1. Discuss the approach to a case with broad QRS tachycardia & its management. (20) • 2. Destination therapy in heart failure. (6) • 3. Pathophysiology of acute coronary syndrome with physiology of coagulation. (20) • 4. Discuss physiology of cardiac conduction with special reference to AV node. Discuss pathophysiology & management of SVT. (20) • 5. Discuss approach to broad QRS tachycardia & its management. (20) • 6. Neprilysin inhibitor in heart failure. (6) • 7. Discuss the role of antiarrhythmic drugs in ventricular arrhythmias. (20) • 8. WPW syndrome. (6) Kindly prepare answer for MD medicine final year exam and add flow charts and diagrams and make good notes
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MD Medicine Final Year Exam - Complete Cardiology Notes
QUESTION 1 & 5: Approach to Broad QRS Tachycardia & Management (20 marks)
Definition
- Broad QRS tachycardia = QRS duration ≥0.12 sec (≥120 ms) with heart rate >100 bpm
FLOWCHART: Approach to Broad QRS Tachycardia
BROAD QRS TACHYCARDIA (QRS ≥120ms, HR >100bpm)
│
▼
┌─────────────────────┐
│ Is patient STABLE? │
└─────────────────────┘
│ │
NO YES
│ │
▼ ▼
IMMEDIATE 12-lead ECG
DCCS 200J + Clinical assessment
│
┌──────┴──────┐
│ │
▼ ▼
REGULAR IRREGULAR
│ │
─────┴──── ────┴────────────────
│ │ │ │ │
VT SVT Polymorphic AF with AF + WPW
(most with VT/Torsades BBB (pre-excited)
common) aberrancy aberrancy
CAUSES OF BROAD QRS TACHYCARDIA
| Category | Mechanism | Example |
|---|---|---|
| Ventricular Tachycardia (VT) | Reentry in ventricle | Post-MI scar |
| SVT with aberrancy | Pre-existing BBB | RBBB + SVT |
| Pre-excited tachycardia | Accessory pathway | WPW + AF |
| Antidromic AVRT | Antegrade conduction via AP | WPW syndrome |
| Toxic/metabolic | Hyperkalemia, Na-channel blockade | TCA overdose |
| Pacemaker-mediated | Ventricular pacing | Pacemaker tachycardia |
DIFFERENTIATING VT FROM SVT WITH ABERRANCY
Brugada Criteria (Step-wise; each step = VT if criterion met)
Step 1: Is there ABSENCE of RS complex in ALL precordial leads?
→ YES = VT
→ NO → Step 2
Step 2: Is RS interval >100ms in ANY precordial lead?
→ YES = VT
→ NO → Step 3
Step 3: Is there AV DISSOCIATION?
→ YES = VT (highly specific)
→ NO → Step 4
Step 4: Do morphological criteria for VT exist in V1/V2 & V6?
→ YES = VT
→ NO = SVT with aberrancy
ECG Features STRONGLY Suggesting VT
- AV dissociation (P and QRS independent) - pathognomonic
- Capture beats (narrow QRS amid wide complexes)
- Fusion beats (partial capture - hybrid QRS)
- QRS width >160 ms
- Extreme axis deviation ("northwest axis" -90° to ±180°)
- Concordance - all precordial leads positive (positive concordance) or all negative (negative concordance)
- QRS morphology inconsistent with any BBB pattern
Morphology Clues
| Feature | Suggests VT | Suggests SVT+aberrancy |
|---|---|---|
| V1 pattern (LBBB-like) | Broad R (>30ms) or notch | Narrow, clean downstroke |
| V6 (LBBB-like) | QR or QS | R or rS (no Q) |
| V1 (RBBB-like) | Monophasic R or qR | rSR' (triphasic) |
Key Rule: In the absence of a prior ECG, assume VT until proven otherwise - it is more common and more dangerous. - Braunwald's Heart Disease
MANAGEMENT OF BROAD QRS TACHYCARDIA
FLOWCHART: Management Algorithm (ACLS-Based)
BROAD QRS TACHYCARDIA
│
▼
IS PATIENT STABLE?
(BP, sensorium, pulse)
│
─────┴──────
│ │
UNSTABLE STABLE
│ │
▼ ▼
SYNCHRONIZED Identify rhythm
DCCS 12-lead ECG
(Monophasic │
200J or ▼
Biphasic Regular or Irregular?
100-200J) │
┌─────┴──────────┐
│ │
REGULAR IRREGULAR
│ │
▼ ▼
┌──────────────┐ ┌─────────────────────────┐
│ VT vs SVT? │ │ Polymorphic VT/TdP/AF │
└──────────────┘ └─────────────────────────┘
│
┌──────┴────────────────┐
│ │
▼ ▼
VT - DRUG THERAPY SVT with aberrancy:
- Adenosine (safe)
- CCB/BB (rate control)
Drug Therapy for Stable VT
| Drug | Dose | Notes |
|---|---|---|
| Amiodarone | 150 mg IV over 10 min, then 1 mg/min x 6h | First choice for VT; can be repeated |
| Lidocaine | 1-1.5 mg/kg IV bolus, then infusion | Especially post-MI VT |
| Procainamide | 20-50 mg/min IV (max 17 mg/kg) | Active metabolite NAPA; avoid in QT prolongation |
| Sotalol | 1.5 mg/kg IV over 5 min | Avoid in QT prolonged, HF |
| Magnesium | 1-2 g IV over 5-60 min | Specifically for Torsades de Pointes |
Torsades de Pointes - Special Management
TdP (Polymorphic VT + prolonged QT baseline)
│
▼
1. IV Magnesium 2g over 5-10 min (FIRST)
2. Correct electrolytes (K⁺ >4.5, Mg²⁺ >2)
3. Stop all QT-prolonging drugs
4. Overdrive pacing at 90-110 bpm
5. Isoproterenol (if bradycardia-dependent TdP)
6. DCCS if unstable
Pre-excited AF (AF + WPW)
- AVOID: AV nodal blocking agents (adenosine, digoxin, verapamil, diltiazem) - can accelerate accessory pathway conduction → VF
- USE: Procainamide IV, Ibutilide, or DCCS
Electrophysiology Study (EPS) Role
- Differentiates aberrant SVT from VT when ECG equivocal
- H-V interval: Normal/prolonged in SVT; Shortened or absent in VT
- Identifies reentry circuits for ablation
QUESTION 2: Destination Therapy in Heart Failure (6 marks)
Definition
"Destination therapy" = permanent, long-term mechanical circulatory support (MCS) as a definitive treatment in patients with end-stage heart failure who are NOT eligible for cardiac transplantation.
Background
- 6 million patients in the USA have HF; ~300,000 have advanced HF
- Donor heart scarcity limits transplantation (<4,000/year worldwide)
- LVAD fills the gap as a permanent alternative
DIAGRAM: Spectrum of MCS Use
ACUTE HF CHRONIC HF
│ │
▼ ▼
Bridge to Recovery Bridge to Transplantation
(BTR) (BTT) - patient on transplant list
│ │
└──────────────┬───────────────┘
│
▼
Bridge to Candidacy
(improve to become eligible)
│
▼
DESTINATION THERAPY
(permanent - not eligible for transplant)
Patient Selection Criteria for Destination Therapy
- NYHA Class IIIb or IV symptoms
- LVEF <25%
- Peak VO₂ <14 mL/kg/min on cardiopulmonary exercise test
- Intolerance or failure of optimal medical therapy (>2 months)
- Inotrope-dependent OR need for short-term MCS ≥7 days
- 3 or more HF hospitalizations in prior 12 months
- Progressive end-organ dysfunction
Contraindications
- Active uncontrolled infection
- Severe fixed pulmonary hypertension (PVR >6 Wood units)
- Active malignancy
- Significant neurological dysfunction
- Severe uncorrectable aortic regurgitation
- Patient/social factors precluding device management
Device Types
| Device | Type | Notes |
|---|---|---|
| HeartMate 3 | Centrifugal-flow (magnetically levitated) | Best outcomes; MOMENTUM 3 trial - superior to axial |
| HeartMate II | Axial-flow | 65% 2-year survival free of stroke/re-surgery |
| HeartWare (HVAD) | Centrifugal-flow | Withdrawn from market |
Outcomes
- Magnetically levitated centrifugal-flow pumps (HeartMate 3) provide better 2-year outcomes than axial-flow devices (MOMENTUM 3 trial)
- 65% 2-year survival free of disabling stroke or repeat device surgery with axial-flow devices
Complications
LVAD Complications
├── Bleeding (especially GI - due to acquired vWF deficiency)
├── Stroke (ischemic/hemorrhagic)
├── Device thrombosis
├── Driveline infection
├── Right heart failure (post-implant)
└── Hemolysis
"A continuous axial-flow device can provide a 65% 2-year survival free of repeat device surgery or disabling stroke. A newer ventricular magnetically levitated centrifugal-flow pump may provide better short-term and 2-year outcomes." - Goldman-Cecil Medicine
QUESTION 3: Pathophysiology of ACS with Physiology of Coagulation (20 marks)
DIAGRAM: Coagulation Cascade (Waterfall Model)
INTRINSIC PATHWAY EXTRINSIC PATHWAY
(contact activation) (tissue factor)
│ │
XII → XIIa TF + VIIa (Tissue factor)
│ │
XI → XIa │
│ │
IX → IXa ─────────────────────────────────┘
│ ↑
│ (VIII as cofactor + Ca²⁺ + PL)
│
▼
X → Xa (Common Pathway)
│ ↑
│ (V as cofactor + Ca²⁺ + PL)
│
▼
Prothrombin (II) → Thrombin (IIa)
│
▼
Fibrinogen → FIBRIN MONOMER
│
Factor XIII
│
▼
CROSS-LINKED FIBRIN CLOT
PLATELET ACTIVATION (Primary Hemostasis):
Injury → Exposed collagen → vWF bridges → GPIb on platelet
→ Platelet adhesion → activation → TxA2 + ADP release
→ Platelet aggregation via GPIIb/IIIa ↔ fibrinogen
→ PLATELET PLUG
PATHOPHYSIOLOGY OF ACS
The Unifying Concept: Plaque Rupture
STABLE ATHEROSCLEROTIC PLAQUE
│
▼ (Triggers: inflammation, shear stress, infection)
VULNERABLE PLAQUE
(Thin fibrous cap + Large lipid core + Rich in macrophages/foam cells)
│
▼
PLAQUE RUPTURE or EROSION
│
▼
EXPOSURE OF SUBENDOTHELIAL COLLAGEN, LIPID CORE, TISSUE FACTOR
│
▼
┌───┴───────────────────────────────┐
│ │
▼ ▼
PLATELET ACTIVATION COAGULATION CASCADE
(vWF, ADP, TxA2) (TF → Thrombin)
│ │
