intervention (general): (1) Symptomatic severe VHD; (2) Asymptomatic severe VHD with LV/RV dysfunction (EF <50%, LV dilation beyond thresholds); (3) Asymptomatic severe VHD undergoing cardiac surgery for another reason; (4) High-risk features (severe PAH, AF, rapid progression).

🔶 Heart Valve Centres

The 2021 ESC Guidelines introduced 'Heart Valve Centres' — multidisciplinary teams (interventional cardiologist, cardiac surgeon, imaging specialist, anaesthesiologist) reviewing all complex cases. Class I recommendation: all TAVI decisions, primary MR repair candidates, and complex multivalvular disease should be discussed in a dedicated heart team.

▶4.2 Aortic Stenosis & TAVR vs SAVR

Aortic stenosis (AS) is the most common valvular disease requiring intervention in the developed world. Predominant cause: calcific/degenerative (age >65 years); congenital bicuspid (younger patients, often associated with aortopathy); rheumatic (still common in Southeast Asia — usually combined with MR and MS).

Echocardiographic Severity Classification:

Parameter	Mild	Moderate	Severe
Mean gradient	<20 mmHg	20–39 mmHg	≥40 mmHg
AVA (valve area)	>1.5 cm²	1.0–1.5 cm²	<1.0 cm²
Vmax	<3 m/s	3–4 m/s	>4 m/s
AVA index	>0.85 cm²/m²	0.6–0.85	<0.6 cm²/m²

Low-flow, Low-gradient AS: Mean gradient <40 mmHg + AVA <1 cm² — two types: (1) Classical low-flow (LVEF <50%) — dobutamine stress echo to distinguish true-severe from pseudo-severe; (2) Paradoxical low-flow (LVEF ≥50%, small LV, high afterload) — CT-AVC scoring (CT aortic valve calcium ≥3000 AU men / 1600 AU women = severe).

TAVI vs. SAVR — Risk Stratification:

Risk Category	STS Score	Preferred Approach	Key Trials
High risk	>8%	TAVI	PARTNER 1: TAVI non-inferior to SAVR; superior to medical therapy
Intermediate risk	4–8%	TAVI (equivalent)	PARTNER 2A, SURTAVI: TAVI non-inferior
Low risk	<4%	TAVI now acceptable	PARTNER 3, Evolut Low Risk: TAVI non-inferior or superior at 2 years; 5-year data pending
Bicuspid AS	Any	SAVR preferred (<75 years); TAVI in experienced centres	TAVI technically more challenging; higher paravalvular leak risk

Indications for intervention (2021 ESC Class I): (1) Symptomatic severe AS (angina, syncope, dyspnoea — any symptom; median survival <2–3 years without intervention); (2) Asymptomatic severe AS + LVEF <50%; (3) Asymptomatic severe AS + LVEF 50–55% + rapid progression + low procedural risk; (4) Undergoing cardiac surgery.

🔶 AVA Paradox — Small Body Size

A small patient (BSA 1.4 m²) with AVA 1.1 cm² may have severe haemodynamic AS — AVAi (indexed) = 1.1/1.4 = 0.79 cm²/m² (severe). Conversely, a large patient (BSA 2.2 m²) with AVA 0.95 cm² — AVAi = 0.43 — truly severe. Always index AVA to BSA, especially in Asian patients who often have smaller body habitus.

Key References — Aortic Stenosis

PARTNER 3 — Mack MJ et al., NEJM 2019
Evolut Low Risk — Popma JJ et al., NEJM 2019
2021 ESC VHD Guidelines
2020 ACC/AHA VHD Guidelines

▶4.3 Aortic Regurgitation

AR: LV volume overload → eccentric hypertrophy → progressive LV dilation. Acute AR (aortic dissection, endocarditis, trauma) — haemodynamic emergency. Chronic AR — long compensated phase then LV dysfunction.

Causes: Valve: bicuspid AoV, rheumatic, IE, myxomatous; Aortic root: Marfan syndrome, aortitis (syphilis, giant cell, Takayasu), aortic aneurysm, hypertension (most common cause of isolated AR in developed world).

Echo severity (severe AR): Vena contracta >6 mm, EROA ≥0.30 cm², RVol ≥60 mL/beat, RF ≥50%, PHT <200 ms, holodiastolic reversal in descending aorta.

Chronic AR — Indications for surgery (2021 ESC Class I):

⚡ AR Surgery Indications

Symptomatic severe AR (any symptoms — NYHA II–IV, angina)
Asymptomatic severe AR + LVEF ≤50%
Asymptomatic severe AR + LVEF 50–55% + LVESD >50 mm (or >25 mm/m² BSA)
Asymptomatic severe AR + progressive LV dilation (LVEDD >65 mm) + low surgical risk
Undergoing cardiac surgery for other valve or coronary

Acute AR: Emergency aortic valve replacement. Medical stabilisation: sodium nitroprusside (reduce afterload) + inotropes (dobutamine) + tachycardia (avoid bradycardia — shorter diastolic time reduces regurgitant fraction). Contraindication: IABP and beta-blockers in acute AR (both prolong diastole → ↑regurgitant volume → haemodynamic collapse).

🔶 IABP Contraindication in AR

IABP inflates in diastole — this augments diastolic pressure and is beneficial in angina/cardiogenic shock. But in AR: diastolic pressure augmentation ↑the driving pressure for regurgitation across the incompetent valve → worsens AR volume overload. IABP is absolutely contraindicated in significant AR.

▶4.4 Mitral Stenosis

MS: impaired LV filling → ↑LA pressure → pulmonary oedema, AF, embolic events. Causes: rheumatic (95% worldwide) — commissural fusion, leaflet thickening, chordal shortening; congenital (cor triatriatum, parachute MV); other: calcific MS (elderly), carcinoid, systemic lupus, drugs.

Echo severity: MVA (planimetry or PHT): <1.0 cm² = very severe, 1.0–1.5 cm² = severe, 1.5–2.0 cm² = moderate. Mean gradient: severe if >10 mmHg (at resting HR; exercise-provoked gradient important).

Wilkins Score (suitability for PTMC): Scores valve mobility, leaflet thickening, subvalvular involvement, calcification — each 0–4 points. Total ≤8: favourable for PTMC. >8 or significant MR or LA thrombus → surgery preferred.

Management:

Intervention	Indication	Class
PTMC (percutaneous trans-mitral commissurotomy)	Severe MS (MVA <1.5 cm²) + symptoms + favourable anatomy (Wilkins ≤8) + no LA thrombus + no significant MR	I
PTMC	Asymptomatic severe MS + new-onset AF or PAH (sPAP >50 mmHg)	IIa
MVR or commissurotomy	Severe MS + unfavourable anatomy + symptoms	I

Medical: Rate control (BB, CCB, digoxin) for AF; anticoagulation for any MS + AF (warfarin preferred — DOACs underrepresented in clinical trials for rheumatic MS; warfarin Class I 2021 ESC for rheumatic MS); diuretics for congestion.

🔶 Rheumatic MS & DOACs — The INVICTUS Trial 2022

INVICTUS: rivaroxaban vs. warfarin in rheumatic AF (mostly MS). Rivaroxaban: higher stroke/SE rate (HR 1.25) + higher all-cause mortality (HR 1.50) vs. warfarin. This confirms: warfarin remains the only anticoagulant recommended for rheumatic MS + AF. DOACs are NOT approved for this indication. This is the single most board-tested anticoagulation pearl in mitral stenosis.

Key References — Mitral Stenosis

INVICTUS — Connolly SJ et al., NEJM 2022
2021 ESC VHD Guidelines

▶4.5 Mitral Regurgitation

MR: most common valvular disease. Two mechanistic categories with very different management.

Primary (organic) MR: Leaflet/chordal pathology — myxomatous (MVP, Barlow's), rheumatic, IE, flail leaflet, cleft MV. Aim: repair before LV dysfunction.

Secondary (functional) MR: LV dilation/dysfunction → tethering of normal leaflets. Substrate is the LV, not the valve. Optimise GDMT first.

Parameter	Severe Primary MR Threshold
EROA	≥0.40 cm²
RVol	≥60 mL
RF	≥50%
Vena contracta	≥7 mm

Surgery indications — Primary MR (2021 ESC Class I):

⚡ Primary MR Surgery Indications

Symptomatic severe primary MR + LVEF >30%
Asymptomatic severe primary MR + LVEF ≤60% or LVESD ≥45 mm
Repair preferred over replacement — Class I if durable repair likely (>95% repair rate in experienced centres)
Watchful waiting only if: asymptomatic, LVEF >60%, LVESD <45 mm — but monitor closely (6-monthly echo)

MitraClip (TEER — transcatheter edge-to-edge repair):

Indication	Trial	Result
Secondary MR + HFrEF on optimal GDMT (EROA ≥0.20 cm², RVol ≥30 mL)	COAPT	47% ↓HF hospitalisation; 38% ↓all-cause mortality at 2 years (HR 0.62)
Secondary MR + HFrEF	MITRA-FR	No benefit — patient selection: COAPT selected "disproportionate" MR vs. MITRA-FR's "proportionate" MR. EROA/LVEDV ratio is key.
Primary MR — prohibitive surgical risk	EVEREST II	Less effective than surgery but acceptable in high-risk patients

🔶 COAPT vs. MITRA-FR — Why Opposite Results

COAPT: selected patients with 'disproportionate' secondary MR (MR severe relative to LV size — EROA ≥0.20 cm², LVEDV ≤96 mL/m²) — these patients have MR as a primary driver of HF. MITRA-FR: enrolled 'proportionate' MR (LV dilated, MR as consequence). Lesson: MitraClip works in secondary MR when MR is driving the HF, not merely accompanying a severely dilated LV. Patient selection by EROA/LVEDV ratio (Grayburn criteria) is essential.

Key References — Mitral Regurgitation

COAPT — Stone GW et al., NEJM 2018
MITRA-FR — Obadia JF et al., NEJM 2018
2021 ESC VHD Guidelines

▶4.6 Tricuspid & Pulmonic Valves

Tricuspid Regurgitation (TR): Most TR (≥80%) is secondary/functional — RV dilation → annular dilation → tethered leaflets. Causes: left-sided HF (most common), pulmonary hypertension, AF-related annular dilation, pacemaker lead-related, rheumatic, carcinoid, IE (IV drug users).

