Cardiac Excitability — Context and Related Syndromes

1. Possible Interpretations

2. Cardiac Channelopathies (Most Likely Intended Concept)

Key Channelopathies

3. Pathophysiology of Cardiac Excitability

• Phase 0 (rapid depolarization): Na⁺ influx via SCN5A-encoded channels
• Phase 1–3 (repolarization): K⁺ efflux, Ca²⁺ dynamics
• Phase 4 (automaticity in pacemaker cells): Funny current (If), Ca²⁺ influx

• Resting membrane potential is less negative (closer to threshold)
• Threshold potential is lowered
• Refractory period is shortened
• Early or delayed afterdepolarizations (EADs/DADs) occur

4. Could You Mean Something Else?

• A term used in a particular curriculum or country
• A synonym for hyperkinetic heart syndrome (hyperdynamic circulation with palpitations, anxiety, tachycardia)
• A colloquial or translated term for autonomic cardiac dysregulation

Bottom Line

Cardiac Excitability Disorders

Classification

1. Long QT Syndrome (LQTS)

Pathophysiology

• Gain-of-function mutations in inward currents (INa — SCN5A → LQT3)
• Loss-of-function mutations in outward K⁺ currents (IKs — KCNQ1 → LQT1; IKr — KCNH2 → LQT2)

Key Subtypes

Diagnosis

• QTc ≥ 480 ms (symptomatic) or ≥ 500 ms (asymptomatic) is diagnostic
• Schwartz score incorporates ECG findings, symptoms, and family history
• Genetic testing confirms diagnosis and enables family screening

Management

• Avoid QT-prolonging drugs (critical for all types)
• Beta-blockers (nadolol or propranolol) — first-line, especially LQT1 and LQT2
• Mexiletine — adjunct in LQT3 (reduces late INa)
• ICD — for survivors of cardiac arrest or refractory symptoms
• Left cardiac sympathetic denervation (LCSD) — for recurrent events despite beta-blockade

2. Brugada Syndrome (BrS)

Pathophysiology

Diagnosis

• Type 1 Brugada pattern: Coved ST elevation ≥ 2 mm in ≥ 1 right precordial lead (V1-V2), spontaneous or unmasked by Na⁺ channel blockers (ajmaline, flecainide)
• ECG is dynamic — fever, vagal tone, and certain drugs can unmask the pattern

Precipitants

• Fever (most common)
• Large meals, alcohol
• QT-prolonging / Na⁺ channel-blocking drugs
• Rest/sleep (vagal predominance)

Management

• Avoid triggers (antipyretics promptly for fever)
• ICD — only proven therapy for high-risk patients (prior cardiac arrest, spontaneous Type 1 ECG + symptoms)
• Quinidine — reduces Ito, used for electrical storms or as ICD adjunct
• Risk stratification remains controversial for asymptomatic patients with spontaneous Type 1 pattern

3. Catecholaminergic Polymorphic VT (CPVT)

Pathophysiology

• RYR2 (ryanodine receptor, autosomal dominant) — most common
• CASQ2 (calsequestrin, autosomal recessive)

Diagnosis

• Normal resting ECG and cardiac structure
• Exercise stress test or adrenaline infusion provokes characteristic bidirectional VT
• Genetic testing (RYR2 positive in ~60%)

Management

• Beta-blockers (nadolol preferred) — cornerstone; must not be discontinued
• Flecainide — adjunct, reduces RyR2-mediated Ca²⁺ leak
• ICD — for cardiac arrest survivors; risk of ICD shocks triggering storms
• LCSD — effective adjunct in refractory cases
• Strict avoidance of competitive sports

4. Short QT Syndrome (SQTS)

Pathophysiology

Diagnosis

• QTc ≤ 340 ms is diagnostic; ≤ 360 ms suspicious with symptoms/family history
• Tall, narrow, symmetric T waves; very short or absent ST segment

Management

• ICD — recommended for symptomatic patients
• Quinidine — prolongs QT, effective pharmacological option (especially when ICD declined)
• Hydroquinidine also used

5. Early Repolarization Syndrome (ERS)

Pathophysiology

Diagnosis

• J-wave (≥ 1 mm J-point elevation) with horizontal/descending ST segment in ≥ 2 inferior or lateral leads
• Distinguished from benign early repolarization by arrhythmic events or family history of SCD

Management

• ICD for survivors of VF
• Isoproterenol/quinidine for electrical storms
• Risk stratification in incidentally found J-waves remains challenging

6. Andersen-Tawil Syndrome (ATS / LQT7)

• KCNJ2 (Kir2.1) loss-of-function
• Triad: periodic paralysis, dysmorphic features, ventricular arrhythmias (bidirectional VT — resembles CPVT)
• QU prolongation rather than true QTc prolongation
• Management: acetazolamide for paralysis; beta-blockers and flecainide for arrhythmias

Shared Management Principles

Genetic Testing Strategy

• Panel-based next-generation sequencing is standard
• Positive yield varies: ~75% in LQTS, ~60% in CPVT, ~20% in BrS, ~20% in SQTS
• Variants of uncertain significance (VUS) are common — require careful interpretation
• Genotype-negative diagnosis remains valid when clinical criteria are met