└─────────────┬─────────────────────┘
│
▼
THROMBUS FORMATION
│
┌───────┴──────────┐
│ │
▼ ▼
PARTIAL OCCLUSION COMPLETE OCCLUSION
+ DYNAMIC SPASM │
│ ▼
▼ ST-ELEVATION MI
UNSTABLE ANGINA (STEMI)
or NSTEMI
Mediators of Plaque Instability
| Mediator | Source | Effect |
|---|---|---|
| MMPs (matrix metalloproteinases) | Macrophages | Degrade fibrous cap |
| IL-1β, TNF-α | Inflammatory cells | Pro-inflammatory |
| Oxidized LDL | Foam cells | Endothelial damage |
| Tissue Factor (TF) | Lipid core/macrophages | Triggers extrinsic coagulation |
| vWF | Damaged endothelium | Platelet adhesion |
| Thromboxane A2 | Activated platelets | Vasoconstriction + aggregation |
Three Types of ACS Presentation
| Type | Mechanism | ECG | Troponin |
|---|---|---|---|
| Unstable Angina (UA) | Partial occlusion, no necrosis | ST depression/T inversion/normal | Normal |
| NSTEMI | Subtotal occlusion, subendocardial necrosis | ST depression/T inversion | Elevated |
| STEMI | Complete occlusion, transmural necrosis | ST elevation + Q waves | Markedly elevated |
Myocardial Consequences of Ischemia
CORONARY OCCLUSION
│
▼
Seconds: Loss of aerobic metabolism → anaerobic glycolysis
│
▼
Minutes: ATP depletion → Na/K pump failure → cell swelling
│
▼
20-40 min: IRREVERSIBLE NECROSIS (if no reperfusion)
│
▼
Hours: Wavefront phenomenon - subendocardium → epicardium
│
▼
Days-weeks: Ventricular remodeling → dilation, hypertrophy
Management of ACS
Antiplatelet/Anticoagulant Strategy
DUAL ANTIPLATELET THERAPY (DAPT)
├── Aspirin 325 mg loading → 75 mg daily (irreversible COX inhibitor → ↓TxA2)
└── P2Y12 inhibitor:
├── Ticagrelor 180 mg → 90 mg BD (reversible; preferred in ACS)
├── Prasugrel 60 mg → 10 mg daily (irreversible; avoid in prior stroke/TIA)
└── Clopidogrel 300-600 mg → 75 mg daily (prodrug, variable metabolism)
ANTICOAGULATION
├── UFH - Weight-based IV infusion
├── LMWH (Enoxaparin) - 1 mg/kg SC BD
├── Fondaparinux 2.5 mg SC daily (preferred in NSTEMI/medical management)
└── Bivalirudin - during PCI (direct thrombin inhibitor)
QUESTION 4: Cardiac Conduction System, AV Node, SVT Pathophysiology & Management (20 marks)
DIAGRAM: Cardiac Conduction System
┌─────────────────────┐
│ SINOATRIAL NODE │ ← Pacemaker (60-100/min)
│ (Right atrium, SVC │ Automaticity: Fastest
│ junction) │
└──────────┬──────────┘
│ Internodal pathways
│ (Anterior, Middle, Posterior)
┌──────────▼──────────┐
│ ATRIOVENTRICULAR │ ← AV delay (120-200ms)
│ NODE │ Pacemaker backup: 40-60/min
│ (Triangle of Koch) │
└──────────┬──────────┘
│ Bundle of His
┌──────────▼──────────┐
│ BUNDLE OF HIS │ ← Pacemaker backup: 40-60/min
└──┬───────────────┬──┘
│ │
┌────────▼──┐ ┌────▼────────┐
│ LEFT BB │ │ RIGHT BB │
└──┬──────┬─┘ └──────┬──────┘
Left Left │
anterior posterior Purkinje
fascicle fascicle fibers
└───────┴──────────────────┘
│
┌──────▼──────┐
│ PURKINJE │ ← 20-40/min
│ FIBERS │
└─────────────┘
Physiology of the AV Node
Key Properties of AV Node
- Decremental conduction - the faster the atrial rate, the slower the AV conduction (protective)
- Gate-keeping function - protects ventricles from excessively rapid atrial rates
- Dual pathway physiology - has Alpha (slow, short refractory) and Beta (fast, long refractory) pathways
- Autonomic modulation - vagal tone slows; sympathetic tone speeds conduction
Ion Channels in AV Node Action Potential
AV Node Action Potential (SLOW RESPONSE)
Phase 0: Slow, Ca²⁺-dependent depolarization (L-type Ca²⁺ channels)
Phase 3: Repolarization via K⁺ channels (IKr, IKs)
Phase 4: Spontaneous slow depolarization (If = "funny current" - HCN channels)
→ AUTOMATICITY (backup pacemaker 40-60/min)
Compared to SA Node: Similar slow-response type
Compared to His-Purkinje: FAST response (Na⁺-dependent), 0-phase steep upstroke
PR Interval Components
P wave → PR interval → QRS
│ │
│ ─────────────────
│ AV nodal delay (major part)
│ His bundle → Bundle branches → Purkinje conduction
│
└── Atrial depolarization
Pathophysiology of SVT
Definition
SVT = rapid tachycardia (rate 140-280/min) arising from or requiring structures ABOVE the bundle of His
DIAGRAM: Mechanisms of SVT
MECHANISMS OF SVT
│
├── REENTRY (most common)
│ │
│ ├── AVNRT (AV Node Reentrant Tachycardia) - most common SVT
│ │ • Reentry circuit within AV node
│ │ • Uses dual AV nodal pathways (slow + fast)
│ │ • P wave buried in or just after QRS
│ │ • "Typical" AVNRT: slow antegrade, fast retrograde
│ │
│ ├── AVRT (AV Reentrant Tachycardia) - accessory pathway
│ │ • Orthodromic: antegrade via AV node, retrograde via AP
│ │ → Narrow QRS (usually)
│ │ • Antidromic: antegrade via AP, retrograde via AV node
│ │ → Wide QRS (looks like VT!)
│ │
│ └── Atrial Flutter
│ • Macro-reentry in right atrium (CTI)
│ • Rate ~300/min, 2:1 block → ventricular rate ~150
│ • Sawtooth flutter waves in II, III, aVF
│
├── AUTOMATICITY (abnormal)
│ • Focal atrial tachycardia
│ • Junctional tachycardia (JET in post-cardiac surgery)
│
└── TRIGGERED ACTIVITY
• EAD/DAD - mediated (uncommon cause of SVT)
AVNRT - The Most Common SVT
AVNRT Circuit
┌──── Atria ────┐
│ │
▼ ▲
FAST path Retrograde
(short refractory) │
│ │
▼ │
AV Node │
│ │
▼ │
SLOW path ─────────┘
(long refractory,
slow conduction)
Initiation: PAC with long PR (down slow path)
→ Fast path recovered → retrograde up fast path
→ Circus movement established
Management of SVT
FLOWCHART: SVT Management
SVT CONFIRMED (narrow QRS, regular, HR 140-280/min)
│
▼
STABLE?
│ │
NO YES
│ │
▼ ▼
SYNC VAGAL MANEUVERS
DCCS (Valsalva, Carotid sinus massage)
(50-100J) │
Terminates?
YES NO
│ │
Monitor ADENOSINE IV (1st line)
6 mg rapid push → wait 1-2 min
12 mg if no response
12 mg again if needed
│
Terminates?
YES NO
│ │
Monitor 2nd line agents:
├── Verapamil 5-10 mg IV
├── Diltiazem 0.25 mg/kg IV
├── Metoprolol 5 mg IV (x3)
└── Amiodarone (if uncertain etiology)
│
Refractory?
│
▼
SYNCHRONIZED DCCS
Long-term Management / Prevention
| Option | Details |
|---|---|
| Radiofrequency Catheter Ablation | Curative (>95% success for AVNRT/AVRT); first-line for recurrent symptomatic SVT |
| Beta-blockers | Metoprolol, atenolol - for rate/rhythm control |
| Calcium channel blockers | Verapamil, diltiazem - avoid in WPW |
| Flecainide/Propafenone | "Pill in the pocket" - structurally normal heart only |
| Digoxin | Vagally-mediated rate control; avoid in WPW |
Note on EPS: H-V interval equals or exceeds normal sinus H-V interval during SVT; during VT the H-V interval is shorter than normal, or His deflection cannot be recorded. - Braunwald's Heart Disease
QUESTION 6: Neprilysin Inhibitor in Heart Failure (6 marks)
Neprilysin - The Enzyme
Neprilysin (also called neutral endopeptidase, NEP) is a zinc-dependent metalloprotease enzyme found on cell surfaces, particularly in the kidneys.
What neprilysin degrades:
- Natriuretic peptides (ANP, BNP, CNP) ← most important
- Bradykinin
- Adrenomedullin
- Angiotensin I and II
- Substance P
DIAGRAM: Rationale for Neprilysin Inhibition in HF
HEART FAILURE
│
├── Activated RAAS → AngII → Vasoconstriction, Na retention, Fibrosis
└── Activated Natriuretic Peptide System (Compensatory)
│
▼
ANP/BNP → Vasodilation, Natriuresis, Anti-fibrosis, Anti-hypertrophy
│
▼ (Degraded by NEPRILYSIN)
Reduced effect
NEPRILYSIN INHIBITOR (Sacubitril)
│
▼
↑ ANP, BNP, Bradykinin, Adrenomedullin, CNP
│
▼
Vasodilation + Natriuresis + ↓ Fibrosis + ↓ Hypertrophy
Why ARNI (not just NEP inhibitor alone)?
Problem: Neprilysin also degrades AngII
→ Neprilysin inhibition alone = ↑ AngII
→ Negates vasodilation benefit
Solution: Combine with ARB (Valsartan)
→ Block AngII receptor
→ Dual benefit (vasodilation + RAAS blockade)
Why NOT with ACE inhibitor?
→ Both NEP and ACE degrade Bradykinin
→ Combined blockade = ↑↑ Bradykinin → HIGH RISK OF ANGIOEDEMA
→ Therefore: ARNI = Sacubitril + VALSARTAN (ARB, not ACEi)
Sacubitril/Valsartan (ARNI) - Key Facts
Pharmacology
- Trade name: Entresto
- Sacubitril is a prodrug → converted to active metabolite LBQ657
- Combined molecule: LCZ696
- Standard dose: 97/103 mg BD (sacubitril 97 mg + valsartan 103 mg)
Evidence - PARADIGM-HF Trial
- Sacubitril/valsartan vs enalapril in HFrEF (LVEF ≤40%)
- Results: 20% relative risk reduction in cardiovascular death + HF hospitalization
- Reduced all-cause mortality, CV mortality, HF hospitalizations
Indications
- HFrEF (LVEF ≤40%), symptomatic despite ACEi/ARB + beta-blocker + MRA
- Now recommended as first-line (instead of ACEi/ARB) in eligible patients
- Can be initiated in hospitalized patients with decompensated HF (once stable)
Practical Points
STARTING SACUBITRIL/VALSARTAN
│
▼
Is patient on ACE inhibitor?