Severity (severe TR): Vena contracta ≥7 mm, EROA ≥40 mm², hepatic vein systolic reversal, PISA radius >9 mm.

Management: Diuretics for congestion. Surgery (tricuspid annuloplasty): Class I if severe TR undergoing left-sided surgery; Class IIa for symptomatic severe isolated TR. Transcatheter: TRILUMINATE PIVOTAL (TriClip): 87% TR reduction; improved KCCQ. TRISCEND II (EVOQUE): transcatheter TR replacement showed clinical benefit 2024.

Pulmonic Stenosis (PS): Usually congenital (isolated PS most common CHD). Balloon valvuloplasty: very effective; Class I for peak gradient >40 mmHg or symptomatic PS. Pulmonic regurgitation: common post-TOF repair — RV volume overload → progressive RV dilation → ventricular arrhythmias. Pulmonary valve replacement (surgical or Melody/Sapien transcatheter) when RV dilation exceeds thresholds.

🔶 Carcinoid Heart Disease

Carcinoid tumours produce serotonin (5-HT) and other vasoactive substances → plaque-like fibrous thickening of right-sided valves (right heart = first cardiac contact from mesenteric venous drainage). Pattern: tricuspid valve — retraction, regurgitation; pulmonic valve — stenosis and regurgitation (both). Left-sided involvement <10% (via PFO or bronchial carcinoids that bypass liver). Elevated 24-h urine 5-HIAA confirms diagnosis.

▶4.7 Infective Endocarditis

IE: infection of endocardium (typically valves). Incidence 3–10/100,000/year; in-hospital mortality 15–20%; 1-year mortality 40%. Vegetation = platelet-fibrin thrombus colonised by bacteria.

Duke Criteria (Modified):

Major	Minor
Positive blood cultures (2 sets ≥12h apart): typical organisms (S. aureus, viridans streptococci, S. gallolyticus, HACEK group, Enterococcus without primary focus) OR persistently positive cultures	Predisposing condition (IV drug use, structural heart disease)
Imaging positive: echo (oscillating mass, abscess, dehiscence) OR 18F-FDG PET/CT (2021 ESC) — new major criterion for prosthetic valve IE	Fever >38°C; Vascular phenomena (septic emboli, Janeway lesions, mycotic aneurysm, conjunctival haemorrhage)
	Immunological phenomena (Osler nodes, Roth spots, RF, GN); Microbiological minor criteria

Empirical Antibiotics (before culture results, 2023 ESC):

Setting	Regimen
Native valve, community-acquired	Ampicillin 12 g/day IV + cloxacillin 12 g/day + gentamicin 3 mg/kg/day (short course ≤5 days)
Prosthetic valve or nosocomial	Vancomycin + gentamicin + rifampin 900–1200 mg/day
MRSA-confirmed	Vancomycin (AUC/MIC-guided); daptomycin alternative
Streptococcal NVE	Penicillin G 12–18 MU/day + gentamicin × 2 weeks (or penicillin alone × 4 weeks)

Surgery indications (urgent within 24–72h): (1) Refractory HF from severe valve regurgitation; (2) Uncontrolled infection (abscess, fistula, progressive vegetation despite 7–10 days antibiotics, fungal); (3) Vegetation >10 mm + embolism despite antibiotics or >15 mm on anterior MV leaflet (high embolism risk).

🔶 IE — Endocarditis Team Approach

2021 ESC introduced the 'Endocarditis Team' concept: cardiologist, cardiac surgeon, infectious disease specialist, and imaging expert review all IE cases. Studies show endocarditis teams ↓in-hospital mortality by ~40%. Key decisions: timing of surgery (early vs. delay in stroke), antibiotic choice, dental prophylaxis planning, and follow-up echo at 1, 3, 6 months post-discharge.

Key References — Infective Endocarditis

2023 ESC Endocarditis Guidelines — Delgado V et al.
POET — Iversen K et al., NEJM 2019 — oral step-down therapy

▶4.8 Prosthetic Valves

Mechanical vs. Bioprosthetic — Decision Framework:

Mechanical (St. Jude, On-X)	Bioprosthetic (pericardial, porcine)
Lifelong VKA required	No VKA needed after initial 3 months (most centres)
Durability: >20–25 years	Durability: 10–15 years (earlier failure if young, CKD, hyperparathyroidism)
Preferred if: age <50 (mitral), <55 (aortic), already on VKA, patient preference	Preferred if: age >65–70, contraindication to anticoagulation, pregnancy planned, patient preference (needle-phobia, active lifestyle)

Anticoagulation targets:

Valve	Position	Thromboembolism Risk	INR Target
Mechanical AVR (low thrombogenicity — On-X, St. Jude Standard)	Aortic	Low risk + no AF	INR 2.5
Mechanical AVR (high thrombogenicity or AF/prior TE/LV dysfunction)	Aortic	High risk	INR 3.0
Mechanical MVR (all)	Mitral	High (low flow)	INR 3.0
Bioprosthetic (first 3 months)	Any	Healing phase	INR 2.5 or aspirin 75–100 mg (debate ongoing)

Prosthetic valve thrombosis: Diagnosis by echo (elevated gradients) + fluoroscopy (restricted leaflet motion). Fibrinolysis: Class IIa for right-sided prosthetic thrombosis or critically ill patients. Surgery: Class I for left-sided prosthetic thrombosis + haemodynamic instability.

🔶 On-X Valve — Lower INR (PROACT Trial)

On-X mechanical valve (Carbon Medical Technologies): double-tilting disc with superior hydraulics. PROACT trial: AVR with On-X + aspirin 75 mg — INR target 1.5–2.0 (lower than standard). Non-inferior to standard INR 2.0–3.0 with 79% reduction in major bleeding. FDA approved 2021 for lower INR 1.5–2.0 in low-risk On-X AVR patients. This is clinically significant: discuss with patients choosing mechanical AVR.

▶4.9 Adult Congenital Heart Disease

Major ACHD categories and key clinical points:

Lesion	Key Features	Complications	Management
ASD (Secundum)	Fixed split S2; RV volume overload; often asymptomatic until 3rd–4th decade	AF, paradoxical embolism, RV failure, PAH (late)	Percutaneous closure if shunt Qp:Qs >1.5 AND no severe PAH (PVR >5 WU contraindicated)
VSD	Holosystolic murmur LLSB; LV volume overload	Eisenmenger (PAH→shunt reversal), AI from cusp prolapse	Closure if Qp:Qs >2 and operability confirmed
PDA	Continuous machinery murmur; pulse pressure ↑	PAH, IE, LV overload	Closure (transcatheter coil/device) unless severe PAH
Coarctation of Aorta	HTN upper limbs; radio-femoral delay; rib notching (3–8th rib); bicuspid AoV 50%	HTN, aortic aneurysm, stroke, premature CAD	Intervention if gradient >20 mmHg (stenting preferred in adults)
TOF (repaired)	Palliated in childhood; now: pulmonary regurgitation dominant issue → RV dilation	VT, SCD, TR, RV failure	PVR when RVEDVI >160 mL/m² or RVEF <45% (Melody/Sapien percutaneous)
Ebstein anomaly	Apical displacement of TV; 'atrialized' RV; ASD present in 50%	RV failure, SVT (accessory pathways), paradoxical embolism	TV repair/replacement + ASD closure when symptomatic; ablation of AP

🔶 Eisenmenger Syndrome

Eisenmenger: long-standing L→R shunt → progressive pulmonary arterial hypertension → shunt reversal (R→L) → cyanosis. Once Eisenmenger established, cardiac repair is CONTRAINDICATED (removing the shunt with fixed PVR → acute RV failure). Management: PAH-targeted therapy (bosentan — BREATHE-5 trial improved 6MWT; sildenafil; treprostinil). Avoid: iron deficiency correction is important (iron deficiency worsens hyperviscosity-related stroke risk). Pregnancy is contraindicated (maternal mortality 30–50%).

▶4.10 Pregnancy & Heart Disease

Cardiovascular disease complicates 1–4% of pregnancies and is the leading cause of maternal mortality in developed countries. Physiological changes: ↑plasma volume (+50%), ↑CO (+40%), ↓SVR, ↑HR, hypercoagulable state, aortocaval compression in late pregnancy.

Modified WHO Risk Classification (mWHO):

mWHO Class	Maternal Mortality Risk	Examples
I	Low (<1%)	Small ASD/VSD/PDA (closed), mild PS, repaired simple defects
II	Low-moderate (1–5%)	Unrepaired ASD/VSD, TOF repaired, mild cardiomyopathy, mild MS
II–III	Moderate (5–15%)	Moderate LV impairment, Marfan (aorta <40 mm), mild systemic RV
III	High (10–25%)	Mechanical valve, Fontan, severe LV dysfunction, severe MS
IV	Very high — pregnancy contraindicated	PAH, Eisenmenger, Marfan aorta ≥45 mm, systemic RV with EF <40%, severe symptomatic AS

Drug safety in pregnancy:

⚡ Cardiac Drugs in Pregnancy — Safety

SAFE: metoprolol/labetalol (preferred BB), digoxin, heparin/LMWH (don't cross placenta), nitrates (short-term), hydralazine, methyldopa
AVOID: warfarin (6–12w — embryopathy; any time — fetal ICH); ACEi/ARB/ARNI (teratogenic, fetal renal failure — absolutely contraindicated all trimesters)
AVOID: statins (teratogenic — stop before conception); amiodarone (neonatal hypothyroidism, prematurity)
DOAC: insufficient safety data — avoid in pregnancy; LMWH preferred for anticoagulation
Adenosine: safe for acute SVT termination

🔶 Mechanical Valve in Pregnancy — The Anticoagulation Dilemma

Warfarin: superior for mechanical valve protection but causes embryopathy (6–12 weeks) and risk of fetal ICH. LMWH: safe for fetus but higher maternal valve thrombosis risk — anti-Xa monitoring essential (target peak anti-Xa 1.0–1.2 IU/mL). Current strategy: LMWH 6–12 weeks and near term (36w → switch to UFH), warfarin 13–35 weeks. Low warfarin dose ≤5 mg/day: fetal risk minimal, acceptable to continue throughout. Discuss all options before conception — heart team decision.

▶4.11 Practice Questions — Valvular & ACHD

Q1. A 75-year-old man with severe AS (AVA 0.8 cm², mean gradient 42 mmHg) is asymptomatic. Repeat echo at 6 months shows LVEF declined from 58% to 48%. What is the next step?