Cardiac Conduction Disorders

Anatomy of the Conduction System

SA Node → Internodal pathways → AV Node → Bundle of His
         → Right Bundle Branch (RBB) → Right ventricle
         → Left Bundle Branch (LBB)
               → Left Anterior Fascicle (LAF)
               → Left Posterior Fascicle (LPF)
                     → Purkinje fibers → Ventricular myocardium

Classification

1. Sinus Node Dysfunction (SND) / Sick Sinus Syndrome (SSS)

Definition

Subtypes

• Sinus bradycardia — rate < 60 bpm, often benign
• Sinus arrest / SA exit block — pause in P-wave activity
• Tachy-brady syndrome — alternating atrial tachyarrhythmias (AF/flutter) and bradycardia
• Chronotropic incompetence — failure to increase HR appropriately with exercise

Etiology

• Intrinsic: Fibrosis/degeneration (most common in elderly), ischemia (RCA territory), cardiomyopathy, infiltrative diseases (amyloidosis, sarcoidosis), myocarditis, post-cardiac surgery
• Extrinsic: Beta-blockers, Ca²⁺ channel blockers, digoxin, antiarrhythmics (amiodarone), hypothyroidism, hypothermia, raised intracranial pressure, obstructive sleep apnea

Clinical Features

ECG Findings

• Sinus pauses > 2–3 seconds
• Sinus bradycardia
• SA exit block (Wenckebach or 2:1 pattern of P-wave dropout)
• AF with slow ventricular response (without AV nodal drugs)

Management

• Treat reversible causes first
• Permanent pacemaker — indicated for symptomatic bradycardia or pauses
  • AAI(R) pacing if AV conduction intact
  • DDD(R) if concurrent AV node disease
• Rate-responsive pacing for chronotropic incompetence
• Antiarrhythmics ± pacemaker for tachy-brady syndrome

2. Atrioventricular (AV) Block

First-Degree AV Block

• PR interval > 200 ms; all P waves conduct
• Usually benign; rarely causes symptoms
• Causes: increased vagal tone (athletes), inferior MI, digoxin, beta-blockers, AV nodal disease
• No pacemaker needed unless symptomatic (rare, "pacemaker syndrome" with very long PR)

Second-Degree AV Block

Mobitz Type I (Wenckebach)

• Progressive PR prolongation → dropped QRS → cycle repeats
• Level: AV node (supranodal)
• Causes: inferior MI, high vagal tone, drugs
• Usually benign; pacemaker only if symptomatic

Mobitz Type II

• Constant PR interval → sudden dropped QRS (no warning)
• Level: infranodal (His bundle or bundle branches)
• Wide QRS common
• High risk of progression to complete heart block
• Pacemaker indicated even if asymptomatic

2:1 AV Block

• Cannot classify as Mobitz I or II from surface ECG alone
• Wide QRS → likely Mobitz II (infranodal); narrow QRS → likely Mobitz I
• Requires EP study if uncertain; pacemaker usually indicated

High-Grade AV Block

• ≥ 2 consecutive non-conducted P waves
• Treated as complete heart block until proven otherwise

Third-Degree (Complete) AV Block

• Complete dissociation between atria and ventricles
• Escape rhythm maintains circulation:
  • Junctional escape (40–60 bpm, narrow QRS) — block at AV node
  • Ventricular escape (20–40 bpm, wide QRS) — infranodal block (less reliable, more dangerous)
• Causes: fibrosis/degeneration, inferior/anterior MI, Lyme disease, sarcoidosis, post-AVR surgery, congenital

3. Bundle Branch and Fascicular Blocks

Right Bundle Branch Block (RBBB)

• QRS ≥ 120 ms; RSR' ("M pattern") in V1; wide S wave in I, V5–V6
• Can be normal variant or associated with RV disease, PE, ASD, ischemia
• Isolated RBBB — no pacemaker needed; evaluate for underlying cause

Left Bundle Branch Block (LBBB)

• QRS ≥ 120 ms; broad monophasic R in I, aVL, V5–V6; absence of septal Q waves
• Never a normal variant — always warrants investigation
• Associated with: CAD, cardiomyopathy, hypertension, aortic valve disease
• Causes dyssynchrony → can precipitate or worsen heart failure
• CRT (cardiac resynchronization therapy) indicated in HFrEF (EF ≤ 35%) with LBBB and QRS ≥ 150 ms

Fascicular Blocks

Bifascicular Block

• RBBB + LAFB (most common) or RBBB + LPFB
• Risk of progression to complete heart block is low (~1–2%/year) but increases with symptoms
• Pacemaker: indicated if syncope or documented high-grade block

Trifascicular Block

• Bifascicular block + 1st-degree AV block (PR prolongation)
• Implies disease in all three fascicles
• Higher risk of complete heart block — pacemaker considered