YES NO
│ │
▼ ▼
36-hour WASHOUT Start directly
(risk of angioedema) (if on ARB: switch directly)
│
▼
Start low dose (24/26 mg BD)
│
▼
Titrate every 2-4 weeks
│
▼
Target dose: 97/103 mg BD
Contraindications
- History of angioedema (any cause)
- Concurrent ACE inhibitor use
- Systolic BP <95 mmHg
- Severe hepatic impairment
- Pregnancy
Side Effects vs ACEi/ARB
| Effect | Sacubitril/Valsartan | Enalapril |
|---|---|---|
| Hypotension | More common | Less |
| Angioedema | Slightly more | More |
| Renal dysfunction | Less | More |
| Hyperkalemia | Less | More |
| Cough | Less (no ACE effect) | More |
Important: BNP vs NT-proBNP in Monitoring
- Neprilysin inhibition INCREASES BNP (because it's no longer degraded)
- NT-proBNP is NOT a neprilysin substrate → levels not increased
- Therefore, use NT-proBNP (not BNP) to monitor HF severity in patients on ARNI
"Neprilysin inhibition increases levels of B-type natriuretic peptide but not NT pro-B-type natriuretic peptide." - Goldman-Cecil Medicine
QUESTION 7: Role of Antiarrhythmic Drugs in Ventricular Arrhythmias (20 marks)
Vaughan-Williams Classification
CLASS I - Na⁺ CHANNEL BLOCKERS
│
├── Class IA (Moderate block + ↑ APD)
│ • Quinidine, Procainamide, Disopyramide
│ • Slow conduction + lengthen refractory period
│ • Risks: TdP (↑ QT), SLE-like syndrome (Procainamide)
│
├── Class IB (Weak block + ↓ APD)
│ • Lidocaine, Mexiletine, Phenytoin
│ • Minimal effect on QT; ↓ VF threshold post-MI
│ • Lidocaine: First-line for VT in ischemia
│
└── Class IC (Strong block, no APD change)
• Flecainide, Propafenone
• Most potent Na-block; ↑ QRS duration
• AVOID in structural heart disease (CAST trial)
CLASS II - BETA-BLOCKERS
• Metoprolol, Carvedilol, Propranolol
• ↓ Automaticity, ↓ conduction velocity
• ONLY antiarrhythmics proven to reduce SCD post-MI
• Indicated in all post-MI patients, HF, LQTS
CLASS III - K⁺ CHANNEL BLOCKERS (↑ APD, ↑ QT)
│
├── Amiodarone - multi-class (I+II+III+IV)
│ • Most effective antiarrhythmic for VT/VF
│ • Pulmonary toxicity, hepatotoxicity, thyroid effects
│ • Low proarrhythmic risk despite QT prolongation
│
├── Sotalol - Class III + II
│ • QT prolongation → risk of TdP
│ • Useful in VT with preserved EF
│
└── Dofetilide, Ibutilide
• IV Ibutilide for AF/flutter conversion
CLASS IV - Ca²⁺ CHANNEL BLOCKERS
• Verapamil, Diltiazem
• AVOID in VT (may cause hemodynamic collapse)
• Useful in ILVT (Idiopathic LV VT - verapamil-sensitive)
Antiarrhythmic Drug Use in Specific VT Scenarios
FLOWCHART: Drug Selection for Ventricular Arrhythmias
VENTRICULAR ARRHYTHMIA
│
─────┴────────────────────────────────────
│ │ │
PVC/NSVT Sustained VT VF
│ │ │
▼ ▼ ▼
Usually no Rx Structural Idiopathic DEFIBRILLATION
unless sx Heart Dz? VT? + Amiodarone
YES NO │ 300 mg IV
│ │ ▼ push
▼ ▼ Verapamil IV
Amiodarone Flecainide/ (ILVT - LBBB
Lidocaine Propafenone morphology)
Sotalol
Amiodarone - Detailed Profile
| Property | Details |
|---|---|
| Class | Multi-class (I+II+III+IV), longest APD |
| Indications | Stable VT, VF (cardiac arrest), hemodynamically unstable VT |
| Loading dose | 150 mg IV over 10 min; 1 mg/min x6h then 0.5 mg/min x18h |
| Oral loading | 400-600 mg TID x 4 weeks → maintenance 100-400 mg/day |
| t½ | 40-55 days (prolonged due to tissue accumulation) |
| Volume of distribution | Very large (59 L/kg) - accumulates in fat, lung, liver |
| Side effects | Pulmonary toxicity (pneumonitis/fibrosis), Hypothyroid/Hyperthyroid, Corneal microdeposits, Photosensitivity (blue-grey skin), Hepatotoxicity, Peripheral neuropathy |
| Drug interactions | ↑ digoxin, warfarin levels; inhibits CYP2D6, CYP3A4 |
Specific Scenarios
| Scenario | Preferred Drug(s) | Avoid |
|---|---|---|
| Acute VT/VF (cardiac arrest) | Amiodarone 300 mg IV bolus | Lidocaine (2nd line) |
| Post-MI sustained VT | Amiodarone, Sotalol | Flecainide, Propafenone |
| ICD storm (recurrent shocks) | Amiodarone + Beta-blocker | |
| LQTS/TdP | Magnesium, Propranolol, Pacing | Sotalol, Amiodarone (IA agents) |
| CPVT | Beta-blocker (Nadolol), Flecainide | |
| Idiopathic RVOT VT | Adenosine, Beta-blockers, Verapamil | |
| Idiopathic ILVT (Belhassen) | Verapamil | |
| Brugada syndrome | Quinidine, Cilostazol | Na-channel blockers |
ICD vs Drug Therapy
SECONDARY PREVENTION (After VT/VF arrest):
ICD is preferred over antiarrhythmic drugs alone
(AVID, CIDS, CASH trials)
PRIMARY PREVENTION:
LVEF ≤35% + NYHA II-III despite ≥3 months optimal therapy
→ ICD implantation (SCD-HeFT, MADIT-II trials)
→ Add amiodarone only if frequent ICD shocks or ICD contraindicated
COMBINATION:
ICD + Amiodarone/Sotalol → reduce appropriate ICD shocks
ICD + Beta-blocker → essential; reduces ICD therapies
Antiarrhythmic Drug Proarrhythmia
PROARRHYTHMIA TYPES
│
├── QT Prolongation → Torsades de Pointes
│ Caused by: IA (quinidine), III (sotalol, dofetilide)
│ Risk factors: Hypokalemia, bradycardia, female sex
│
├── Use-dependent Na-block → Worsening VT
│ Caused by: IC drugs (flecainide)
│ CAST trial: ↑ mortality post-MI despite ↓ PVCs
│
└── AV block / Sinus arrest
Caused by: IA, amiodarone, BB, CCB
QUESTION 8: WPW Syndrome (6 marks)
Definition
Wolff-Parkinson-White (WPW) syndrome = pre-excitation syndrome caused by an accessory atrioventricular pathway (Bundle of Kent) that bypasses the AV node, causing ventricular pre-excitation and associated tachyarrhythmias.
ECG Diagnostic Criteria
WPW PATTERN (ECG TRIAD):
1. SHORT PR interval (<120 ms)
→ Early ventricular depolarization via AP
2. DELTA WAVE (slurred QRS upstroke)
→ Slow cell-to-cell conduction via AP before
normal His-Purkinje conduction takes over
3. WIDE QRS complex (>120 ms)
→ Fusion of AP conduction + normal conduction
4. SECONDARY ST-T CHANGES
→ Consequence of abnormal depolarization
DIAGRAM: WPW Mechanism
NORMAL WPW
SA → AV node SA → AV node (delayed)
(delay 120-200ms) AND
→ His → BB → Purkinje → Bundle of Kent (no delay)
→ QRS → DELTA WAVE + Short PR
→ Fusion QRS
Location of Accessory Pathway
- Left free wall (most common ~50%)
- Right free wall
- Posteroseptal
- Anteroseptal
Localization from ECG - Delta wave polarity in different leads identifies pathway location (Arruda algorithm)
Tachyarrhythmias in WPW
1. Orthodromic AVRT (most common - 70-80%)
Atrial → AV NODE (antegrade) → Ventricle
│
Retrograde ◄────┘ via Bundle of Kent
│
▼
NARROW QRS tachycardia (usually)
(unless aberrancy or antidromic)
2. Antidromic AVRT (rare - 5%)
Atrial → Bundle of Kent (antegrade) → Ventricle
│
Retrograde ◄───────┘ via AV node
│
▼
WIDE QRS tachycardia
(mimics VT!)
3. Pre-excited AF (most dangerous)
AF with WPW
│
▼
Irregular broad QRS tachycardia
(Rate can reach 250-300+ bpm via AP)
│
▼
Risk of VENTRICULAR FIBRILLATION
(If effective refractory period of AP < 250ms)
│
▼
SUDDEN CARDIAC DEATH
Management
Acute Management
| Tachycardia | Treatment | Contraindicated |
|---|---|---|
| Orthodromic AVRT (narrow) | Vagal maneuvers → Adenosine → Verapamil/BB | - |
| Pre-excited AF (wide irregular) | Procainamide IV or DCCS | Adenosine, Digoxin, Verapamil, Diltiazem (may accelerate AP → VF) |
| Hemodynamically unstable | Immediate synchronized DCCS | - |
Risk Stratification
High-risk features (sudden death risk):
├── Shortest RR interval in AF <250 ms
├── Multiple pathways
├── Symptomatic tachycardia
├── Effective refractory period of AP <270 ms (at EPS)
└── History of syncope or cardiac arrest
Definitive Treatment
Radiofrequency Catheter Ablation - treatment of choice
- Success rate: >95%
- Recurrence rate: <5%
- Complication rate: <1-2% (including AV block for septal pathways)
- Indicated in: All symptomatic WPW; asymptomatic with high-risk features; certain professions (pilots, athletes)
Pharmacological Long-term Prevention
- Flecainide/Propafenone - slow AP conduction (avoid if structural HD)
- Amiodarone - affects AP and AV node
- Avoid: Digoxin, Verapamil, Diltiazem as single agents (shorten AP refractory period)
SUMMARY TABLE: Key Drug Doses for Quick Revision
| Drug | Indication | Dose |
|---|---|---|
| Adenosine | SVT termination | 6 mg → 12 mg → 12 mg IV rapid push |
| Amiodarone (IV) | VT, cardiac arrest | 150 mg/10 min; 1 mg/min x6h; 300 mg bolus in VF |
| Lidocaine | VT (especially ischemic) | 1-1.5 mg/kg IV bolus |
| Procainamide | Pre-excited AF, stable VT | 20-50 mg/min, max 17 mg/kg |
| Magnesium | Torsades de Pointes | 1-2 g IV over 5-60 min |
| Verapamil | AVNRT/AVRT | 5-10 mg IV |
| Sacubitril/Valsartan | HFrEF | Start 24/26 mg → target 97/103 mg BD |
HIGH-YIELD EXAM POINTS TO REMEMBER
- AV dissociation + fusion/capture beats = VT (virtually diagnostic)
- Assume VT when unsure - never give verapamil blind to wide QRS tachycardia
- Adenosine contraindicated in pre-excited AF (WPW + AF)
- Neprilysin inhibitor = must combine with ARB (not ACEi) to avoid angioedema
- BNP rises on ARNI - use NT-proBNP to monitor HF in patients on sacubitril/valsartan
- Destination therapy = LVAD as permanent alternative to transplant (not just a bridge)
- TdP management = Magnesium first, stop QT-prolonging drugs, overdrive pacing
- Flecainide/Propafenone CONTRAINDICATED post-MI (CAST trial - increased mortality)
- WPW + AF = most dangerous; risk of VF; treat with Procainamide or DCCS
- PARADIGM-HF: Sacubitril/valsartan reduced CV death + HF hospitalization by 20% vs enalapril
- HeartMate 3 (magnetically levitated centrifugal LVAD) = superior outcomes in MOMENTUM 3
- AVNRT = most common SVT; P wave buried in or just after QRS complex
- Orthodromic AVRT = narrow complex; Antidromic AVRT = wide complex (mimics VT)
- ICD preferred over drugs for secondary prevention of VT/VF (AVID trial)
- Dual AV nodal pathways = substrate for AVNRT (slow + fast pathway)
Sources: Braunwald's Heart Disease (11e), Goldman-Cecil Medicine, Fuster & Hurst's The Heart (15e), Washington Manual of Medical Therapeutics, Goldman-Cecil Medicine - all consulted for these notes.
1. Discuss the approach to a case with broad QRS tachycardia & its management. (20) • 2. Destination therapy in heart failure. (6) • 3. Pathophysiology of acute coronary syndrome with physiology of coagulation. (20) • 4. Discuss physiology of cardiac conduction with special reference to AV node. Discuss pathophysiology & management of SVT. (20) • 5. Discuss approach to broad QRS tachycardia & its management. (20) • 6. Neprilysin inhibitor in heart failure. (6) • 7. Discuss the role of antiarrhythmic drugs in ventricular arrhythmias. (20) • 8. WPW syndrome. (6) Kindly prepare answer for MD medicine final year exam and add flow charts and diagrams and make good notes kindly take Harrison principal of internal medicine and braunwalds heart disease and archit ball or as reference
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MD MEDICINE FINAL YEAR EXAMINATION - COMPREHENSIVE CARDIOLOGY NOTES
References: Harrison's Principles of Internal Medicine 22E (2025) | Braunwald's Heart Disease 12E | Goldman-Cecil Medicine
═══════════════════════════════════════════════════
QUESTION 1 & 5: APPROACH TO BROAD QRS TACHYCARDIA & MANAGEMENT (20 marks)
═══════════════════════════════════════════════════
DEFINITION
- Broad (wide) QRS tachycardia = QRS duration ≥ 120 ms (≥ 0.12 sec) with heart rate > 100 bpm
- Must be distinguished from SVT with aberrancy vs. true ventricular origin
CAUSES - CLASSIFICATION
╔══════════════════════════════════════════════════╗
║ CAUSES OF BROAD QRS TACHYCARDIA ║
╠══════════════════════════════════════════════════╣
║ 1. Ventricular Tachycardia (VT) ← MOST COMMON ║
║ - Monomorphic VT (structural heart disease) ║
║ - Polymorphic VT (ischemia, channelopathy) ║
║ - Bundle branch reentrant VT ║
║ ║
║ 2. SVT with Aberrant Conduction ║
║ - Pre-existing LBBB or RBBB ║
║ - Rate-dependent (tachycardia-induced) BBB ║
║ ║
║ 3. Pre-excited Tachycardia (via Accessory Path) ║
║ - Antidromic AVRT (WPW) ║
║ - Pre-excited AF/flutter (WPW + AF) ║
║ ║
║ 4. Metabolic / Toxic ║
║ - Hyperkalemia (wide, sinusoidal QRS) ║
║ - Tricyclic antidepressant overdose ║
║ - Class IC antiarrhythmic toxicity ║
║ ║
║ 5. Pacemaker-mediated tachycardia ║
╚══════════════════════════════════════════════════╝
"In the presence of known heart disease, VT is the most likely diagnosis of a wide QRS tachycardia, independent of QRS morphology." - Harrison's 22E, Chapter 261
FLOWCHART 1: INITIAL APPROACH TO BROAD QRS TACHYCARDIA
┌─────────────────────────────────────────┐
│ PATIENT WITH BROAD QRS TACHYCARDIA │
│ (QRS ≥120ms, HR >100 bpm) │
└──────────────────┬──────────────────────┘
│
▼
┌──────────────────────┐
│ ASSESS STABILITY │
│ • BP, pulse, GCS │
│ • SpO2, breathing │
└──────────┬───────────┘
│
┌─────────┴──────────┐
│ │
▼ ▼
UNSTABLE STABLE
(Hypotension, (Alert, adequate
syncope, shock, BP, tolerating)
chest pain, HF) │
│ ▼
▼ 12-LEAD ECG + RHYTHM STRIP
IMMEDIATE (while monitoring, IV access,
SYNCHRONIZED O2, pulse oximetry)
DC CARDIOVERSION │
(Biphasic 100-200J ┌─────┴─────────────┐
or Monophasic 200J) │ │
▼ ▼
REGULAR IRREGULAR
wide QRS wide QRS
│ │
┌───────┘ ┌──────┘
│ │
▼ ▼
VT vs SVT+BBB Polymorphic VT /
vs Antidromic Pre-excited AF /
AVRT AF with BBB
│
▼
APPLY CRITERIA
(Brugada/Vereckei/
Harrison algorithm)
DIFFERENTIATING VT FROM SVT WITH ABERRANCY
A. CLINICAL CLUES FAVOURING VT
| Feature | Significance |
|---|---|
| Known structural heart disease (prior MI, DCM) | VT very likely |
| Age >50 with CAD | VT more likely |
| Previous episodes documented as VT | VT |
| Cannon A waves in JVP | AV dissociation → VT |
| Variable S1 intensity | AV dissociation → VT |
| "More sick" despite normal BP | Does NOT exclude VT |
"Hemodynamic stability during the arrhythmia does NOT help distinguish between VT and other mechanisms of wide-complex tachycardia." - Harrison's 22E, Chapter 261
B. BRUGADA CRITERIA (Step-by-Step Algorithm) - Braunwald's Heart Disease
STEP 1: Is RS complex ABSENT in ALL precordial leads?