Urgent referral for TAVI/SAVR — LVEF <50% in asymptomatic severe AS is a Class I indication for intervention.

2021 ESC Class I: asymptomatic severe AS + LVEF <50% → intervene. At 75 years, TAVI is the preferred approach (low to intermediate surgical risk at this age, and PARTNER 2A/3 data support TAVI equivalence). Do not wait for symptoms once EF begins to decline.

Q2. A 55-year-old woman with AF and rheumatic mitral stenosis (MVA 1.1 cm²) is started on rivaroxaban by her GP. What is the correct management?

Switch to warfarin. INVICTUS trial (2022) showed rivaroxaban inferior to warfarin in rheumatic AF — higher stroke rate and higher mortality.

Rheumatic MS + AF = warfarin (INR 2–3) is Class I. DOACs are contraindicated. INVICTUS 2022 confirmed this: rivaroxaban had 25% higher stroke/SE rate and 50% higher mortality vs warfarin in this population. This is the most important anticoagulation trial for rheumatic heart disease.

Q3. A 32-year-old woman with a mechanical mitral valve wants to become pregnant. She is currently on warfarin. How do you counsel her?

mWHO Class III — high-risk pregnancy. Anticoagulation: LMWH with anti-Xa monitoring at 6–12 weeks (embryopathy risk), warfarin 13–35 weeks, switch to UFH/LMWH at 36 weeks for delivery. If warfarin dose ≤5 mg/day, may continue throughout with lower fetal risk.

Mechanical mitral valves carry the highest thrombosis risk in pregnancy — do not use DOACs (no safety data). Warfarin crosses the placenta causing embryopathy (6–12 weeks) and fetal intracranial haemorrhage at delivery. The warfarin-LMWH-UFH strategy optimises maternal safety while minimising fetal risk. Multidisciplinary management essential.

5Pericardial & Aortic Disease

▶5.1 Acute & Recurrent Pericarditis

Pericarditis: inflammation of pericardium. Incidence 27.7/100,000/year. Causes: idiopathic/viral (90% developed world); bacterial (TB — important in Southeast Asia and immunocompromised); autoimmune (SLE, RA, sarcoidosis); post-cardiac injury syndrome (post-MI Dressler, post-pericardiotomy); neoplastic; uraemic.

Diagnostic criteria (2015 ESC — 2 of 4 required):

⚡ Pericarditis Diagnostic Criteria

1. Pericarditic chest pain — sharp, pleuritic, worse supine, better leaning forward
2. Pericardial friction rub — 3-component (atrial systole, ventricular systole, early diastole); pathognomonic
3. New widespread ST-elevation or PR depression on ECG
4. Pericardial effusion (new or worsening on echo)
Supportive: elevated CRP/ESR/WBC; CMR evidence of pericardial inflammation

Treatment:

Drug	Dose	Duration	Notes
Aspirin	750–1000 mg q8h	1–2 weeks, then taper	Preferred post-MI pericarditis (avoid NSAIDs that impair healing)
Ibuprofen	600 mg q8h	1–2 weeks, then taper	Good gastric tolerability; preferred first-line in idiopathic pericarditis
Colchicine	0.5 mg BD (<70 kg: 0.5 mg OD)	3 months (first episode)	COPE, ICAP: colchicine ↓recurrence 50%; always add to NSAID — Class I 2015 ESC
Prednisone	0.2–0.5 mg/kg/day, taper over weeks–months	Minimum effective dose	Only if NSAID/colchicine failure or specific indication (connective tissue disease, uraemia, TB after anti-TB started); avoid in idiopathic — promotes recurrence

Recurrent pericarditis: After ≥4–6 weeks symptom-free. Colchicine 6 months + NSAID taper. For refractory/colchicine-intolerant: anakinra (IL-1 receptor antagonist) — AIRTRIP trial: 72% recurrence reduction; approved 2021. Pericardiectomy for truly refractory chronic constrictive/recurrent disease.

🔶 Colchicine — The Anti-Recurrence Drug

COPE trial: colchicine + aspirin vs. aspirin alone — 50% ↓recurrence at 18 months. ICAP trial: colchicine 0.5 mg BD × 3 months → 56% ↓recurrence. CORP/CORP-2: colchicine 6 months → ↓recurrent pericarditis relapses. Mechanism: inhibits IL-1β via NLRP3 inflammasome suppression, same pathway as anakinra. Never prescribe pericarditis without colchicine — it is the most impactful co-therapy.

Key References — Pericarditis

ICAP — Imazio M et al., NEJM 2013
AIRTRIP — Imazio M et al., NEJM 2016
2015 ESC Pericardial Diseases Guidelines

▶5.2 Pericardial Effusion & Cardiac Tamponade

Pericardial effusion causes tamponade when intrapericardial pressure exceeds cardiac filling pressure — rate of accumulation matters more than absolute size (acute 150 mL can tamponade; chronic 2 L may not).

Beck's Triad (classic cardiac tamponade): Hypotension + JVD (↑JVP) + Muffled heart sounds. Also: pulsus paradoxus >10 mmHg (inspiratory ↓SBP — pathological in tamponade), sinus tachycardia, electrical alternans (QRS axis alternates — pathognomonic but insensitive), low voltage QRS.

Pulsus paradoxus mechanism: Inspiration → ↑venous return → RV expands → IVS shifts left → ↓LV filling → ↓SBP. Exaggerated in tamponade because pericardial fluid limits total cardiac volume expansion.

Echo signs of tamponade:

⚡ Echo Signs — Pericardial Tamponade

RA diastolic collapse (earliest sign — right-sided because lowest pressure)
RV diastolic collapse (more specific than RA — seen in early diastole)
IVC plethora: IVC >2.1 cm + <50% inspiratory collapse (>99% sensitivity)
Exaggerated respiratory variation: mitral inflow E-wave >25%, tricuspid inflow >40%
Swinging heart (electrical alternans correlate)

Management: Pericardiocentesis — urgent if haemodynamic compromise. Preferred approach: echo-guided subxiphoid (apical or parasternal alternative). Fluoroscopy-guided in cath lab if complex anatomy. Surgical drainage: if anterior approach needed, recurrent effusion, purulent/loculated, or biopsy required.

🔶 Low-Pressure Tamponade

Tamponade can occur with haemodynamically significant effusion in a hypovolaemic patient with normal (low) filling pressures — JVD may NOT be present, Beck's triad incomplete. Clue: hypotension + echo effusion + IVC plethora. IV fluid challenge (250 mL NS) temporises by ↑RA/RV pressure, restoring cardiac filling until pericardiocentesis. Avoid diuretics — worsens haemodynamics.

▶5.3 Constrictive Pericarditis

Constrictive pericarditis (CP): thickened, fibrotic, non-compliant pericardium → impaired diastolic filling → equalisation of diastolic pressures. Causes: TB (most common worldwide, especially Asia/Africa), prior pericarditis, radiation, post-cardiac surgery, connective tissue disease, idiopathic.

Haemodynamic hallmarks (right heart catheterisation):

⚡ Constrictive Pericarditis — Haemodynamic Features

Elevated and equalised filling pressures: RVEDP = LVEDP (usually within 5 mmHg)
Square root sign (dip-and-plateau) in RV/LV pressure waveform
Kussmaul sign: paradoxical rise in JVP with inspiration (fixed constrictive shell prevents RV expansion)
Discordance: RV and LV systolic pressures move in OPPOSITE directions with respiration (hallmark of CP vs. restriction)
PCWP: early prominent y-descent (rapid early filling then abrupt halt = 'M' or 'W' wave pattern)

CP vs. Restrictive CM — Key Differentiators:

Feature	Constrictive Pericarditis	Restrictive Cardiomyopathy
Septal bounce	Yes (ventricular interdependence)	No
E/e' ratio (echo)	<15 (pericardium limits; tissue Doppler relatively preserved)	>15
Respiratory variation (mitral E)	>25% (interdependence)	<10%
RHC — diastolic equalisation	Yes	Usually LVEDP > RVEDP by >5 mmHg
Pericardial thickness (CT/CMR)	≥4 mm (specific but not always present)	Normal
BNP	Relatively low (preserved natriuretic peptide)	Very elevated

Treatment: Definitive — pericardiectomy (mortality 6–12%, high-volume centres lower). Transient/reversible CP (especially post-inflammatory): trial of anti-inflammatory therapy (colchicine + NSAIDs) × 2–3 months before committing to surgery.

🔶 Kussmaul Sign vs. Pulsus Paradoxus

Kussmaul: JVP rises (or fails to fall) with inspiration — seen in CP, RV failure, severe TS. Pulsus paradoxus: SBP falls >10 mmHg with inspiration — seen in cardiac tamponade, severe COPD, massive PE. In tamponade: pulsus paradoxus is present, Kussmaul is NOT (pericardium distensible so RV can expand slightly). In CP: Kussmaul is present, pulsus paradoxus is NOT typical.

▶5.4 Aortic Aneurysm — TAA & AAA

Thoracic Aortic Aneurysm (TAA): Most commonly involves ascending aorta. Risk: Marfan, bicuspid aortic valve (associated aortopathy in 50–70%), Loeys-Dietz, familial thoracic aortic aneurysm. Hypertension → descending thoracic/abdominal.

TAA Intervention Thresholds (2022 AHA):

Aortic Segment	Standard Threshold	Lower Threshold (special conditions)
Ascending aorta	≥5.5 cm	≥5.0 cm: Marfan, Loeys-Dietz, BAV with family SCD; ≥4.5 cm: growth >0.5 cm/year, planned AVR, family history dissection
Arch	≥5.5–6.0 cm	Lower if combined with root intervention
Descending thoracic	≥6.0 cm (endovascular TEVAR preferred)	≥5.5 cm: growth, connective tissue disease

Abdominal Aortic Aneurysm (AAA):

AAA Diameter	Management
<3.0 cm	No follow-up needed
3.0–3.9 cm	USS every 3 years
4.0–4.9 cm	USS every 12 months
5.0–5.4 cm	USS every 6 months; surgical planning
≥5.5 cm men / ≥5.0 cm women	Repair: EVAR (endovascular) or open surgery; EVAR preferred if anatomy suitable

Medical management: Beta-blockers (atenolol or metoprolol — reduces aortic stiffness and wall stress; Class I in Marfan). Losartan (inhibits TGF-β signalling — theory in Marfan; COMPARE and MacGen trials: similar to atenolol). Statin + aspirin: cardiovascular risk reduction. Blood pressure target <130/80 mmHg.