4. Inherited Conduction Disorders

Pacemaker Indications Summary

Key Investigations

• 12-lead ECG — first-line; defines block type and level
• Holter/ambulatory monitoring — for intermittent symptoms
• Exercise stress test — chronotropic incompetence, rate-dependent block
• Echocardiography — structural disease, LBBB evaluation
• Electrophysiology (EP) study — His-Purkinje conduction (HV interval), infranodal disease
• Genetic testing — family history of conduction disease or cardiomyopathy
• MRI/biopsy — infiltrative causes (amyloid, sarcoid)

Typical Manifestations of Cardiovascular System Dysfunction & Compensation Mechanisms

PART I — TYPICAL MANIFESTATIONS OF CARDIOVASCULAR DYSFUNCTION

1. Low cardiac output → inadequate tissue perfusion
2. Elevated filling pressures → congestion (pulmonary and/or systemic)

A. Symptoms

1. Dyspnea (Breathlessness)

2. Fatigue and Exercise Intolerance

• Weakness
• Early muscle fatigue
• Cognitive slowing (cerebral hypoperfusion)

3. Edema

• Begins in the ankles/feet (gravity-dependent)
• Progresses to legs, thighs, genitalia, abdominal wall
• Ascites — fluid in peritoneal cavity (right HF, constrictive pericarditis)
• Anasarca — massive generalized edema in severe disease
• Pleural effusions — usually right-sided or bilateral; causes dyspnea

4. Palpitations

• Compensatory tachycardia
• Atrial fibrillation (most common arrhythmia in HF)
• Ventricular ectopy
• Neurohormonal activation (catecholamine excess)

5. Chest Pain / Angina

• Reflects myocardial ischemia (reduced coronary perfusion pressure or elevated wall tension)
• Present when HF results from or coexists with coronary artery disease

6. Nocturia

7. Gastrointestinal Symptoms

8. Cyanosis

• Central cyanosis: V/Q mismatch, reduced SaO₂ (pulmonary edema, congenital heart disease with right-to-left shunt)
• Peripheral cyanosis: increased O₂ extraction due to slow capillary flow in low output states

9. Syncope / Presyncope

• Arrhythmias (VT, complete heart block, SSS)
• Severe outflow obstruction (critical aortic stenosis, HOCM)
• Vasovagal or orthostatic hypotension
• Cardiac tamponade

B. Signs

Left-Sided Dysfunction

Right-Sided Dysfunction

C. Manifestations by Syndrome

PART II — COMPENSATION MECHANISMS

1. Frank-Starling Mechanism (Preload Compensation)

• When venous return (preload) increases, the ventricle is stretched
• Increased sarcomere length → greater actin-myosin overlap → increased force of contraction
• Result: stroke volume increases to match increased filling

2. Neurohormonal Activation

A. Sympathetic Nervous System (SNS)

• ↑ Heart rate (positive chronotropy)
• ↑ Contractility (positive inotropy) via β₁-adrenoceptor stimulation
• Vasoconstriction (↑ afterload) — maintains BP and perfuses vital organs
• Venoconstriction → ↑ venous return → augments preload

B. Renin-Angiotensin-Aldosterone System (RAAS)

C. Antidiuretic Hormone (ADH / Vasopressin)

• Released in response to low cardiac output and Ang II
• Promotes free water retention → dilutional hyponatremia in severe HF
• Vasoconstriction via V1 receptors

D. Natriuretic Peptides (Counter-regulatory)

• ANP (atrial) and BNP (ventricular) released in response to wall stretch
• Promote natriuresis, diuresis, vasodilation, and inhibit RAAS
• Biomarkers of HF severity (BNP, NT-proBNP)
• This system is overwhelmed in advanced HF

3. Ventricular Hypertrophy and Remodeling

A. Concentric Hypertrophy (Pressure Overload — e.g., Hypertension, Aortic Stenosis)

• Sarcomeres added in parallel → increased wall thickness
• Wall stress (Laplace): σ = Pr/2h — thicker wall (h↑) reduces wall stress
• Initially adaptive: normalizes wall stress, maintains contractility
• Maladaptive: reduced compliance → diastolic dysfunction; impaired coronary flow

B. Eccentric Hypertrophy (Volume Overload — e.g., MR, AR, DCM)

• Sarcomeres added in series → elongated myocytes → ventricular dilatation
• Increased cavity volume → preserves stroke volume via Frank-Starling
• Maladaptive: progressive dilatation → spherical geometry → further MR, wall stress, systolic dysfunction

Pathological Remodeling Features:

• Myocyte apoptosis and necrosis
• Interstitial fibrosis (collagen deposition)
• Fetal gene re-expression (β-MHC, ANP)
• Mitochondrial dysfunction
• Ca²⁺ handling abnormalities (reduced SERCA2a activity)

4. Summary Table: Compensatory Mechanisms

5. The Vicious Cycle of Decompensation

Myocardial Injury
      ↓
↓ Cardiac Output
      ↓
SNS + RAAS + ADH activation
      ↓
↑ HR, vasoconstriction, Na⁺/H₂O retention
      ↓
↑ Wall stress, volume overload, neurohormonal toxicity
      ↓
Further myocardial damage and remodeling
      ↓
Progressive HF → Decompensation