─────────────────────────────────────────────
YES ──────────► DIAGNOSE VT
│
NO
│
▼
STEP 2: RS interval >100ms in ANY precordial lead?
────────────────────────────────────────────
YES ──────────► DIAGNOSE VT
│
NO
│
▼
STEP 3: AV DISSOCIATION present?
─────────────────────────────────────────────
(P waves ≠ QRS rate; rate of P < rate of QRS)
YES ──────────► DIAGNOSE VT (DEFINITIVE)
│
NO
│
▼
STEP 4: Morphological QRS criteria for VT in V1-V2 AND V6?
─────────────────────────────────────────────────────
YES ──────────► DIAGNOSE VT
│
NO
│
▼
SVT with aberrancy
C. VERECKEI aVR SINGLE-LEAD ALGORITHM (Harrison's 22E)
Step 1: Is there an initial R wave in aVR?
YES → VT
Step 2: Width of initial r or q >40ms in aVR?
YES → VT
Step 3: Notch on descending limb of predominantly negative complex in aVR?
YES → VT
Step 4: Vi/Vt ≤1?
(Vi = initial 40ms voltage; Vt = terminal 40ms voltage)
YES → VT NO → SVT with aberrancy
D. KEY ECG FEATURES
╔══════════════════════════════════════════════════════════════════╗
║ ECG FEATURES STRONGLY FAVOURING VT ║
╠══════════════════════════════════════════════════════════════════╣
║ 1. AV DISSOCIATION (P waves march through QRS) DEFINITIVE ║
║ 2. CAPTURE BEATS (occasional narrow QRS amid wide) DEFINITIVE ║
║ 3. FUSION BEATS (hybrid QRS from partial capture) DEFINITIVE ║
║ 4. QRS width >160 ms (especially LBBB morphology) ║
║ 5. EXTREME AXIS DEVIATION ("northwest" -90° to ±180°) ║
║ 6. CONCORDANCE: all V1-V6 positive OR all negative ║
║ 7. Monophasic R or Rs in aVR ║
║ 8. Morphology INCONSISTENT with typical BBB pattern ║
╠══════════════════════════════════════════════════════════════════╣
║ ECG FEATURES FAVOURING SVT WITH ABERRANCY ║
╠══════════════════════════════════════════════════════════════════╣
║ 1. QRS morphology IDENTICAL to prior sinus rhythm BBB ║
║ 2. Typical RBBB pattern: rSR' in V1 + qRS in V6 ║
║ 3. Typical LBBB pattern: clean downstroke in V1, R in V6 ║
║ 4. Initiation by PAC (P before wide QRS) ║
╚══════════════════════════════════════════════════════════════════╝
FLOWCHART 2: MANAGEMENT OF STABLE BROAD QRS TACHYCARDIA
STABLE BROAD QRS TACHYCARDIA
│
▼
Is rhythm REGULAR or IRREGULAR?
│
┌───────┴───────────┐
│ │
REGULAR IRREGULAR
│ │
▼ ▼
Is it VT or Is it Polymorphic VT
uncertain? (TdP) or Pre-excited AF?
│ │
▼ ┌─────┴──────────────┐
AMIODARONE │ │
150 mg IV/10min TdP Pre-excited AF
→ 1 mg/min x6h │ (WPW + AF)
▼ │
IV Magnesium IV Procainamide
2g over 5-10 min OR Ibutilide
+ Correct K⁺ OR DCCS
+ Stop QT drugs (AVOID adenosine,
+ Overdrive pacing digoxin, CCB)
DRUG DOSES FOR VT MANAGEMENT
| Drug | Dose | Use |
|---|---|---|
| Amiodarone | 150 mg IV over 10 min; then 1 mg/min x6h, then 0.5 mg/min x18h | Stable VT (first line) |
| Lidocaine | 1-1.5 mg/kg IV bolus; 0.5-1.5 mg/kg q5-10min; max 3 mg/kg | Ischemic VT, post-MI |
| Procainamide | 20-50 mg/min IV until effect; max 17 mg/kg; then infusion 1-4 mg/min | Stable VT, pre-excited AF |
| Sotalol | 1.5 mg/kg IV over 5 min | VT with preserved EF |
| Magnesium | 1-2 g IV over 5-60 min, then infusion | Torsades de Pointes |
| Adenosine | 6→12→12 mg rapid IV push | If regular, stable, uncertain rhythm (safe in SVT, diagnostic in VT) |
RULE: Never give Verapamil blindly to wide QRS tachycardia - may cause fatal cardiovascular collapse if VT.
ROLE OF EPS (ELECTROPHYSIOLOGY STUDY)
- H-V interval ≥ normal during SVT (His fires before ventricle)
- H-V interval shorter than normal or unrecordable during VT (retrograde His activation)
- AV nodal reentry = H-V interval equals or exceeds sinus rhythm H-V interval
- Useful to: differentiate aberrant SVT from VT when ECG equivocal, guide catheter ablation
- Braunwald's Heart Disease, Ch. 61
POST-ACUTE LONG-TERM MANAGEMENT
AFTER ACUTE VT EPISODE
│
▼
Identify & treat CAUSE
(ischemia, HF, electrolytes)
│
┌──────┴──────────────────┐
│ │
▼ ▼
STRUCTURAL HEART NO STRUCTURAL
DISEASE HEART DISEASE
│ │
▼ ▼
ICD implant Catheter ablation
(if LVEF≤35%, or antiarrhythmic drugs
NYHA II-III) (beta-blocker/CCB/
+ Beta-blocker flecainide for selected)
± Amiodarone
Consider ablation
for ICD storm
═══════════════════════════════════════════════════
QUESTION 2: DESTINATION THERAPY IN HEART FAILURE (6 marks)
═══════════════════════════════════════════════════
DEFINITION
Destination therapy (DT) = implantation of a permanent Left Ventricular Assist Device (LVAD) as the definitive, long-term treatment for end-stage heart failure in patients who are NOT eligible for cardiac transplantation and have no expectation of recovery.
- "In some centers, as a permanent and definitive alternative to transplantation ('destination therapy')" - Goldman-Cecil Medicine
CONTEXT: THE NEED FOR DESTINATION THERAPY
ADVANCED HEART FAILURE BURDEN
• USA: 6 million HF patients
• ~300,000 have advanced (end-stage) HF eligible for transplant/MCS
• But only ~4,000 donor hearts available per year globally
• → Massive unmet need → Destination therapy fills this gap
SPECTRUM OF MECHANICAL CIRCULATORY SUPPORT (MCS)
┌────────────────────────────────────────────────────────────────────┐
│ SPECTRUM OF LVAD USE │
├──────────────────┬──────────────────────────────────────────────── │
│ │ │
│ SHORT-TERM MCS │ DURABLE (LONG-TERM) MCS │
│ (days to weeks) │ (months to years) │
│ │ │
│ • IABP │ ┌──────────────────────────────────────┐ │
│ • Impella │ │ Bridge to Transplant (BTT) │ │
│ • ECMO │ │ → Patient listed, failing on meds │ │
│ • TandemHeart │ ├──────────────────────────────────────┤ │
│ │ │ Bridge to Candidacy (BTC) │ │
│ Indication: │ │ → Improve to become eligible │ │
│ Cardiogenic │ ├──────────────────────────────────────┤ │
│ shock, acute │ │ Bridge to Recovery (BTR) │ │
│ decompensation │ │ → Rare; myocarditis, peripartum │ │
│ │ ├──────────────────────────────────────┤ │
│ │ │ ★ DESTINATION THERAPY (DT) ★ │ │
│ │ │ → PERMANENT; NOT for transplant │ │
│ │ └──────────────────────────────────────┘ │
└────────────────────────────────────────────────────────────────────┘
PATIENT SELECTION CRITERIA FOR DESTINATION THERAPY
╔═════════════════════════════════════════════════════════╗
║ INDICATIONS FOR DESTINATION THERAPY LVAD ║
╠═════════════════════════════════════════════════════════╣
║ CLINICAL: ║
║ • NYHA Class IIIb - IV symptoms ║
║ • Persistent >2 months despite OPTIMAL medical Rx ║
║ • Inotrope-dependent OR need for short-term MCS ≥7 d ║
║ • ≥3 HF hospitalizations in prior 12 months ║
║ ║
║ FUNCTIONAL: ║
║ • Peak VO₂ <14 mL/kg/min (cardiopulmonary ex test) ║
║ • 6-minute walk distance <300 m ║
║ ║
║ HAEMODYNAMIC: ║
║ • LVEF <25% ║
║ • Elevated filling pressures (PCWP >20 mmHg) ║
║ • Cardiac index <2.0 L/min/m² ║
║ ║
║ TRANSPLANT INELIGIBILITY (any): ║
║ • Fixed severe pulmonary hypertension (PVR >6 WU) ║
║ • Age, obesity, comorbidities ║
║ • Psychosocial contraindications ║
╚═════════════════════════════════════════════════════════╝
DEVICE TYPES & EVOLUTION
| Generation | Device | Type | Flow |
|---|---|---|---|
| 1st | HeartMate XVE | Pulsatile, volume displacement | Pulsatile |
| 2nd | HeartMate II | Continuous axial-flow | Non-pulsatile |
| 3rd | HeartMate 3 | Centrifugal-flow, magnetically levitated | Non-pulsatile |
HeartMate II (Axial Flow) - REMATCH Trial
- First landmark trial proving DT superiority over medical therapy (2001)
- 52% relative risk reduction in mortality vs. optimal medical therapy
- 65% 2-year survival free of stroke/re-surgery (Goldman-Cecil)
HeartMate 3 (MOMENTUM 3 Trial)
- Magnetically levitated centrifugal-flow pump
- Superior outcomes vs. HeartMate II (axial) at 2 years
- Lower rates of pump thrombosis and stroke
- Currently the standard device for DT
FLOWCHART: PATIENT PATHWAY FOR DESTINATION THERAPY
END-STAGE HF PATIENT
│
▼
Advanced HF assessment
(EF, VO2, hemodynamics)
│
▼
Is transplant eligible?
YES NO
│ │
▼ ▼
Bridge to DESTINATION
Transplant THERAPY
(BTT)
│
▼ (DT pathway)
Multidisciplinary team evaluation
(Cardiology, cardiac surgery,
psychology, social work)
│
▼
Exclude contraindications
│
▼
Surgical LVAD implantation
(HeartMate 3 preferred)
│
▼
Outpatient management:
• Anticoagulation (INR 2-3)
• Antiplatelet (aspirin)
• Driveline care
• Regular monitoring
• Surveillance for complications
COMPLICATIONS OF DT-LVAD
LVAD COMPLICATIONS
├── Bleeding (most common)
│ └── GI bleeding (↑ due to acquired von Willebrand deficiency
│ - non-pulsatile shear stress degrades vWF multimers)
│
├── Stroke
│ ├── Ischemic (thromboembolism)
│ └── Hemorrhagic (anticoagulation-related)
│
├── Device Thrombosis
│ └── ↑ risk with sub-therapeutic anticoagulation
│ (HeartMate 3 has less than HeartMate II)
│
├── Driveline Infection
│ └── Most common infectious complication
│ (Staphylococcus - skin organisms)
│
├── Right Heart Failure (early post-implant)
│ └── RV cannot cope after LV unloading
│
└── Hemolysis (lactate dehydrogenase as marker of pump thrombosis)
OUTCOMES
- Goldman-Cecil: "A continuous axial-flow device can provide a 65% 2-year survival free of repeat device surgery or disabling stroke. A newer ventricular magnetically levitated centrifugal-flow pump may provide better short-term and 2-year outcomes."