🔶 Marfan vs. Loeys-Dietz — Aortic Thresholds

Marfan (FBN1 mutation): intervention at root ≥50 mm, or ≥45 mm with family dissection/rapid growth. Loeys-Dietz (TGFBR1/2 mutation): MORE aggressive — intervene at ≥45 mm (or ≤42 mm in some guidelines) due to dissection at smaller sizes. Loeys-Dietz syndrome is now divided into subtypes 1–5 based on gene involved. Key: LDS aortas dissect at smaller diameters than Marfan — don't apply Marfan thresholds to LDS patients.

▶5.5 Acute Aortic Syndromes

Acute aortic syndromes (AAS): spectrum of emergencies sharing common pathological process — disruption of aortic media. Includes: classic aortic dissection (AD), intramural haematoma (IMH), penetrating atherosclerotic ulcer (PAU).

Stanford Classification: Type A — involves ascending aorta (regardless of origin; 60% of dissections) → surgical emergency. Type B — descending aorta only (spares ascending) → medical management initially.

Classic Clinical Presentation of Type A AD: Sudden tearing/ripping chest or back pain (89%), pulse deficit (limb ischaemia), neurological deficit (carotid involvement), aortic regurgitation (acute), haemopericardium/tamponade. Chest XR: widened mediastinum (>8 cm) — insensitive. CT aortography (gold standard — sensitivity/specificity >95%).

DeBakey Classification: Type I (whole aorta), Type II (ascending only), Type III (descending — IIIa: above diaphragm; IIIb: below).

Management:

Type	Treatment	Notes
Type A (ascending)	Emergency surgical repair	Mortality 1–2%/hour without surgery; 25–30% in-hospital mortality even with surgery
Type B — uncomplicated	Medical management: esmolol or labetalol IV (HR <60, SBP 100–120 mmHg) + pain control; TEVAR controversial but may be considered	INSTEAD: TEVAR vs. medical — TEVAR improved 5-year aorta-specific survival
Type B — complicated (malperfusion, rupture, refractory pain)	TEVAR (thoracic endovascular aortic repair)	Class I indication for complicated Type B

🔶 Hypertension Control Targets in Aortic Dissection

Initial medical stabilisation: (1) HR target <60 bpm — reduces aortic wall stress (dP/dt reduction). Use esmolol (titratable IV beta-blocker) or labetalol (combined alpha+beta). (2) SBP 100–120 mmHg AFTER HR controlled (to avoid reflex tachycardia from vasodilators). Never start vasodilators before beta-blockers. (3) Avoid femoral arterial line in Type A — may be in false lumen; use radial artery.

Key References — Aortic Syndromes

INSTEAD — Nienaber CA et al., Circulation 2009
2022 AHA/ACC Aortic Disease Guidelines
2014 ESC Aortic Disease Guidelines

▶5.6 Pulmonary Embolism

PE: obstruction of pulmonary vasculature by thrombus, causing haemodynamic compromise and right ventricular pressure overload. DVT-PE = VTE spectrum. Annual incidence 60–70/100,000; 3-month mortality: massive PE up to 30–50%, submassive 3–15%.

Risk Stratification — 2019 ESC Classification:

Category	Definition	Mortality	Treatment
High risk (Massive PE)	Haemodynamic instability: SBP <90 mmHg ≥15 min, or vasopressors, or cardiac arrest, or shock index >1.0	30–50%	Systemic thrombolysis (alteplase 100 mg/2h) → surgical embolectomy/catheter-directed if contraindicated
Intermediate-high risk	PESI class III–IV or sPESI ≥1 + both RV dysfunction AND elevated troponin	3–15%	Anticoagulation; consider rescue thrombolysis for clinical deterioration; PERT team
Intermediate-low risk	PESI class III–IV or sPESI ≥1 + RV dysfunction OR elevated troponin (not both)	1–3%	Anticoagulation; monitor closely
Low risk	PESI class I–II or sPESI 0; no RV dysfunction; no elevated biomarkers	<1%	Anticoagulation; consider early discharge (HESTIA criteria)

Anticoagulation for acute PE: DOACs preferred. Rivaroxaban or apixaban: parenteral lead-in NOT required (dose reduction after initial period). Apixaban 10 mg BD × 7d → 5 mg BD; rivaroxaban 15 mg BD × 3w → 20 mg OD. LMWH-VKA or LMWH-edoxaban/dabigatran (parenteral lead-in required). Duration: 3 months (provoked/transient risk); 6 months minimum (cancer-associated); indefinite (unprovoked PE + acceptable bleeding risk).

🔶 Thrombolysis in PE — PEITHO Trial

PEITHO: tenecteplase vs. heparin in intermediate-risk PE (RV dysfunction + troponin+). Tenecteplase: ↓haemodynamic collapse (1.6% vs. 5%) but ↑major bleeding (11.5% vs. 2.4%) and ICH (2% vs. 0.2%). No mortality benefit. Lesson: systemic thrombolysis reserved for HIGH-RISK (massive) PE. In intermediate-high risk: rescue thrombolysis only for haemodynamic deterioration. Catheter-directed thrombolysis (lower dose, local delivery) may have better safety profile — ongoing trials.

Key References — Pulmonary Embolism

PEITHO — Meyer G et al., NEJM 2014
EINSTEIN PE — NEJM 2012 — rivaroxaban
AMPLIFY — Agnelli G et al., NEJM 2013 — apixaban
2019 ESC PE Guidelines

▶5.7 PAD & Marfan Syndrome

Peripheral Arterial Disease (PAD): ABI (ankle-brachial index) ≤0.90 = PAD. Severity: mild (0.7–0.9), moderate (0.5–0.69), severe/critical limb ischaemia (CLI) ≤0.5. ABI >1.3: arterial incompressibility (calcification — common in DM, CKD) — use toe-brachial index (TBI) or pulse volume recordings.

PAD Management:

⚡ PAD Treatment Principles

Risk factor control: smoking cessation (most important), BP <130/80, LDL <55 mg/dL (high-intensity statin + ezetimibe/PCSK9i if needed)
Antiplatelet: aspirin or clopidogrel 75 mg OD — Class I. CHARISMA: clopidogrel superior to aspirin for symptomatic PAD
COMPASS trial: rivaroxaban 2.5 mg BD + aspirin 100 mg OD → 28% ↓MACE + ↓MALE (major adverse limb events) vs. aspirin alone — Class I 2023 ESC for symptomatic PAD without high bleeding risk
Supervised exercise therapy: Class I for claudication — equivalent to angioplasty in improving walking distance
Revascularisation: endovascular (angioplasty ± stent) or surgical bypass for lifestyle-limiting claudication refractory to exercise + critical limb ischaemia

Marfan Syndrome: FBN1 mutation → fibrillin-1 deficiency → connective tissue disease. Clinical: aortic root dilation/dissection (leading cause of death), ectopia lentis (upward lens subluxation), dolichostelopelvia (arm span > height), pectus excavatum, dural ectasia, MVP. Diagnosis: Ghent nosology 2010 (aortic root Z-score ≥2 + ectopia lentis = Marfan without FBN1 testing required). Beta-blockers (atenolol) or losartan: reduce rate of aortic dilation. Annual aortic imaging.

🔶 COMPASS Dual Pathway Inhibition in PAD

COMPASS: rivaroxaban 2.5 mg BD + aspirin 100 mg vs. aspirin alone in stable atherosclerotic disease. In PAD subgroup: 46% ↓MALE (major adverse limb events including amputation), 28% ↓MACE. This combination is now Class I in symptomatic PAD (2023 ESC). Key: rivaroxaban 2.5 mg BD is a very low dose — acts primarily on atherothrombosis prevention, not systemic anticoagulation. Bleeding risk (primarily GI) is increased but net clinical benefit is positive.

▶5.8 Practice Questions — Pericardial & Aortic

Q1. A 28-year-old man presents with sharp pleuritic chest pain, worse supine. ECG shows diffuse ST elevation with PR depression in multiple leads. CRP is 85 mg/L. What is the most important treatment to ADD to ibuprofen?

Colchicine 0.5 mg BD × 3 months.

ICAP trial: colchicine added to aspirin/NSAIDs for 3 months → 56% reduction in recurrent pericarditis. 2015 ESC Class I recommendation. Without colchicine, 30% of idiopathic pericarditis recurs. Colchicine should ALWAYS accompany NSAIDs in acute pericarditis.

Q2. A 68-year-old hypertensive man presents with sudden severe tearing back pain radiating to the abdomen. BP left arm 180/100, right arm 150/90. HR 112 bpm. CXR: widened mediastinum. What is the immediate management priority?

IV esmolol or labetalol — achieve HR <60 bpm first, then reduce SBP to 100–120 mmHg. Urgent CT aortography.

Suspected Type A aortic dissection. HR control first (esmolol infusion) to reduce dP/dt — then add vasodilator if needed. Do NOT give vasodilators before beta-blockers (reflex tachycardia increases wall stress). CT aortography confirms diagnosis. If Type A confirmed → emergency cardiac surgery. Do not delay for echo — CT is faster and diagnostic.

Q3. A haemodynamically stable patient has a submassive PE (RV dilation on CTPA, troponin I elevated, sPESI = 2). What is the appropriate treatment?

Therapeutic anticoagulation (DOAC — apixaban or rivaroxaban). Close monitoring. Reserve systemic thrombolysis for haemodynamic deterioration only.

Intermediate-high risk PE: RV dysfunction + elevated troponin but haemodynamically stable. PEITHO showed thrombolysis reduces haemodynamic collapse but increases ICH (2%) with no mortality benefit in this group. Standard anticoagulation with close monitoring is the correct approach. Escalate to rescue thrombolysis only if clinical deterioration (BP drop, desaturation) occurs despite anticoagulation.

6Prevention & Special Topics

▶6.1 Hypertension — 2023 ESC Guidelines

Hypertension affects 30–45% of adults globally; a major modifiable risk factor for stroke, MI, HF, CKD, and PAD. New 2023 ESC guidelines introduced important classification changes.