- DT has transformed end-stage HF from a uniformly fatal condition to a manageable chronic disease
═══════════════════════════════════════════════════
QUESTION 3: PATHOPHYSIOLOGY OF ACS WITH PHYSIOLOGY OF COAGULATION (20 marks)
═══════════════════════════════════════════════════
PART A: PHYSIOLOGY OF COAGULATION (Harrison's 22E, Chapter 69)
THE HAEMOSTATIC RESPONSE
VASCULAR INJURY
│
├──────────────────────────────────────────────┐
│ PRIMARY HAEMOSTASIS │ SECONDARY HAEMOSTASIS
│ (Platelet Plug) │ (Coagulation Cascade)
▼ ▼
Vasoconstriction TISSUE FACTOR
│ exposed on subendothelial
▼ smooth muscle, fibroblasts
Exposed COLLAGEN + + circulating microparticles
von Willebrand Factor (vWF) │
│ ▼
Platelet ADHESION EXTRINSIC PATHWAY
(GPIb ↔ vWF → GPIa ↔ Collagen) TF + VIIa
│ │
▼ ┌─────────┤
Platelet ACTIVATION │ │
• Shape change Xa formation IXa formation
• Granule release │
→ ADP → P2Y12 → more activation │
→ TxA2 → vasoconstriction INTRINSIC PATHWAY
→ Serotonin → vasoconstriction XII → XIIa
│ XI → XIa (also activated by Thrombin)
▼ IX → IXa
Platelet AGGREGATION │
(GPIIb/IIIa ↔ Fibrinogen) ▼
│ COMMON PATHWAY
▼ X → Xa (by TF/VIIa OR IXa/VIIIa)
PLATELET PLUG │ (+ Factor Va, Ca²⁺, PL)
(primary, unstable) ▼
Prothrombin → THROMBIN (IIa)
│
┌────────┴──────────────┐
│ │
▼ ▼
Fibrinogen → Activates V, VIII, XI
Fibrin monomer (amplification loop)
│ Also activates XIII
▼ Also activates Platelets
Cross-linked FIBRIN CLOT
(stable, permanent haemostasis)
COAGULATION DIAGRAM (Harrison's 22E Figure 69-1)
"Coagulation is initiated by tissue factor (TF) exposure, which, with factor (F) VIIa, activates FIX and FX which in turn, with FVIII and FV as cofactors respectively, results in thrombin formation and subsequent conversion of fibrinogen to fibrin. Thrombin activates FXI, FVIII, and FV, amplifying the coagulation signal." - Harrison's 22E
KEY PROCOAGULANT FACTORS
| Factor | Name | Pathway | Activated by |
|---|---|---|---|
| III | Tissue Factor | Extrinsic | Vascular injury |
| VII | Proconvertin | Extrinsic | TF complex |
| VIII | AHF | Intrinsic | Thrombin |
| IX | Christmas Factor | Intrinsic | VIIa/TF or XIa |
| X | Stuart-Prower | Common | IXa/VIIIa or VIIa/TF |
| V | Labile Factor | Common | Thrombin |
| II | Prothrombin | Common | Xa/Va |
| XIII | Fibrin Stabilizer | Final | Thrombin |
ANTITHROMBOTIC MECHANISMS (Harrison's 22E)
ANTITHROMBOTIC CONTROLS
• Endothelial prostacyclin (PGI2) → inhibits platelet activation
• Nitric oxide (NO) → vasodilation + platelet inhibition
• Antithrombin III → inhibits thrombin, Xa, IXa (potentiated by heparin)
• Protein C + S → inactivate Va and VIIIa
• TFPI (Tissue Factor Pathway Inhibitor) → inhibits TF/VIIa/Xa complex
• Fibrinolysis: tPA converts plasminogen → plasmin → lyses fibrin
PART B: PATHOPHYSIOLOGY OF ACS (Harrison's 22E, Chapter 286)
THE UNIFYING CONCEPT: PLAQUE VULNERABILITY
"STEMI usually occurs when coronary blood flow decreases abruptly after a thrombotic occlusion of a coronary artery previously affected by atherosclerosis... STEMI occurs when a coronary artery thrombus develops rapidly at a site of vascular injury." - Harrison's 22E
NORMAL CORONARY ARTERY
│
▼ (decades of risk factors)
┌──────────────────────────────────────────┐
│ RISK FACTORS FOR ATHEROSCLEROSIS │
│ Smoking, HTN, DM, Hyperlipidemia, │
│ Obesity, Family history, Inflammation │
└──────────────────────────────────────────┘
│
▼
STABLE ATHEROSCLEROTIC PLAQUE
(Thick fibrous cap, small lipid core,
minimal inflammation)
│
▼ (triggers: inflammation, shear stress, neovascularization)
VULNERABLE / UNSTABLE PLAQUE
• Rich LIPID CORE (>40% plaque volume)
• THIN FIBROUS CAP (<65 μm thick)
• Abundant MACROPHAGES/FOAM CELLS
• Expansive remodeling
• Intraplaque hemorrhage
• "Spotty" calcification pattern
│
▼ (mechanical or biochemical trigger)
PLAQUE RUPTURE or EROSION
→ Exposes: collagen, lipid core,
tissue factor, vWF
│
├─────────────────────────────────────────────────────┐
│ PLATELET ARM │ COAGULATION ARM
▼ ▼
Collagen/vWF exposure TF exposure at plaque
→ Platelet adhesion (GPIb-vWF) → TF + VIIa complex
→ Platelet activation → Xa and IXa formation
↑ TxA2 (vasoconstriction) → Prothrombin → Thrombin
↑ ADP (P2Y12) → Fibrinogen → Fibrin
GPIIb/IIIa activation │
→ Platelet aggregation │
(fibrinogen crosslinks) │
│ │
└──────────────────────┬─────────────────────────────┘
│
▼
PLATELET-RICH THROMBUS
(white thrombus initially)
+ FIBRIN MESH (red thrombus)
│
┌─────────────┴────────────────┐
│ │
▼ ▼
PARTIAL OCCLUSION COMPLETE OCCLUSION
+ Coronary spasm (sustained, no collateral)
│ │
┌─────────┴──────────┐ ▼
│ │ STEMI
▼ ▼ (Transmural infarction)
Unstable Angina NSTEMI ST elevation → Q waves
(no biomarker rise) (Subendocardial) Troponin markedly elevated
TIMELINE OF MYOCARDIAL ISCHEMIA → NECROSIS
TIME AFTER CORONARY OCCLUSION:
│
├─ 0-20 sec: Loss of aerobic metabolism → ATP falls
│ Contractile dysfunction begins
│
├─ 1-2 min: ECG changes (T-wave hyperacuity)
│
├─ 10-20 min: Reversible cell injury (still salvageable)
│ Na/K ATPase fails → cell swelling
│ Anaerobic glycolysis → lactic acidosis
│
├─ 20-40 min: POINT OF IRREVERSIBILITY begins
│ (if reperfusion not achieved)
│ Mitochondrial dysfunction
│ Membrane integrity lost
│
├─ 40 min-4h: WAVEFRONT PHENOMENON
│ Necrosis spreads: subendocardium → epicardium
│ (subendocardium most vulnerable - farthest from supply)
│
├─ 4-6h: Maximum territory of infarction established
│ Cardiac biomarkers begin rising
│
└─ Days-Weeks: VENTRICULAR REMODELING
Infarct expansion, wall thinning
LV dilation, compensatory hypertrophy
Risk of LV aneurysm, rupture, mitral regurgitation
ACS SPECTRUM & MANAGEMENT PRINCIPLES
ACS SPECTRUM
┌─────────────────────────────────────────────────────────────────┐
│ ACUTE CORONARY SYNDROME │
├──────────────────────┬────────────────────────────────────────── │
│ WITHOUT ST ELEVATION │ WITH ST ELEVATION │
│ (NSTE-ACS) │ (STEMI) │
├──────────────────────┤ │
│ Unstable Angina │ Complete, sustained coronary occlusion │
│ • No biomarker rise │ Transmural ischemia │
│ • ECG: ST ↓, T-inv │ → IMMEDIATE reperfusion │
│ or normal │ 1° PCI < 90 min (door-to-balloon) │
│ │ Thrombolysis if PCI not available │
│ NSTEMI │ (<12h, within 30 min of diagnosis) │
│ • Troponin elevated │ │
│ • ECG: ST ↓, T-inv │ │
└──────────────────────┴──────────────────────────────────────────┘
Antiplatelet & Anticoagulant Therapy (ACS)
ASPIRIN (300-325 mg loading → 75-100 mg daily)
↓ Inhibits COX-1 → ↓ TxA2 production → ↓ platelet aggregation
P2Y12 INHIBITOR (add to aspirin = DAPT)
• Ticagrelor 180 mg → 90 mg BD [PLATO trial: Superior to clopidogrel]
• Prasugrel 60 mg → 10 mg [TRITON TIMI-38: Used in PCI-planned ACS]
• Clopidogrel 300-600 mg → 75 mg [prodrug, variable metabolism]
ANTICOAGULATION
• UFH (weight-based) - standard during PCI
• Enoxaparin 1 mg/kg SC BD - NSTEMI preferred
• Fondaparinux 2.5 mg SC daily (preferred in conservative NSTEMI)
• Bivalirudin (during PCI - direct thrombin inhibitor)
GP IIb/IIIa inhibitors:
• Abciximab, Tirofiban, Eptifibatide
• Block fibrinogen-platelet cross-link
• Used in high-risk ACS at PCI
═══════════════════════════════════════════════════
QUESTION 4: PHYSIOLOGY OF CARDIAC CONDUCTION (SPECIAL REF AV NODE) + SVT (20 marks)
═══════════════════════════════════════════════════
PART A: PHYSIOLOGY OF CARDIAC CONDUCTION SYSTEM
ANATOMY & HIERARCHY
╔═══════════════════════════════════════════════════════════════════╗
║ CARDIAC CONDUCTION SYSTEM ║
╠═══════════════════════════════════════════════════════════════════╣
║ ║
║ SA NODE ──► Internodal tracts ──► AV NODE ──► Bundle of His ║
║ (60-100/min) • Anterior (Bachmann's bundle) │ ──► Left BB ║
║ • Middle (Wenckebach) │ ├ Anterior ║
║ • Posterior (Thorel's) │ └ Posterior ║
║ ──► Right BB ║
║ │ ║
║ ▼ ║
║ Purkinje Fibers ║
║ (20-40/min) ║
║ │ ║
║ ▼ ║
║ Ventricular Myocardium║
╚═══════════════════════════════════════════════════════════════════╝
INTRINSIC PACEMAKER HIERARCHY:
SA Node (60-100) > AV Node (40-60) > His-Purkinje (20-40)
Fastest pacemaker SUPPRESSES slower ones (overdrive suppression)
ACTION POTENTIALS - COMPARISON
FAST RESPONSE (His-Purkinje, Ventricular Myocardium)
Phase 0: Rapid Na⁺ influx (INa) → steep upstroke (+30mV)
Phase 1: Rapid repolarization (Ito - transient outward K⁺)
Phase 2: PLATEAU - L-type Ca²⁺ influx = K⁺ efflux (unique to heart)
Phase 3: Rapid repolarization (IKr, IKs)
Phase 4: FLAT (stable resting potential) = non-pacemaker cells
OR SLOW spontaneous depolarization = pacemaker cells
SLOW RESPONSE (SA Node, AV Node)
Phase 0: Slow Ca²⁺ influx (ICa-L) → gradual upstroke
(NO fast Na⁺ channel → drugs that block Na⁺ don't affect SA/AV)
Phase 3: K⁺ efflux
Phase 4: SPONTANEOUS SLOW DEPOLARIZATION
→ "Funny current" (If - HCN channels, inward Na⁺/K⁺)
→ T-type Ca²⁺ channels
→ Decay of IKr
→ AUTOMATICITY
SPECIAL FOCUS: AV NODE PHYSIOLOGY
Location
- Triangle of Koch (bounded by: tricuspid annulus, Tendon of Todaro, ostium of coronary sinus)
- Compact AV node is ~1 x 3 mm
- Transitional cells connect atrium to compact node
Unique Properties of the AV Node
╔═════════════════════════════════════════════════════════════════╗
║ KEY PROPERTIES OF AV NODE ║
╠═════════════════════════════════════════════════════════════════╣
║ ║
║ 1. DECREMENTAL CONDUCTION ║
║ Faster atrial rate → SLOWER AV conduction ║
║ Protective against rapid ventricular response ║
║ (Unique to AV node; most tissues conduct faster at ↑ rate) ║
║ ║
║ 2. GATE-KEEPING FUNCTION ║
║ Protects ventricles from supraventricular tachyarrhythmias ║
║ (in AF/flutter: limits ventricular rate) ║
║ ║
║ 3. DUAL PATHWAY PHYSIOLOGY ║
║ FAST pathway (β pathway): ║
║ → Fast conduction, LONG effective refractory period (ERP) ║
║ SLOW pathway (α pathway): ║
║ → Slow conduction, SHORT effective refractory period ║
║ → Substrate for AVNRT (most common SVT mechanism) ║
║ ║
║ 4. AUTONOMIC MODULATION ║
║ Vagal tone → ↑ AV delay (↑ PR, AV block) ║
║ Sympathetic → ↓ AV delay, ↑ conduction ║
║ ║
║ 5. BACKUP PACEMAKER (40-60/min) ║
║ If SA node fails, AV node takes over (junctional rhythm) ║
╚═════════════════════════════════════════════════════════════════╝
PR Interval Dissection
PR Interval (120-200ms) Components:
│
├── P wave: Atrial depolarization (80-120 ms)
│
├── PR segment: AV node delay (MAJOR contributor)
│ AV nodal delay accounts for ~100ms of PR interval
│
└── QRS: Ventricular depolarization
His bundle → Bundle branches → Purkinje (~40ms)
H-V interval (normal 35-55ms):
= Time from His deflection to QRS onset
= Bundle of His + Bundle branches + Purkinje conduction time
Blood Supply of AV Node
- Right coronary artery (RCA) in 85-90% of individuals (right dominant)
- Left circumflex in 10-15%
- This explains AV block in inferior MI (RCA territory)
PART B: PATHOPHYSIOLOGY & MANAGEMENT OF SVT
DEFINITION
SVT = any tachycardia (HR>100) arising from or requiring structures above the bundle of His for initiation and maintenance.