2023 ESC Classification:

Category	SBP (mmHg)	DBP (mmHg)
Optimal	<120	<80
Normal	120–129	80–84
High-normal	130–139	85–89
Grade 1 HTN	140–159	90–99
Grade 2 HTN	160–179	100–109
Grade 3 HTN	≥180	≥110
Isolated systolic HTN	≥140	<90

Treatment targets (2023 ESC): Most patients: SBP 120–129 mmHg (primary target); elderly ≥65 years: SBP 130–139 mmHg (to avoid J-curve); CKD: SBP 120–129 mmHg if tolerated. Note: AHA/ACC 2017 target was <130/80 — 2023 ESC aligned more closely.

Drug treatment strategy (2023 ESC single-pill combination approach):

⚡ 2023 ESC Hypertension — Key Treatment Principles

Start with combination therapy (SPC — single pill combination) from the outset for most Grade 1–2 HTN
Step 1: RAS blocker (ACEi or ARB) + CCB or thiazide/thiazide-like diuretic
Step 2: Triple SPC — ACEi/ARB + CCB + thiazide-like diuretic
Step 3 (resistant HTN): Add spironolactone 25–50 mg (PATHWAY-2: most effective 4th agent), or doxazosin, or beta-blocker
Beta-blockers: use when specific indication (HF, AF, post-MI, angina) — not primary choice without indication
SGLT2i: Class IIa as adjunct antihypertensive — also cardiorenal protection

Resistant hypertension: BP >140/90 mmHg on 3 drugs (including diuretic) at optimal doses. Rule out: secondary causes (hyperaldosteronism, renal artery stenosis, OSA, phaeochromocytoma, Cushing). Renal denervation: SPYRAL HTN-ON MED, RADIANCE trials — significant SBP reduction; approved in Europe/Australia 2023.

🔶 PATHWAY-2 — Spironolactone as 4th-line Agent

PATHWAY-2: resistant HTN patients randomised to spironolactone 25–50 mg, doxazosin, bisoprolol, or placebo as 4th agent. Spironolactone was most effective — home SBP reduced 8.7 mmHg vs. placebo (superior to doxazosin by 4.3 mmHg and bisoprolol by 4.5 mmHg). Mechanism: 2/3 of resistant HTN is sodium-retaining / primary aldosteronism-related. Check K+ before starting; contraindicated if eGFR <45 or K+ >4.5.

Key References — Hypertension

2023 ESC Hypertension Guidelines — Mancia G et al.
PATHWAY-2 — Williams B et al., Lancet 2015
SPRINT — NEJM 2015 — intensive BP control

▶6.2 Dyslipidaemia & PCSK9 Inhibitors

LDL-C targets by CV risk (2019 ESC):

Risk Category	LDL-C Target	Percentage Reduction
Very high (ASCVD, DM with organ damage, eGFR <30, FH + ASCVD)	<55 mg/dL (<1.4 mmol/L)	≥50% reduction from baseline
High (DM without organ damage, eGFR 30–59, grade 3 HTN, 10-year SCORE ≥5%)	<70 mg/dL (<1.8 mmol/L)	≥50% reduction
Moderate (SCORE 1–5%)	<100 mg/dL	—
Low (SCORE <1%)	<116 mg/dL	—

Lipid-lowering therapy ladder:

Agent	LDL-C Reduction	Key Evidence
Atorvastatin 40–80 mg / Rosuvastatin 20–40 mg (high-intensity)	50–60%	JUPITER, PROVE-IT, 4S, WOSCOPS
+ Ezetimibe 10 mg OD	Additional 20–25%	IMPROVE-IT: 6.4% ↓major CV events at 7 years; HR 0.936
+ PCSK9 inhibitor: evolocumab 140 mg q2w / alirocumab 75–150 mg q2w	Additional 50–60% (total ↓LDL 75–85%)	FOURIER: evolocumab ↓CV death/MI/stroke 15%; ODYSSEY OUTCOMES: alirocumab ↓death 15%
Inclisiran 284 mg SC q6mo (after initial dose)	~50% LDL reduction (sustained)	ORION-10/11: non-inferior to PCSK9 mAbs; twice-yearly dosing improves adherence
Bempedoic acid 180 mg OD	18–25%	CLEAR Outcomes: ↓MACE 13% in statin-intolerant patients (HR 0.87); oral

🔶 FOURIER vs. ODYSSEY OUTCOMES — Mortality Signal

FOURIER (evolocumab): no significant all-cause mortality reduction (HR 0.85, p=0.055) — trial may have been too short (2.2 years). ODYSSEY OUTCOMES (alirocumab): significant all-cause mortality reduction (HR 0.85, p=0.026) — longer follow-up (2.8 years). Meta-analyses confirm PCSK9i reduce CV mortality. Key: lower achieved LDL is not associated with increased adverse events — no J-curve for LDL. PCSK9i achieve LDL levels of 20–30 mg/dL safely.

Key References — Dyslipidaemia

FOURIER — Sabatine MS et al., NEJM 2017
ODYSSEY OUTCOMES — Schwartz GG et al., NEJM 2018
CLEAR Outcomes — Nissen SE et al., NEJM 2023
IMPROVE-IT — Cannon CP et al., NEJM 2015
2019 ESC Dyslipidaemia Guidelines

▶6.3 Diabetes & Cardiovascular Risk

Diabetes doubles cardiovascular mortality risk. CV death accounts for 50–80% of T2DM mortality. Glucose control alone (HbA1c reduction) has modest CV benefit — intensive glucose lowering actually increased mortality in ACCORD trial. The CV benefit of newer glucose-lowering drugs (SGLT2i, GLP-1RA) is independent of glycaemic control.

SGLT2 Inhibitors — Cardiorenal Benefits:

Trial	Drug	Population	Key Result
EMPA-REG OUTCOME	Empagliflozin 10/25 mg	T2DM + established ASCVD	14% ↓3P-MACE; 38% ↓CV death; 35% ↓HF hospitalisation
CANVAS	Canagliflozin 100/300 mg	T2DM + high CV risk	14% ↓MACE; 33% ↓HF/renal progression; ↑amputation risk (caution PAD)
DECLARE-TIMI 58	Dapagliflozin 10 mg	T2DM + ASCVD or risk factors	No significant MACE reduction; 27% ↓HF/renal endpoint
CREDENCE	Canagliflozin	T2DM + CKD (eGFR 30–90)	30% ↓renal endpoints; 31% ↓CV death/HF hospitalisation

GLP-1 Receptor Agonists — CV Outcomes:

Trial	Drug	Result
LEADER	Liraglutide 1.8 mg SC OD	13% ↓MACE (HR 0.87); 15% ↓CV death
SUSTAIN-6	Semaglutide 0.5/1 mg SC weekly	26% ↓MACE (driven by stroke reduction)
SOUL	Oral semaglutide 14 mg OD	14% ↓MACE (first oral GLP-1RA with proven CV benefit — 2024)
SELECT	Semaglutide 2.4 mg SC (obesity dose, no DM requirement)	20% ↓MACE in obese/overweight without DM — 2023; major paradigm shift

🔶 SELECT Trial — GLP-1RA Without Diabetes

SELECT (N=17,604): semaglutide 2.4 mg weekly vs. placebo in obese/overweight patients (BMI ≥27) with established ASCVD but WITHOUT diabetes. 20% ↓3P-MACE (HR 0.80). This is the first demonstration that GLP-1RA provides CV benefit independent of glucose lowering. Implications: semaglutide should be considered for CV risk reduction in obese patients with ASCVD even without DM. 2024 FDA approved semaglutide for CV risk reduction in this population.

▶6.4 Pulmonary Arterial Hypertension

PAH (Group 1 PH): mean PAP ≥20 mmHg + PVR ≥3 WU + PCWP ≤15 mmHg (2022 updated definition — lowered mPAP threshold from 25 to 20 mmHg). Pathophysiology: vasoconstriction + endothelial dysfunction + smooth muscle proliferation/remodelling of pulmonary vasculature → progressive RV failure.

WHO PH Classification Groups: Group 1 (PAH — idiopathic, heritable BMPR2, drugs, CTD, HIV, portal HTN); Group 2 (left heart disease — most common cause of PH); Group 3 (lung disease/hypoxia — COPD, ILD); Group 4 (CTEPH — chronic thromboembolic — potentially curable with PEA); Group 5 (multifactorial).

PAH-specific therapy (targeting 3 pathways):

Pathway	Drug	Class	Key Trial
Endothelin receptor antagonist (ERA)	Macitentan 10 mg OD Ambrisentan 5–10 mg OD Bosentan 62.5→125 mg BD	I	SERAPHIN: macitentan ↓morbidity/mortality 45%
PDE5 inhibitor	Tadalafil 40 mg OD Sildenafil 20 mg TID	I	PHIRST: tadalafil ↑6MWT, ↓clinical worsening
Prostacyclin pathway	Selexipag (oral prostacyclin IP agonist) Epoprostenol IV (continuous infusion — gold standard severe PAH) Treprostinil SC/inhaled/IV	I	GRIPHON: selexipag 40% ↓morbidity/mortality; TRIUMPH: inhaled treprostinil; epoprostenol: survival benefit in severe PAH
sGC stimulator	Riociguat (soluble guanylate cyclase) — also for Group 4 CTEPH	I	PATENT-1: ↑6MWT, ↓PVR

Initial combination therapy (2022 ESC): ERA + PDE5i as upfront dual therapy (Class I) for most newly diagnosed PAH. AMBITION trial: ambrisentan + tadalafil → 50% ↓risk of clinical failure vs. monotherapy.

🔶 CTEPH — The Curable Form of PH

Chronic Thromboembolic PH (Group 4): organised thrombus in proximal pulmonary vessels → fixed mechanical obstruction + small vessel arteriopathy. Unlike PAH, CTEPH is potentially curable: pulmonary endarterectomy (PEA) — removes organised thrombus under cardiopulmonary bypass; excellent long-term outcomes if accessible disease. Riociguat (CHEST-1) + balloon pulmonary angioplasty (BPA) for inoperable CTEPH. V/Q scintigraphy: most sensitive screening test for CTEPH (mismatched perfusion defects).

▶6.5 Cardio-Oncology

Cancer treatment cardiovascular toxicity is the second leading cause of long-term morbidity and mortality in cancer survivors. Cardio-oncology aims to enable cancer treatment while monitoring and mitigating cardiac toxicity.

Major Cardiotoxic Cancer Therapies:

Agent	Cardiac Toxicity	Mechanism	Management
Anthracyclines (doxorubicin, epirubicin)	Cardiomyopathy — dose-dependent and irreversible (cumulative doxorubicin >400 mg/m²)	Reactive oxygen species → myocyte death	Liposomal formulation (lower cardiotoxicity); dexrazoxane (cardioprotection); baseline + serial echo; GDMT if LV dysfunction develops
Trastuzumab (HER2 inhibitor)	LV dysfunction/HF — reversible in most (Type II toxicity)	HER2/ErbB2 signalling important for cardiomyocyte survival	Hold if LVEF falls >10% to below 50%; restart after recovery; ACEi/BB prophylaxis in high-risk (MANTICORE trial)
Immune checkpoint inhibitors (ICI): anti-PD-1, anti-CTLA-4	Immune-mediated myocarditis (1–2% incidence; mortality 25–50% if severe)	T-cell autoreactivity against cardiac antigens	High-dose steroids (methylprednisolone 1 g/day); consider abatacept/ruxolitinib; troponin + echo monitoring; hold ICI
VEGF/TKI inhibitors (sunitinib, sorafenib, pazopanib)	Hypertension (up to 30%), cardiomyopathy, QT prolongation	VEGF inhibition → endothelial dysfunction; off-target kinase inhibition	Intensive BP monitoring; dose reduction for severe HTN; avoid concomitant QT-prolonging drugs
Fluorouracil (5-FU), capecitabine	Coronary vasospasm → ischaemia (1–8% of patients)	Endothelial dysfunction + vasospasm	Stop infusion during symptoms; sublingual nitrate; rechallenge with CCB prophylaxis (diltiazem/amlodipine) if essential; continuous infusion → higher risk than bolus

🔶 ICI Myocarditis — Rapidly Fatal

Immune checkpoint inhibitor myocarditis presents 1–3 months post-initiation (median 34 days). Clinical: acute dyspnoea, chest pain, arrhythmias, AV block. Troponin elevation in virtually all cases. Echo: often preserved EF (but can be fulminant). CMR (T2 mapping, LGE): confirms diagnosis. Key: mortality 25–50% if fulminant — much higher than other cardiomyopathies. Treat aggressively: hold ICI immediately, high-dose corticosteroids (methylprednisolone 1 g/day), involve heart team. Unlike anthracycline toxicity, recovery is possible with immunosuppression.

▶6.6 Perioperative Cardiovascular Management

Pre-operative cardiac evaluation for non-cardiac surgery: balance surgical risk (procedure type) + patient clinical risk (RCRI/Lee Index) + functional capacity.

Revised Cardiac Risk Index (RCRI/Lee Index) — 6 predictors, 1 point each:

⚡ RCRI Predictors

1. High-risk surgery (intraperitoneal, intrathoracic, suprainguinal vascular)
2. Ischaemic heart disease (history MI, Q waves, angina, nitrates, positive stress test)
3. Congestive heart failure
4. Cerebrovascular disease (prior stroke or TIA)
5. Insulin-dependent diabetes
6. Pre-operative creatinine >2.0 mg/dL

RCRI 0 = <1% MACE; 1–2 = 1–10%; ≥3 = >10%. Consider further testing or coronary evaluation if high risk + low functional capacity (<4 METs).

Key management principles (2022 ESC):

Issue	Recommendation
Beta-blockers	Continue if on chronic BB. Do NOT start de novo BB within 24h of surgery (POISE trial: ↑stroke, mortality despite ↓MI). If indicated, start ≥2 weeks pre-op, titrate to HR 60–70 bpm
Statins	Continue perioperatively — abrupt withdrawal ↑risk. Start pre-op if vascular surgery (Class IIa)
ACEi/ARB	Withhold morning of surgery (hypotension risk with anaesthesia); restart when haemodynamically stable post-op
Aspirin	Continue if coronary stent <3 months or recent ACS; otherwise withhold 5–7 days before surgery
Elective surgery timing post-MI	Delay ≥60 days; ideally 6 months post-MI for elective non-cardiac surgery
Timing after PCI	BMS: delay ≥4 weeks; DES: delay ≥6 months; emergency surgery: aspirin + heparin bridge, continue aspirin

🔶 POISE Trial — Why Not Start Beta-Blockers Acutely?

POISE: metoprolol succinate 100 mg started 2–4 hours before surgery (then continued × 30 days) vs. placebo in high-risk patients. Results: metoprolol ↓MI (4.2% vs. 5.7%) but ↑stroke (1% vs. 0.5%) and ↑all-cause mortality (3.1% vs. 2.3%). The stroke increase was related to perioperative hypotension + bradycardia → haemodynamic cerebral ischaemia. Lesson: never start beta-blockers de novo <24 hours before surgery.

▶6.7 Cardiovascular Disease in Women

CV disease remains underdiagnosed and undertreated in women. Biological differences influence presentation, risk factors, and outcomes.

Sex-specific risk factors (women):

⚡ Female-Specific CV Risk Factors

Pregnancy complications: pre-eclampsia (3× ↑future HT/CVD risk), gestational DM, preterm birth, placental abruption
Menopause: accelerated atherosclerosis post-menopause; oestrogen loss → adverse lipid profile, ↑visceral fat, ↑insulin resistance
PCOS: 2× ↑metabolic syndrome, DM, HTN; ↑CVD risk even without DM
Autoimmune disease: SLE, RA — 2–3× ↑CVD risk (inflammation + accelerated atherosclerosis)
Breast cancer treatment: anthracyclines, trastuzumab, radiation to left chest
Premature menopause (<40 years): 2× ↑CVD risk vs. age-matched

Atypical presentation of ACS in women: More likely to present with dyspnoea, nausea, jaw/back/arm pain, fatigue, and epigastric pain (vs. classic crushing chest pain in men). Higher rate of plaque erosion vs. rupture. Higher rate of SCAD and MINOCA (MI with non-obstructive coronary arteries).

MINOCA: MI (troponin rise + symptoms) + coronary arteries non-obstructive (<50% stenosis). Causes: plaque rupture in mild disease, coronary vasospasm, microvascular dysfunction, Takotsubo, SCAD, coronary embolism. Work-up: CMR (myocardial injury pattern — helps distinguish vasospasm/Takotsubo from true MINOCA). Treat underlying cause; ACEi/statin beneficial.

🔶 Takotsubo (Stress) Cardiomyopathy

Acute LV dysfunction triggered by physical or emotional stressor — typically post-menopausal women (90% female, 50–75 years). ECG: ST elevation (anterior leads) or deep T inversions — mimics STEMI. Cath: non-obstructive coronaries. Echo/ventriculography: apical ballooning (octopus trap shape). Mechanism: catecholamine surge → myocardial stunning + microvascular spasm. Recovery: LVEF normalises in 4–8 weeks in most. Management: supportive (ACEi, BB, diuretics if needed); avoid inotropes (may worsen); anticoagulate if thrombus. Recurrence: 5–10%.

▶6.8 Sports Cardiology & Exercise

Exercise is cardioprotective — regular aerobic exercise reduces all-cause mortality 30–35% and CV mortality 35%. Recommendations: ≥150 min/week moderate-intensity or ≥75 min/week vigorous-intensity aerobic activity (2023 ESC).

Pre-participation screening for competitive athletes: ECG + history + physical examination (European model). Abnormal ECG findings requiring further evaluation:

⚡ Athlete ECG — Training-Related vs. Pathological

NORMAL in athletes (do NOT investigate): sinus bradycardia, 1° AVB, incomplete RBBB, early repolarisation (J-point elevation), isolated LVH voltage criteria
BORDERLINE (evaluate in context): complete RBBB, T-wave inversion V1–V2 only, left axis deviation, left atrial enlargement — investigate if additional features
ABNORMAL (always investigate): ST depression, T-wave inversion ≥V3 (lateral, inferior), pathological Q waves, LBBB, WPW, long QT, Brugada pattern, epsilon wave — stop sport pending evaluation

Sudden Cardiac Death (SCD) in athletes: Leading causes in young athletes (<35 years): HCM (most common USA), ARVC (most common Italy/Mediterranean), coronary artery anomalies, channelopathies (LQTS, CPVT, BrS), myocarditis. Leading cause >35 years: atherosclerotic CAD.

Return to sport after cardiac events: HCM: no competitive sport (universal restriction in most guidelines). ARVC: restrict from all competitive sport (accelerates disease). Long QT: restrict based on risk stratification and symptoms; LQT2 most dangerous with exercise. Post-myocarditis: 3–6 months rest, reassess with echo + Holter + exercise testing before return.

🔶 HCM and Sport — Recreational vs. Competitive

HCM guidelines have evolved: 2022 AHA/ACC allow shared decision-making for competitive sport in HCM patients after comprehensive evaluation (absence of sustained VT, unexplained syncope, EF >60%, no extreme hypertrophy >30 mm, no outflow obstruction >100 mmHg, no LGE on CMR). Low-intensity recreational sport: generally permitted. This represents a significant change from the prior blanket restriction — personalised counselling is now standard.

▶6.9 Practice Questions — Prevention & Special Topics

Q1. A 62-year-old man with T2DM and established ASCVD has LDL-C 72 mg/dL on atorvastatin 40 mg + ezetimibe 10 mg. His target LDL-C is <55 mg/dL. What is the next step?

Add a PCSK9 inhibitor (evolocumab or alirocumab) or consider inclisiran.

Very high-risk patient (DM + ASCVD): LDL target <55 mg/dL. He is on maximum statin + ezetimibe but still above target. Next step: PCSK9 inhibitor (evolocumab 140 mg q2w or alirocumab 75 mg q2w) — will further reduce LDL by 50–60% to target. Inclisiran (twice-yearly injection) is an alternative. FOURIER and ODYSSEY OUTCOMES both showed CV event reduction with PCSK9i on top of statin + ezetimibe.

Q2. A breast cancer patient develops dyspnoea 6 months into trastuzumab therapy. Echo shows LVEF decline from 62% to 45% (drop of 17%). What do you do?

Hold trastuzumab. Start ACEi + beta-blocker. Recheck LVEF in 4–6 weeks.

Trastuzumab cardiotoxicity is Type II — reversible in most. Hold if LVEF drops >10% to below 50%. Start GDMT (ACEi + BB). If LVEF recovers to >50% at 4–6 weeks, can restart trastuzumab with close monitoring. Unlike anthracyclines (irreversible), trastuzumab toxicity is usually reversible with GDMT. Oncology-cardiology co-management essential.