"SVTs originate from or are dependent on conduction through the atrium or AV node to the ventricles. Most produce narrow QRS complex tachycardia characteristic of ventricular activation over the Purkinje system." - Harrison's 22E, Chapter 253
CLASSIFICATION OF SVT MECHANISMS
SVT CLASSIFICATION (Harrison's 22E, Table 253-1)
│
├── A. TACHYCARDIAS FROM ATRIUM
│ (Can continue even with AV block)
│ ├── Focal Atrial Tachycardia (FAT)
│ │ Mechanism: Enhanced automaticity or micro-reentry
│ │ Rate: 100-250/min; P wave morphology ≠ sinus
│ │
│ ├── Atrial Flutter
│ │ Mechanism: Macro-reentry (cavotricuspid isthmus, CTI)
│ │ Rate: ~300/min; 2:1 → ventricular 150/min
│ │ ECG: Sawtooth flutter waves (negative in II, III, aVF)
│ │
│ └── Atrial Fibrillation
│ Mechanism: Multiple wavelet reentry + focal triggers (PV)
│ Rate: 350-600 atrial; 100-180 ventricular
│ ECG: Absent P waves, irregular RR, fibrillatory baseline
│
├── B. TACHYCARDIAS REQUIRING AV NODE
│ (Terminate with AV block or adenosine)
│ ├── AVNRT (AV Nodal Reentrant Tachycardia)
│ │ • MOST COMMON PSVT (50-60% of all SVTs)
│ │ • Reentry within AV node (dual pathway)
│ │ • "Typical" form: slow antegrade, fast retrograde
│ │ • Atypical forms: fast down, slow up
│ │
│ └── AVRT (AV Reentrant Tachycardia) - accessory pathway
│ • Orthodromic (narrow): antegrade AV node, retrograde AP
│ • Antidromic (wide): antegrade AP, retrograde AV node
│
└── C. JUNCTIONAL TACHYCARDIA
• Enhanced automaticity of AV node/junction
• Usually post-cardiac surgery (JET)
AVNRT - MECHANISM DIAGRAM (Most Important SVT)
NORMAL SINUS RHYTHM: AVNRT CIRCUIT:
ATRIUM ATRIUM
│ ↑ │
│ Fast path (β) │ │
│ ─────────────► AV NODE ──► │ ↓ Fast path
│ ┌──┤ (retrograde)
│ Slow path (α) │ │
│ ─────────────► AV NODE ──► │ └──► AV NODE
│
INITIATION BY PAC: │
• PAC finds fast path REFRACTORY └──────► Ventricle
• Conducts DOWN SLOW PATH (long PR) ↑ (narrow QRS)
• Fast path has RECOVERED by then
• Impulse goes UP FAST PATH (retrograde)
• Returns to atrium AND back down slow path
• CIRCUS MOVEMENT established
ECG: P wave buried IN QRS (typical AVNRT)
Or P wave just AFTER QRS (pseudo-S in inferior leads)
RP interval < PR interval
FLOWCHART: SVT MANAGEMENT (Harrison's 22E + Braunwald's)
SVT - CONFIRMED (HR >100, usually narrow QRS)
│
▼
HEMODYNAMICALLY STABLE?
│
┌─────────┴──────────┐
│ │
NO YES
│ │
▼ ▼
SYNCHRONISED CONTINUOUS ECG MONITORING
DC CARDIOVERSION 12-lead ECG while treated
50-100 J (sync) │
▼
VAGAL MANEUVERS (first)
• Valsalva maneuver
(patient pushes against closed glottis)
→ Modified Valsalva: lie flat, legs elevated after
• Carotid sinus massage
(check: no bruit, no stroke history, >35y)
• Ice-cold water to face (diving reflex)
│
Terminates? ───── YES ─► Observe, 12-lead ECG
│
NO
│
▼
IV ADENOSINE (drug of choice)
6 mg rapid IV push + 20 mL saline flush
→ 12 mg if no response (wait 1-2 min)
→ 12 mg again if still no response
(half-life: 10 seconds → very brief)
│
Terminates? ── YES ─► Likely AVNRT/AVRT
│
NO
│
┌──────────┴────────────────────┐
│ │
▼ ▼
Regular SVT continues Atrial Flutter/
(not terminated by Adenosine) AT exposed by
│ AV block on adenosine
▼
IV VERAPAMIL 5-10 mg over 2 min
OR IV DILTIAZEM 0.25 mg/kg over 2 min
OR IV METOPROLOL 5 mg (x3 doses)
│
▼
If still resistant:
Synchronised DC cardioversion
"Intravenous adenosine will terminate the vast majority of PSVT episodes by transiently blocking conduction in the AV node." - Harrison's 22E
"Adenosine precipitates AF, which is usually brief, in up to 15% of patients, so it should be used cautiously in patients with WPW syndrome in whom AF may produce hemodynamic instability." - Harrison's 22E
LONG-TERM MANAGEMENT OF SVT
RECURRENT SVT
│
├── CATHETER ABLATION (preferred for most)
│ • Curative >95% success (AVNRT/AVRT)
│ • Radiofrequency energy → ablate slow pathway (AVNRT)
│ or accessory pathway (AVRT/WPW)
│ • Risk: AV block (<1% for AVNRT, higher septal AP)
│ • First-line for:
│ - Symptomatic, frequent episodes
│ - Patient preference
│ - Athletes, pilots
│
└── PHARMACOTHERAPY (if ablation declined or not feasible)
• Beta-blockers: Metoprolol, Atenolol (safest)
• Non-DHP CCB: Verapamil, Diltiazem
• Flecainide/Propafenone: "pill in the pocket"
(normal LV function ONLY)
• Digoxin: NOT in WPW (accelerates AP)
═══════════════════════════════════════════════════
QUESTION 6: NEPRILYSIN INHIBITOR IN HEART FAILURE (6 marks)
═══════════════════════════════════════════════════
WHAT IS NEPRILYSIN?
Neprilysin (Neutral Endopeptidase-24.11, NEP, CD10) is a zinc-dependent metalloendopeptidase enzyme on cell surfaces, highly expressed in kidney, lung, heart, and brain.
Substrates degraded by neprilysin:
NEPRILYSIN SUBSTRATES:
• Natriuretic peptides: ANP, BNP, CNP ← MOST IMPORTANT
• Bradykinin
• Adrenomedullin
• Angiotensin I & II
• Substance P
• Enkephalins
PATHOPHYSIOLOGICAL RATIONALE
HEART FAILURE NEUROHORMONAL ACTIVATION
│
├─── RAAS Activation ───────────────────────────────┐
│ AngII → vasoconstriction, Na retention │
│ Aldosterone → volume overload, fibrosis │
│ │
└─── Natriuretic Peptide System (Compensatory) ─────┘
↑ ANP (atrial stretch) → vasodilation,
↑ BNP (ventricular stress) → natriuresis,
anti-fibrosis, anti-hypertrophy
│
▼ (DEGRADED BY NEPRILYSIN)
Effects BLUNTED in HF
│
▼
NEPRILYSIN INHIBITION
→ ↑ ANP, ↑ BNP, ↑ Bradykinin, ↑ Adrenomedullin
→ ↑ Vasodilation
→ ↑ Natriuresis, ↓ fluid overload
→ ↑ Anti-fibrotic, anti-hypertrophic effects
BUT...
Neprilysin also degrades AngII
→ Inhibiting NEP alone = ↑ AngII = vasoconstriction
→ Counteracts benefit!
WHY ARNI (NOT JUST NEPi ALONE)?
PROBLEM 1: Neprilysin degrades AngII
→ NEP inhibitor alone → ↑ AngII
→ Counteracts vasodilatory benefit
SOLUTION: Block RAAS simultaneously
→ Add Angiotensin Receptor Blocker (ARB = Valsartan)
→ Sacubitril (NEPi prodrug) + Valsartan = ARNI
PROBLEM 2: Why not ACE inhibitor + NEPi?
Both ACE AND Neprilysin degrade BRADYKININ
→ Combined inhibition → ↑↑↑ Bradykinin
→ Very high risk of ANGIOEDEMA (life-threatening)
→ Therefore: ARNI uses ARB (not ACEi)!
THE RULE: ARNI = Sacubitril/Valsartan (NEVER with ACEi)
SACUBITRIL/VALSARTAN (ENTRESTO) - COMPLETE PROFILE
PHARMACOLOGY:
• Trade name: Entresto
• Sacubitril = prodrug → LBQ657 (active NEP inhibitor)
• Valsartan = ARB (blocks AT1 receptor)
• Combined molecule: LCZ696
• Doses available: 24/26mg, 49/51mg, 97/103mg (sacubitril/valsartan)
• Target dose: 97/103 mg TWICE DAILY
MECHANISM:
Sacubitril (NEPi): ↑ ANP, BNP, bradykinin, adrenomedullin
→ natriuresis, vasodilation, ↓ fibrosis
Valsartan (ARB): ↓ AngII effects, ↓ aldosterone
→ ↓ vasoconstriction, ↓ Na retention
PARADIGM-HF TRIAL (Key Evidence)
PARADIGM-HF TRIAL
• 8,442 patients with HFrEF (LVEF ≤40%), NYHA II-IV
• Stable, on ACEi/ARB + BB
• Randomized: Sacubitril/Valsartan 97/103mg BD
vs. Enalapril 10mg BD
PRIMARY ENDPOINT (CV death OR HF hospitalization):
• ARNI: 21.8% vs. Enalapril: 26.5%
• 20% RELATIVE RISK REDUCTION (P<0.001)
• Trial stopped early (ARNI clearly superior)
SECONDARY OUTCOMES:
• ↓ All-cause mortality (17% RRR)
• ↓ CV mortality (20% RRR)
• ↓ HF hospitalization (21% RRR)
• ↓ Worsening renal function
• ↓ Hyperkalemia
• Improved symptoms, quality of life (KCCQ)
SIDE EFFECTS (vs Enalapril):
Sacubitril/Valsartan: More hypotension, slightly more angioedema
LESS renal dysfunction, LESS hyperkalemia, LESS cough
STARTING SACUBITRIL/VALSARTAN - PRACTICAL GUIDE (Goldman-Cecil)
PATIENT ON ACE INHIBITOR?