Q3. A 58-year-old woman has resistant hypertension (BP 162/98 mmHg on amlodipine 10 mg, perindopril 10 mg, indapamide 2.5 mg — all at maximum doses). eGFR 72. K+ 4.1. What is the most effective 4th-line agent?

Spironolactone 25 mg OD (titrate to 50 mg if K+ permits).

PATHWAY-2 trial demonstrated spironolactone is the most effective 4th-line agent in resistant HTN — superior to bisoprolol and doxazosin. 2/3 of resistant HTN is sodium-related/hyperaldosteronism-related. Contraindicated if eGFR <45 or K+ >4.5. She has eGFR 72 and K+ 4.1 — appropriate candidate. Monitor renal function and K+ at 1 and 4 weeks.

7Cardiac Diagnostics

▶7.1 ECG — Systematic Interpretation

Systematic 10-step ECG approach: (1) Rate; (2) Rhythm (regular/irregular, P waves present?); (3) P-wave axis and morphology; (4) PR interval; (5) QRS axis; (6) QRS morphology/duration; (7) ST segment; (8) T-wave; (9) QT interval; (10) Overall interpretation.

Rate: Regular rhythm: 300/large squares between R–R. Approximate: 300 → 150 → 100 → 75 → 60 → 50 (count down large squares). Irregular: count QRS in 6-second strip × 10.

QRS Axis:

Axis	Lead I	aVF	Clinical Causes
Normal (−30° to +90°)	+	+	Normal
Left axis deviation (LAD) −30° to −90°	+	−	LBBB, LAHB, inferior MI, LVH, HCM, WPW (posterior AP), pacing
Right axis deviation (RAD) +90° to +180°	−	+	RBBB, LPHB, RVH, PE, lateral MI, WPW (septal AP), normal in children
Northwest axis (extreme RAD) −90° to ±180°	−	−	Hyperkalemia, VT, artificial pacing, AVRT with anterior AP

Bundle Branch Blocks:

Feature	LBBB	RBBB
QRS duration	≥120 ms	≥120 ms
V1	Broad S wave (QS or rS)	RSR' pattern ('rabbit ears')
V5/V6	Broad notched R wave (M-shape)	Wide S wave
Lateral leads I, aVL	Broad R (no Q)	Wide S
ST/T changes	Discordant ST/T (opposite to QRS) — normal in LBBB	Minor repolarisation change in V1–V3

🔶 Sgarbossa Criteria — STEMI in LBBB

Sgarbossa criteria identify STEMI in LBBB: (1) Concordant STE ≥1 mm (same direction as QRS) — 5 pts — most specific; (2) Concordant ST depression ≥1 mm in V1–V3 — 3 pts; (3) Discordant STE ≥5 mm — 2 pts. Score ≥3 = likely MI. Modified Sgarbossa: discordant STE/S ratio ≥0.25 (Smith modification) has higher sensitivity. New LBBB alone is no longer a STEMI equivalent in 2023 ESC (changed from 2012 guidelines).

▶7.2 ECG — Complex & High-Yield Patterns

High-yield ECG patterns for fellowship/board exams:

Pattern	ECG Findings	Significance
De Winter T-waves	ST depression at J-point + tall symmetric T waves V1–V6; no STE; upsloping ST → T wave	LAD total occlusion equivalent — activate cath lab immediately
Wellens syndrome	Biphasic T waves (Type A) or deep symmetric T inversions (Type B) in V2–V3 during pain-free period	Critical proximal LAD stenosis — high risk imminent STEMI; avoid stress test
Posterior STEMI	ST depression + tall R waves + upright T waves in V1–V3; posterior leads V7–V9 STE ≥0.5 mm confirm	LCx or RCA-PDA occlusion — activate cath lab
aVR STE pattern	STE in aVR (≥1 mm) + diffuse ST depression in other leads	Left main or proximal LAD occlusion (global subendocardial ischaemia) OR severe LMCA disease
Epsilon wave	Small notch/deflection at end of QRS in V1–V3	ARVC — represents delayed RV depolarisation from fibrofatty tissue
Osborn wave (J-wave)	Positive notch at J-point, most prominent V2–V5	Hypothermia (most common), hypercalcaemia, Brugada
Brugada pattern (Type 1)	Coved-type STE ≥2 mm in V1–V2 (high leads V1/V2 placement increases sensitivity)	Brugada syndrome — risk VF/SCD
Hyperkalemia progression	K+ 5.5: peaked T waves → K+ 6.5: flat P waves → K+ 7.0: widened QRS → K+ 8.0: sine wave → VF	Medical emergency — IV calcium gluconate + dialysis/kayexalate

🔶 Hyperkalemia — Calcium First

In suspected severe hyperkalemia (peaked T waves, widened QRS): (1) IV calcium gluconate 10 mL 10% IV over 10 min — stabilises myocardial membrane immediately (does NOT lower K+); (2) Sodium bicarbonate if acidosis; (3) Insulin 10 U + dextrose 50%; (4) Salbutamol nebulisation; (5) Dialysis or polystyrene sulphonate for definitive removal. Calcium takes effect within minutes — always the first drug in haemodynamically compromised hyperkalemia.

▶7.3 Echocardiography — TTE & TEE

Echocardiography is the most widely used cardiac imaging modality. Transthoracic echo (TTE): 2D, M-mode, spectral and colour Doppler, tissue Doppler imaging (TDI), strain analysis. Transoesophageal echo (TEE): superior resolution for posterior structures (LA, LAA, aorta, prosthetic valves, endocarditis).

Standard TTE Windows and Views:

Window	Views Obtained	Structures Best Seen
Parasternal long axis (PLAX)	LV length/thickness, aortic root, MV, LA	LV size + function, LVOT, AoV, MV apparatus
Parasternal short axis (PSAX)	AV level, MV level, PM level, apex	Commissural MS (AV/MV), RV pressure estimate (PSAX apex-TG), wall motion
Apical 4-chamber (A4C)	All 4 chambers, both AV valves	Biventricular function, mitral/tricuspid valves, LA/RA size
Apical 2-chamber (A2C)	LV anterior + inferior walls, mitral valve	Anterior + inferior wall motion assessment
Subcostal	4-chamber, IVC, pericardium	IVC diameter/collapsibility, pericardial effusion, RV thickness
Suprasternal notch	Aortic arch, main PA	Coarctation, PDA, aortic arch aneurysm

Diastolic Function Grading (ASE/EACVI 2016):

⚡ Diastolic Dysfunction Classification

Grade I (impaired relaxation): e' <7 cm/s septal; E/A <0.8; E/e' <10; TR velocity <2.8 m/s — normal LAP
Grade II (pseudonormal): E/A 0.8–2; 2 of 4 criteria suggest elevated LAP (E/e' >14, TR >2.8 m/s, LAVi >34 mL/m², e' septal <7 or lateral <10 cm/s)
Grade III (restrictive): E/A >2; E/e' >14; TR >2.8 m/s; short DT (<150 ms) — markedly elevated LAP
Indeterminate: E/A 0.8–2 + 2 criteria do not clearly agree — clinical context + additional imaging

🔶 Global Longitudinal Strain (GLS) — Early Toxicity Detection

GLS measures myocardial deformation (shortening) in the longitudinal direction via speckle-tracking echo. Normal GLS: −20% to −22% (more negative = better function). GLS detects subclinical LV dysfunction before LVEF falls. Key use: monitoring chemotherapy cardiotoxicity (anthracyclines, trastuzumab) — GLS deterioration >15% (relative) from baseline predicts future LVEF decline. Also useful in HCM, amyloid (reduced GLS with preserved LVEF and apical sparing pattern in amyloid).

▶7.4 Stress Testing & Cardiac CT

Exercise Stress Testing: Bruce protocol (standard); modified Bruce (elderly/deconditioned). Indications: diagnosis/exclusion of CAD, risk stratification post-ACS, functional capacity assessment, exercise-induced arrhythmia evaluation.

High-risk features on exercise stress test (↑specificity for significant CAD):

⚡ High-Risk Stress Test Findings

ST depression ≥2 mm, early onset (<5 METs or <stage 2 Bruce), prolonged recovery
ST elevation in non-Q lead (indicates transmural ischaemia)
Failure to achieve 85% MPHR (submaximal test) — reduced sensitivity
Duke Treadmill Score = exercise time (min) − (5 × max ST deviation) − (4 × angina score 0-2)
DTS ≥5: low risk; DTS −10 to +4: intermediate; DTS ≤ −11: high risk (annual mortality >5%)
Functional capacity <5 METs: poor prognosis indicator; ≥10 METs: excellent prognosis
Sustained or symptomatic VT during exercise
Hypotensive BP response (SBP drop >10 mmHg during exercise) — suggests 3-vessel/LM disease

Cardiac CT — CCTA (Coronary CT Angiography):

Application	Key Finding	Evidence/Guideline
Stable chest pain — rule out CAD	Negative CCTA: excellent NPV (>99%) for obstructive CAD; safe to discharge	PROMISE: CCTA equivalent to functional testing; SCOT-HEART: CCTA ↓MI at 5 years
Acute chest pain (ED rule-out)	CCTA-first strategy: faster discharge, no missed MI	ROMICAT-II: CCTA ↓LOS; HEART pathway integration
Calcium scoring (CAC)	CAC = 0: very low 10-year ASCVD risk; CAC ≥400: equivalent to established ASCVD	MESA study; ACC/AHA 2019: CAC for intermediate-risk decision aid on statin initiation
Pre-TAVI planning	Annulus sizing, leaflet calcium, access route planning	Mandatory pre-TAVI CT evaluation
Aortic assessment	Aneurysm sizing, dissection, anomalous coronary	CT aortography gold standard for acute aortic syndromes

🔶 CAC Score 0 — The Power of Zero

CAC score = 0 (no detectable calcium): 10-year ASCVD event rate <1% regardless of Framingham risk score. MESA: CAC 0 → mortality rate similar to general population. Clinical use: in intermediate-risk patients (7.5–20% 10-year ASCVD) where statin initiation decision is uncertain, CAC = 0 allows safe deferral of statin therapy. CAC ≥100 or ≥75th percentile for age/sex: start statin. CAC 1–99: consider statin. Reclassifies ~30–50% of intermediate-risk patients.

▶7.5 Cardiac MRI

CMR is the gold standard for myocardial tissue characterisation. No ionising radiation; excellent spatial resolution; reproducible volumes.

Key CMR Sequences and Clinical Applications:

Sequence	What It Shows	Clinical Use
Cine SSFP	Cardiac anatomy, wall motion, volumes, EF	Gold standard for LVEF/RVEF; cardiomyopathy evaluation
Late Gadolinium Enhancement (LGE)	Myocardial fibrosis/scar (gadolinium accumulates in expanded extracellular space)	MI pattern (subendocardial/transmural — coronary distribution); non-ischaemic CM (mid-wall, patchy, insertion points); amyloid (global subendocardial); myocarditis (epicardial/mid-wall)
T2 mapping / T2-STIR	Myocardial oedema (acute injury, inflammation)	Acute MI (oedema at area at risk); myocarditis; ARVC (fatty infiltration)
T1 mapping / ECV (extracellular volume)	Diffuse fibrosis; ECV >30% = significant interstitial fibrosis	Amyloid (markedly elevated ECV — often >40%); HCM; DCM prognosis
Perfusion imaging (first-pass gadolinium)	Myocardial blood flow at rest and stress (adenosine/regadenoson)	Non-invasive assessment of ischaemia; equivalent to SPECT in ISCHEMIA trial
Phase-contrast velocity mapping	Quantifies blood flow, valve regurgitation, shunts	Regurgitant fraction for AR/MR; Qp:Qs for shunts; coarctation gradient

🔶 LGE Pattern Identifies Aetiology

Mid-wall linear LGE in DCM: marker of fibrosis and adverse prognosis — predicts SCD independent of LVEF. Mid-wall LGE present → lower threshold for ICD. Insertion point LGE (RV-LV junction): normal variant or mild ARVC/sarcoid. Subepicardial LGE: myocarditis, sarcoid, Chagas. Diffuse subendocardial LGE: cardiac amyloid (unique pattern with amyloid). No LGE: reversible cardiomyopathy more likely (tachycardia-mediated, metabolic, drug-induced).

▶7.6 Right Heart Catheterisation & Haemodynamics

Right heart catheterisation (RHC) is the gold standard for haemodynamic assessment — direct measurement of intracardiac pressures, cardiac output, and pulmonary vascular resistance.

Normal Haemodynamic Values:

Parameter	Normal Value	Clinical Significance
RAP (RA pressure)	2–8 mmHg	↑ in RV failure, TR, tamponade, CP
RV systolic/diastolic	15–30 / 0–8 mmHg	↑ systolic = PAH, PE, severe PS
PA systolic/diastolic	15–30 / 8–12 mmHg	mPAP ≥20 mmHg = PH (2022 definition)
PCWP (wedge)	6–12 mmHg	Estimates LAP; >18 mmHg = pulmonary congestion; >15 mmHg + mPAP ↑ = Group 2 PH
Cardiac output (Fick)	4–8 L/min	CI = CO/BSA; CI <2.2 L/min/m² = haemodynamic compromise
PVR	<3 WU (Wood units)	≥3 WU = PAH; >5 WU = severe PAH; >5 WU fixed = contraindication to heart transplant
SVR	800–1200 dyn·s·cm⁻⁵	↑ in cardiogenic shock; ↓ in distributive shock

Fick Principle for Cardiac Output: CO = VO₂ (mL/min) / [CaO₂ − CvO₂] (Hgb × 13.4 × SaO₂ − Hgb × 13.4 × SvO₂). Thermodilution CO: rapid, less accurate in low CO states and TR. Fick: gold standard especially for low CO.

🔶 Vasoreactivity Testing in PAH

Before initiating long-term therapy, vasoreactivity testing with inhaled nitric oxide (iNO) or IV epoprostenol or adenosine in Group 1 PAH: a positive response (mPAP falls ≥10 mmHg to <40 mmHg with maintained or improved CO) identifies patients who may respond to calcium channel blockers (nifedipine, diltiazem, or amlodipine). Only 10–15% of iPAH patients are vasoreactive — but these have significantly better prognosis. Vasoreactive patients: CCB Class I; non-vasoreactive: ERA + PDE5i combination.

▶7.7 Coronary Physiology — FFR & iFR

Coronary physiology guides PCI decision-making when angiographic severity is uncertain (typically 40–70% stenosis).

Fractional Flow Reserve (FFR): Ratio of mean distal coronary pressure to mean aortic pressure during maximal hyperaemia (induced by adenosine IV 140 µg/kg/min or IC bolus). FFR ≤0.80 = haemodynamically significant → PCI benefit. FFR >0.80 → medical management safe.

Key FFR trials:

Trial	Question	Result
FAME	FFR-guided vs. angio-guided PCI in multivessel CAD	FFR-guided: 28% ↓MACE; fewer stents placed; no difference in adverse events
FAME 2	FFR-guided PCI vs. medical therapy for FFR ≤0.80	PCI: 34% ↓urgent revascularisation; 2024 update: mortality benefit at 15 years
DEFER	PCI deferral for FFR >0.75 lesions	Safe to defer — 5-year event rate no different from revascularised patients

iFR (Instantaneous Wave-Free Ratio): Pressure ratio measured during diastolic rest period (wave-free period) — adenosine NOT required. iFR ≤0.89 = functionally significant. iFR and FFR show strong correlation; iFR preferred when adenosine contraindicated (severe asthma, 2°/3° AVB, severe COPD) or unavailable.

DEFINE-FLAIR and iFR-SWEDEHEART: iFR non-inferior to FFR for clinical outcomes; iFR has shorter procedure time, no adenosine side effects.

🔶 ISCHEMIA Trial — Stable CAD Management

ISCHEMIA (N=5,179): stable CAD with moderate-severe ischaemia on stress testing. Invasive strategy (angiography + PCI/CABG if indicated) vs. optimal medical therapy. No significant difference in primary endpoint (CV death/MI) at 3.2 years. However: invasive strategy ↓spontaneous MI; medical strategy ↓procedural MI; angina relief better with invasive. Key message: for stable angina with medical treatment feasible, initial conservative management is reasonable. PCI/CABG reserved for refractory symptoms or high-risk features (LM, proximal LAD).

▶7.8 Nuclear Cardiology & Multimodality Imaging

Nuclear stress testing (SPECT/PET): SPECT MPI (myocardial perfusion imaging) with technetium-99m sestamibi or thallium-201. Stress (exercise or pharmacological): adenosine, regadenoson (A2A selective, fewer side effects), dobutamine (if adenosine contraindicated — asthma). Sensitivity 85–90%, specificity 75–85% for obstructive CAD.

PET MPI: Rubidium-82 or N-13 ammonia. Superior image quality, lower radiation, shorter acquisition time, absolute quantification of myocardial blood flow (MBF) in mL/min/g. MBF reserve (stress/rest) <2.0 = impaired microvascular function — identifies diffuse three-vessel CAD or microvascular disease missed by SPECT.

Radionuclide ventriculography (MUGA scan): Highly reproducible serial LVEF measurement — used for chemotherapy monitoring (anthracyclines).

Bone scan (Tc-99m PYP) for ATTR amyloid: Grade 2–3 cardiac uptake + absence of monoclonal protein = non-biopsy diagnosis of ATTR amyloid (99% specificity). Now Class I in diagnostic algorithm for suspected ATTR.

Cardiac sarcoidosis imaging: FDG-PET: detects active inflammatory infiltration (high glucose uptake in sarcoid granulomas); CMR LGE: patchy mid-wall/epicardial enhancement (distinct from typical non-ischaemic pattern). Combined FDG-PET + perfusion scan: most sensitive for cardiac sarcoidosis.

🔶 Multimodality Imaging Cheat Sheet

Question: Best for LV volumes/EF — CMR (gold standard) or echo. Best for myocardial scar/fibrosis — CMR LGE. Best for amyloid — Tc-99m PYP (ATTR) + bone scan or CMR (T1/ECV). Best for CAD/ischaemia non-invasive — CCTA (anatomy) or stress CMR/PET (physiology). Best for valve anatomy pre-TAVI — CT. Best for LAA thrombus — TEE or CT. Best for pericardial disease — CMR (inflammation, thickness). Best for active sarcoid — FDG-PET.

▶7.9 Practice Questions — Diagnostics

Q1. A 70-year-old man has severe AS (AVA 0.75 cm²) but mean gradient is only 28 mmHg with LVEF 35%. What is the next diagnostic step?

Low-dose dobutamine stress echo (DSE) to distinguish true severe from pseudo-severe AS.

Low-flow, low-gradient AS with reduced LVEF (classical LFLG AS): AVA <1 cm² + mean gradient <40 mmHg + LVEF <50%. DSE: infuse dobutamine 5–20 µg/kg/min. If true severe AS: AVA stays <1 cm², gradient increases ≥40 mmHg as flow increases. If pseudo-severe: AVA increases (calcified but not truly severe — degree of stenosis depends on opening force). Also assess contractile reserve (LVEF increases ≥5% with dobutamine) — predicts surgical benefit.

Q2. A patient with ECG showing a narrow complex tachycardia at 150 bpm with no visible P waves. IV adenosine 6 mg is given — the rate briefly slows to reveal regular sawtooth flutter waves at 300 bpm, then returns to 150 bpm. What is the diagnosis and treatment?

Atrial flutter with 2:1 block. Adenosine unmasked flutter waves (diagnostic use). Definitive treatment: DC cardioversion or CTI ablation.

Classic 150 bpm narrow complex tachycardia = flutter until proven otherwise. Adenosine transiently increases AV block, revealing the flutter waves — diagnostic manoeuvre. It does NOT terminate flutter (it terminates AVNRT/AVRT). Next: rate control (diltiazem/BB), anticoagulate if AF criteria met, then cardioversion or CTI ablation (95% curative).

Q3. CMR shows a 55-year-old woman with new DCM (LVEF 32%) and mid-wall LGE in the lateral wall. Coronary angiography is normal. What is the clinical significance of the mid-wall LGE?

Mid-wall LGE in non-ischaemic DCM indicates myocardial fibrosis — an independent predictor of SCD. Lower threshold for ICD implantation even if LVEF borderline.

In non-ischaemic DCM, mid-wall or lateral LGE represents replacement fibrosis — a substrate for ventricular arrhythmias. Multiple studies show mid-wall LGE predicts SCD independent of LVEF. 2022 guidelines increasingly support using LGE to guide ICD decisions in DCM. In this patient with LVEF 32% + LGE, ICD should be implanted after optimising GDMT (minimum 3 months).