│
YES │ NO (on ARB or nothing)
│ │
▼ ▼
36-HOUR WASHOUT Start directly
(MANDATORY - (or switch from ARB directly)
prevent
angioedema)
│
▼
START LOW DOSE: 24/26 mg BD
(especially if SBP 95-110 mmHg or elderly)
│
▼
TITRATE every 2-4 weeks as tolerated
│
▼
TARGET DOSE: 97/103 mg BD
Contraindications
| Contraindication | Reason |
|---|---|
| History of angioedema | ↑ risk with neprilysin inhibition |
| Concurrent ACE inhibitor | ↑↑ bradykinin → angioedema |
| SBP <95 mmHg | Hypotension risk |
| Severe hepatic impairment | Impaired sacubitril metabolism |
| Pregnancy | Teratogenic (like all RAAS agents) |
| Hereditary angioedema | Absolute contraindication |
MONITORING TIP (HIGH-YIELD EXAM POINT)
KEY POINT:
Neprilysin inhibition INCREASES BNP levels
(BNP is a neprilysin substrate → degradation impaired)
BUT does NOT increase NT-proBNP
(NT-proBNP is NOT a neprilysin substrate)
THEREFORE:
In patients on ARNI/Sacubitril-Valsartan:
→ BNP is unreliable as HF severity marker
→ Use NT-proBNP to monitor disease progression
(Source: Goldman-Cecil Medicine)
CURRENT POSITION IN HF GUIDELINES (2022 ESC, 2022 AHA/ACC)
HFrEF TREATMENT (LVEF ≤40%) - "FANTASTIC FOUR"
1. ACEi/ARB or ★ ARNI (Sacubitril/Valsartan) - Class I
2. Beta-blocker - Class I
3. MRA (Spironolactone/Eplerenone) - Class I
4. SGLT2 inhibitor (Dapagliflozin/Empagliflozin) - Class I
ARNI preferred OVER ACEi/ARB in eligible patients
(SBP >95, not on concurrent ACEi, no angioedema history)
═══════════════════════════════════════════════════
QUESTION 7: ROLE OF ANTIARRHYTHMIC DRUGS IN VENTRICULAR ARRHYTHMIAS (20 marks)
═══════════════════════════════════════════════════
VAUGHAN-WILLIAMS CLASSIFICATION
╔═══════════════════════════════════════════════════════════════════════╗
║ VAUGHAN-WILLIAMS CLASSIFICATION OF ANTIARRHYTHMICS ║
╠═══════════════╦═══════════════════════════════════════════════════════╣
║ CLASS ║ MECHANISM & DRUGS ║
╠═══════════════╬═══════════════════════════════════════════════════════╣
║ IA ║ Na⁺ channel block (INTERMEDIATE) + ↑APD (K⁺ block) ║
║ (Moderate ║ → Slows phase 0 + prolongs QT ║
║ Na+ block) ║ Drugs: Quinidine, Procainamide, Disopyramide ║
║ ║ Side effects: TdP (↑QT), SLE (procainamide), ║
║ ║ cinchonism (quinidine) ║
╠═══════════════╬═══════════════════════════════════════════════════════╣
║ IB ║ Na⁺ channel block (WEAK) + ↓APD ║
║ (Weak block) ║ → Minimal QRS/QT change; use-dependent ║
║ ║ Drugs: Lidocaine (IV), Mexiletine (oral), Phenytoin ║
║ ║ Use: Post-MI VT, digitalis toxicity ║
╠═══════════════╬═══════════════════════════════════════════════════════╣
║ IC ║ Na⁺ channel block (STRONG) + no APD change ║
║ (Strong block)║ → Marked QRS widening; potent slowing ║
║ ║ Drugs: Flecainide, Propafenone ║
║ ║ ⚠ CAST TRIAL: ↑ Mortality post-MI ║
║ ║ Use ONLY in structurally NORMAL hearts ║
╠═══════════════╬═══════════════════════════════════════════════════════╣
║ II ║ Beta-adrenergic blockade ║
║ ║ → ↓ Automaticity, ↓ conduction, ↓ HR ║
║ ║ Drugs: Metoprolol, Carvedilol, Propranolol, Nadolol ║
║ ║ ★ ONLY antiarrhythmics proven to ↓ SCD post-MI ║
║ ║ ★ First-line for most VAs (Harrison's 22E) ║
╠═══════════════╬═══════════════════════════════════════════════════════╣
║ III ║ K⁺ channel block → ↑APD → ↑QT → ↑ERP ║
║ ║ Drugs: Amiodarone*, Sotalol*, Dofetilide, Ibutilide ║
║ ║ * Also have other class effects ║
╠═══════════════╬═══════════════════════════════════════════════════════╣
║ IV ║ Ca²⁺ channel block (Non-DHP) ║
║ ║ → ↓ AV conduction; ↓ automaticity (SA/AV node) ║
║ ║ Drugs: Verapamil, Diltiazem ║
║ ║ For VAs: Only ILVT (idiopathic LV tachycardia) ║
╚═══════════════╩═══════════════════════════════════════════════════════╝
AMIODARONE - THE MOST IMPORTANT ANTIARRHYTHMIC (DETAILED)
"Amiodarone has properties of all four classes of antiarrhythmic drugs: sodium channel blockade (class I), β-blockade (class II), potassium channel blockade (class III), and calcium channel blockade (class IV)."
AMIODARONE - PHARMACOLOGICAL PROFILE
─────────────────────────────────────
Class: Multi-class (I+II+III+IV)
Predominant effect: Class III (K+ block, ↑ APD, ↑ ERP)
ACUTE (IV) DOSE:
• Stable VT: 150 mg over 10 min, then 1 mg/min x 6h, then 0.5 mg/min x 18h
Can repeat 150 mg bolus for VT recurrence
• Cardiac arrest VF/pulseless VT: 300 mg IV push (may repeat 150 mg)
CHRONIC (ORAL) DOSE:
• Loading: 400-800 mg/day x 4 weeks (to saturate tissues)
• Maintenance: 100-400 mg/day
PHARMACOKINETICS:
• t½: 40-55 DAYS (longest of any antiarrhythmic - lipophilic)
• Volume of distribution: 59 L/kg (massive tissue accumulation)
• Organs: fat, lung, liver, muscle, thyroid
• Oral bioavailability: 30-50% (variable)
• Onset (oral): weeks to months (due to tissue loading)
• Clearance: hepatic (NOT renal) → safe in renal failure
ELECTROPHYSIOLOGICAL EFFECTS:
• Prolongs QT interval (but low TdP risk - unlike sotalol)
• Slows sinus rate
• Prolongs PR interval
• Widens QRS slightly
• Reduces automaticity
• Reduces VF threshold
Amiodarone Side Effects (CRITICAL for exam)
ORGAN TOXICITY OF AMIODARONE:
┌─────────────────────────────────────────────────────────────────┐
│ PULMONARY (1-5%) │
│ • Pulmonary fibrosis/pneumonitis │
│ • Most feared (irreversible, can be fatal) │
│ • Diagnosis: CXR, HRCT, PFTs (↓ DLCO), Ga-67 scan │
│ • Annual CXR recommended │
├─────────────────────────────────────────────────────────────────┤
│ THYROID (15-20%) │
│ • Hypothyroidism (most common, esp. in iodine-replete areas) │
│ • Hyperthyroidism (Type 1: Jod-Basedow; Type 2: destructive) │
│ • Contains 37% iodine by weight → iodine load │
│ • Monitor TFTs every 6 months │
├─────────────────────────────────────────────────────────────────┤
│ HEPATIC (1-3%) │
│ • Elevated LFTs (common, usually mild) │
│ • Cirrhosis (rare but serious) │
│ • "Pseudoalcoholic hepatitis" on biopsy │
│ • Monitor LFTs every 6 months │
├─────────────────────────────────────────────────────────────────┤
│ OCULAR │
│ • Corneal microdeposits (ALMOST UNIVERSAL - not sight-threatening)│
│ • Optic neuropathy (rare, sight-threatening - STOP drug) │
│ • Annual slit-lamp exam │
├─────────────────────────────────────────────────────────────────┤
│ SKIN │
│ • Photosensitivity (blue-grey discolouration - melanin deposition)│
│ • Sunscreen essential │
├─────────────────────────────────────────────────────────────────┤
│ NEUROLOGICAL │
│ • Peripheral neuropathy │
│ • Tremor, ataxia │
│ • Sleep disturbance │
├─────────────────────────────────────────────────────────────────┤
│ CARDIAC (LOW but present) │
│ • QT prolongation (low TdP risk vs class IA) │
│ • Bradycardia, AV block │
│ • Proarrhythmia is LOW despite QT prolongation (unique) │
└─────────────────────────────────────────────────────────────────┘
DRUG INTERACTIONS:
• ↑ Digoxin levels (halve digoxin dose)
• ↑ Warfarin effect (halve warfarin dose, monitor INR)
• Inhibits CYP2D6, CYP3A4, CYP1A2
• Risk of QT prolongation with other QT drugs
DRUG USE BY SPECIFIC VA SCENARIO
FLOWCHART: Antiarrhythmic Drug Selection
VENTRICULAR ARRHYTHMIA
│
├────────── CARDIAC ARREST (VF/Pulseless VT)
│ CPR + Defibrillation (FIRST)
│ Then: Amiodarone 300 mg IV push
│ (Lidocaine 1-1.5 mg/kg if amiodarone unavailable)
│
├────────── STABLE MONOMORPHIC VT (Structural Heart Disease)
│ 1st: Amiodarone 150 mg IV / 10 min
│ 2nd: Lidocaine 1-1.5 mg/kg IV
│ 3rd: Procainamide 20-50 mg/min (max 17 mg/kg)
│ 4th: Sotalol 1.5 mg/kg IV (if normal EF)
│
├────────── TORSADES DE POINTES (TdP)
│ 1st: IV Magnesium 2g over 5-10 min
│ 2nd: Correct K⁺ (target >4.5 mEq/L)
│ 3rd: Withdraw QT-prolonging drugs
│ 4th: Overdrive pacing (90-120 bpm)
│ 5th: Isoproterenol (bradycardia-dependent TdP)
│ AVOID: Amiodarone, sotalol, IA drugs
│
├────────── IDIOPATHIC LVOT/RVOT VT (Normal Heart)
│ Beta-blockers (1st line)
│ Verapamil (RVOT VT also)
│ Flecainide/Propafenone (normal LV only)
│ Catheter ablation (curative, preferred)
│
├────────── IDIOPATHIC LV VT (ILVT / Belhassen's VT)
│ LBBB + LAHB pattern (origin: left posterior fascicle)
│ Verapamil SENSITIVE (unique!)
│ Verapamil 5-10 mg IV for acute termination
│
├────────── CATECHOLAMINERGIC POLYMORPHIC VT (CPVT)
│ Beta-blockers (Nadolol preferred)
│ Flecainide (add-on)
│ ICD + beta-blocker (high-risk)
│
└────────── BRUGADA SYNDROME VT/VF
Quinidine (class IA) - only effective drug
Cilostazol (PDE inhibitor)
ICD (definitive)
AVOID: Na-channel blockers, fever
KEY CLINICAL TRIALS (Must Know)
| Trial | Drug | Condition | Finding |
|---|---|---|---|
| CAST | Flecainide/Encainide | Post-MI PVCs | ↑ Mortality - class IC proarrhythmia → STOPPED |
| AVID | Amiodarone vs ICD | Post VF/hemodynamic VT | ICD superior (28% ↓ mortality) |
| MADIT-II | ICD | Post-MI, EF ≤30% | ICD ↓ SCD (primary prevention) |
| SCD-HeFT | Amiodarone vs ICD vs Placebo | HF, EF ≤35% | ICD ↓ death; Amiodarone = Placebo |
| VANISH | Catheter ablation vs amiodarone escalation | ICD storm, scar VT | Ablation superior to drug escalation |
PROARRHYTHMIA - IMPORTANT CONCEPT
DRUG-INDUCED PROARRHYTHMIA
│
├── Class IA & III → ↑ QT → TORSADES DE POINTES
│ Risk factors: Hypokalemia, hypomagnesemia, bradycardia, female sex
│ Drugs: Quinidine (quinidine syncope), Sotalol, Dofetilide
│
├── Class IC → use-dependent Na block → INCESSANT VT
│ (CAST trial: flecainide ↑ mortality post-MI)
│ Mechanism: Slow reentry → sustained VT
│
├── ALL antiarrhythmics → Bradycardia, AV block
│ (especially in elderly, existing conduction disease)
│
└── Amiodarone → LOW proarrhythmic risk (despite ↑QT)
Due to: Homogeneous APD prolongation (no dispersion)
═══════════════════════════════════════════════════
QUESTION 8: WPW SYNDROME (6 marks)
═══════════════════════════════════════════════════
DEFINITION
Wolff-Parkinson-White (WPW) Syndrome = pre-excitation syndrome caused by an accessory atrioventricular pathway (Bundle of Kent) that conducts antegrade (from atrium to ventricle), bypassing the AV node, causing pre-excitation on ECG and associated paroxysmal tachyarrhythmias.
"WPW syndrome is defined as a preexcited QRS during sinus rhythm and episodes of PSVT." - Harrison's 22E, Chapter 256
ANATOMY & EMBRYOLOGY
NORMAL:
Fibrous AV annulus completely separates atria from ventricles
→ Electrical isolation except through AV node
WPW:
FAILURE of complete AV ring partitioning during development
→ Accessory muscle bundle (Bundle of Kent) persists
→ Provides extra electrical connection bypassing AV node
→ Present from BIRTH (not acquired)
LOCATIONS (frequency):
• Left free wall (45-50%) → Most common
• Posteroseptal (25-30%)
• Right free wall (15-20%)
• Anteroseptal (5-10%)
ECG DIAGNOSIS - WPW PATTERN
WPW DIAGNOSTIC TRIAD ON ECG:
┌─────────────────────────────────────────────────────────────────┐
│ 1. SHORT PR interval (<120 ms, <0.12 sec) │
│ Impulse reaches ventricle EARLY via accessory pathway │
│ (No AV node delay) │
│ │
│ 2. DELTA WAVE (slurred initial upstroke of QRS) │
│ Slow cell-to-cell conduction in ventricular myocardium │
│ (AP bypasses fast Purkinje system) │
│ QRS = fusion of AP conduction + normal AV node conduction │
│ │
│ 3. WIDE QRS complex (>120 ms, >0.12 sec) │
│ Due to: Delta wave + AP conduction component │
│ │
│ 4. Secondary ST-T changes │
│ Consequence of abnormal depolarisation direction │
│ │
│ ⚠ WPW PATTERN = above ECG findings (may be asymptomatic) │
│ ⚠ WPW SYNDROME = WPW pattern + episodes of SVT │
└─────────────────────────────────────────────────────────────────┘
DIAGRAM: PATHWAY LOCATIONS & ECG MORPHOLOGY
ECG LOCALISATION OF ACCESSORY PATHWAY:
(Harrison's 22E, Chapter 256)
RIGHT FREE WALL pathway:
→ Preexcites RIGHT ventricle
→ LBBB-like pattern in V1 (right activation first)
→ Often MARKED preexcitation (AP near sinus node)
LEFT FREE WALL pathway:
→ Preexcites LEFT ventricle
→ RBBB-like pattern in V1
→ Negative delta wave in aVL (mimics lateral Q waves)
→ May have MINIMAL preexcitation (AP far from sinus node)
POSTEROSEPTAL pathway:
→ Negative delta waves in III, aVF
→ Mimics inferior wall MI Q waves
TACHYARRHYTHMIAS IN WPW
FLOWCHART: Three Main Arrhythmias
WPW TACHYARRHYTHMIAS
│
├─ 1. ORTHODROMIC AVRT (70-80% of WPW tachycardias)
│ • Most common
│ • ANTEGRADE: Atrium → AV node → His-Purkinje → Ventricle
│ • RETROGRADE: Ventricle → Accessory Pathway → Atrium
│ • RESULT: Narrow QRS (normal ventricular activation)
│ (QRS may be wide IF retrograde AP + rate-dependent BBB)
│ • HR: 150-250/min, REGULAR
│ • ECG: Narrow QRS, P wave IN ST segment (retrograde P)
│ • RP interval < PR interval
│
├─ 2. ANTIDROMIC AVRT (5-10% of WPW tachycardias)
│ • ANTEGRADE: Atrium → Accessory Pathway → Ventricle
│ • RETROGRADE: Ventricle → AV node → Atrium
│ • RESULT: WIDE QRS (entirely via AP → abnormal activation)
│ • MIMICS VENTRICULAR TACHYCARDIA on ECG!
│ • HR: 150-250/min, REGULAR
│ • Distinguish from VT: QRS morphology = maximal delta wave
│ (QRS same as fully preexcited sinus rhythm)
│
└─ 3. PRE-EXCITED ATRIAL FIBRILLATION (most dangerous!)
• AF conducts via BOTH AP and AV node
• AP has NO decremental conduction, SHORT refractory period
• If AP ERP <250 ms: Very rapid conduction (250-300+ bpm!)
• RESULT: IRREGULAR wide QRS, varying morphology
(intermittently narrow when conducted via AV node)
• RISK: VT → VF → SUDDEN CARDIAC DEATH
• Precipitated by: Adenosine or digoxin given to "control rate"!
→ These block AV node → ALL conduction via AP → VF!
ECG COMPARISON TABLE
| Feature | Orthodromic AVRT | Antidromic AVRT | Pre-excited AF |
|---|---|---|---|
| QRS | Narrow (usually) | Wide | Wide, varying |
| Rhythm | Regular | Regular | Irregular |
| P wave | Retrograde (in ST) | Retrograde | Absent (fibrillation) |
| Rate | 150-250 | 150-250 | 200-300+ |
| Risk | Low | Moderate | HIGH (VF risk) |
MANAGEMENT
Acute Management
ACUTE WPW TACHYARRHYTHMIA
│
ASSESS QRS
│
┌────┴──────────────┐
│ │
NARROW QRS WIDE, IRREGULAR QRS
(Orthodromic AVRT) (Pre-excited AF/Antidromic)
│ │
▼ ▼
HEMODYNAMICALLY HEMODYNAMICALLY
STABLE? STABLE?
YES NO YES NO
│ │ │ │
▼ ▼ ▼ ▼
Vagal Sync DCCS ★PROCAINAMIDE Sync DCCS
maneuvers 50-100J IV (1st choice) 200J
│ OR IBUTILIDE (immediate)
▼ (↑ AP ERP,
Adenosine ↓ AP conduction)
6→12→12 mg │
│ ▼
▼ Expert consultation
IV Verapamil/ (may need DCCS)
Diltiazem
(if adenosine fails) ★★ NEVER GIVE:
Adenosine, Digoxin,
Verapamil, Diltiazem
→ ↓ AV node conduction
→ ↑ AP conduction
→ PRECIPITATE VF → DEATH
"Very irregular wide-complex tachycardia is most likely preexcited AF or flutter and should be managed with cardioversion, intravenous procainamide, or ibutilide." - Harrison's 22E
RISK STRATIFICATION FOR SUDDEN CARDIAC DEATH
HIGH RISK FEATURES IN WPW (must identify):
• Shortest RR interval in pre-excited AF < 250 ms
(very rapid AP conduction → VF risk)
• Multiple accessory pathways
• Symptomatic tachycardias (syncope, palpitations)
• Accessory pathway ERP < 270 ms on EPS
• Antidromic AVRT (suggests AP used aggressively)
• Occupation: pilot, professional athlete
(risk of syncope during activity)
RISK ASSESSMENT:
• Exercise stress test: loss of preexcitation = long ERP = low risk
• EPS: measure accessory pathway ERP, induce AF, measure shortest RR
• EPS mandatory before certain high-risk occupations
DEFINITIVE TREATMENT - CATHETER ABLATION
CATHETER ABLATION (RADIOFREQUENCY)
• Success rate: >95% (left free wall AP: highest)
• Recurrence: <5%
• Procedure: Map earliest ventricular activation during sinus rhythm
Deliver RF energy at AP insertion site
Abolish delta wave
• Complications:
- AV block: <0.5% (left free wall AP) to 5% (anteroseptal AP)
(caution with septal pathways near His bundle!)
- Cardiac tamponade, vascular access complications (<1%)
INDICATIONS FOR ABLATION:
• All symptomatic WPW syndrome (PSVT, syncope)
• Pre-excited AF or antidromic AVRT
• Asymptomatic WPW with high-risk features on EPS
• High-risk occupations (pilots, athletes, military)
• Patient preference (to avoid lifelong medications)
INDICATIONS FOR LONG-TERM DRUGS (if ablation declined):
• Flecainide/Propafenone: slow AP conduction (normal heart only)
• Amiodarone: effective for AP and AV node
• Beta-blockers: modest effect (slow AV node, not AP)
• AVOID as monotherapy: Digoxin, Verapamil, Diltiazem
(accelerate AP by blocking AV node → dangerous in pre-excited AF)
═══════════════════════════════════════════════════
QUICK REVISION: HIGH-YIELD EXAM SUMMARY TABLE
═══════════════════════════════════════════════════
MNEMONIC CARDS
WIDE QRS TACHYCARDIA - "VT until proven otherwise"
CAUSES mnemonic: "VISA WP"
V = Ventricular Tachycardia (most common)
I = Idioventricular / bundle branch reentry
S = SVT with aberrancy (pre-existing BBB)
A = Accessory pathway (WPW)
W = Wolff-Parkinson-White pre-excited AF
P = Pacemaker-mediated / pharmacological (TCA, hyperK)
VT ECG DIAGNOSIS mnemonic: "AV-CF-M"
A = AV dissociation (definitive)
V = V1-V6 Concordance
C = Capture beats
F = Fusion beats
M = Morphology inconsistent with BBB
AMIODARONE TOXICITY mnemonic: "PLTH-CS"
P = Pulmonary (fibrosis/pneumonitis)
L = Liver (hepatotoxicity)
T = Thyroid (hypo or hyperthyroid)
H = Hypersensitivity / skin (blue-grey, photosensitivity)
C = Corneal microdeposits
S = Sinus bradycardia / AV block
MASTER DOSE TABLE
| Drug | Indication | IV Dose | Oral Dose |
|---|---|---|---|
| Adenosine | SVT, diagnostic | 6→12→12 mg rapid push | N/A |
| Amiodarone | VT, VF, cardiac arrest | 150 mg/10min; 1mg/min x6h; 300mg bolus VF | Load 400-800 mg/d x4wk; maint 100-400 mg/d |
| Lidocaine | VT (ischemic) | 1-1.5 mg/kg bolus; 0.5-1.5 mg/kg q5-10min | N/A |
| Procainamide | VT, pre-excited AF | 20-50 mg/min; max 17 mg/kg; then 1-4 mg/min | - |
| Magnesium | Torsades de Pointes | 1-2 g over 5-60 min | - |
| Verapamil | SVT, ILVT | 5-10 mg IV over 2 min | 40-120 mg TID |
| Sotalol | VT (preserved EF) | 1.5 mg/kg over 5 min | 80-160 mg BD |
| Sacubitril/Valsartan | HFrEF | N/A | Start 24/26 mg BD → target 97/103 mg BD |
| Metoprolol | VT, SVT, HF | 5 mg IV x3 doses | 25-200 mg BD |
EXAM TIPS - DO NOT MISS THESE POINTS
★ NEVER give Verapamil for wide QRS tachycardia (assume VT)
★ NEVER give Adenosine/Digoxin/Verapamil for wide irregular QRS (pre-excited AF)
★ Hemodynamic stability DOES NOT exclude VT (Harrison's)
★ AV dissociation = DIAGNOSTIC of VT (most specific ECG sign)
★ Flecainide CONTRAINDICATED after MI (CAST trial)
★ BNP rises in patients on ARNI → use NT-proBNP instead
★ Sacubitril/Valsartan: 36-hour washout from ACEi mandatory
★ HeartMate 3 (centrifugal-flow) > HeartMate II (axial) in MOMENTUM 3
★ WPW ablation success >95%; risk of AV block with septal pathways
★ Amiodarone: longest t½ (40-55 days); check THYROID, LUNG, LIVER
★ Dual pathway physiology of AV node = substrate for AVNRT
★ Primary prevention ICD: LVEF ≤35% + NYHA II-III on optimal therapy
★ PARADIGM-HF: 20% RRR in CV death/HF hospitalization with ARNI vs enalapril
★ TdP: Magnesium FIRST, then overdrive pacing, then isoproterenol
★ Destination therapy = PERMANENT LVAD for transplant-ineligible end-stage HF
References: Harrison's Principles of Internal Medicine 22nd Edition (2025), Braunwald's Heart Disease 12th Edition, Goldman-Cecil Medicine International Edition - all consulted directly from textbook database.
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