Hypertrophic cardiomyopathy (HCM)

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy without an identifiable cause (e.g. hypertension, aortic stenosis).

It is an autosomal dominant disorder with variable penetrance, most commonly caused by mutations in contractile sarcomeric proteins (e.g. beta myosin heavy chain and myosin binding protein C) of the cardiomyocytes.

Pathophysiology:-
a. Diastolic dysfunction (due to increased left ventricular thickness that decreases cavity of the left ventricle and hence compliance of the left ventricle; Also impairs relaxation of the left ventricle).
b. Left ventricular outflow tract obstruction in 2/3rd of the cases (i.e. narrowed tract 2° to hypertrophied septum and systolic anterior motion (SAM) of anterior MV leaflet towards the hypertrophied septum (i.e. venturi effect); The obstruction is dynamic (i.e. Also known as dynamic left ventricular dysfunction).
c. Mitral regurgitation (due to SAM of anterior leaflet of mitral valve towards the hypertrophied septum).
d. Myocardial ischemia.
e. Syncope.

Histologic shows extreme cardiomyocyte hypertrophy with exaggerated myocyte branching, myocyte disarray, and interstitial fibrosis. 

Figure:- Pathophysiology of Hypertrophic Cardiomyopathy (Pathophysiology of Heart Disease, Sixth Edition)

Clinical features:-

1. Dyspnea

2. Angina

3. Syncope

4. Sudden cardiac death (SCD) in high risk patients

Physical examination:-

a. Harsh, crescendo-decrescendo systolic murmur heard best at LLSB. Murmur intensity decreases with increased preload or venous return (e.g. squatting, lying supine) and increased afterload or SVR (e.g. handgrip) whereas murmur intensity increases with decreased preload or venous return (e.g. Valsalva, standing) and decreased afterload or SVR (e.g. vasodilators).

b. Pulsus Bisferiens.

c. S4 (+).

d. Holosystolic murmur of MR at apex (due to SAM of anterior leaflet of mitral valve towards the hypertrophied septum causing MR).

Diagnosis:-

1. Chest X-ray shows LVH.

2. ECG shows VT/VFib, AFib, LVH, Deep Q waves in inferior leads (II, III, aVF) and lateral leads (I, aVL, V5-V6), diffuse T-wave inversions.

3. Echocardiography shows LV wall thickness >15mm, asymmetric wall thickness (due to hypertrophy of interventricular septum), decreased diameter of ventricular lumen, systolic anterior motion of anterior leaflet of mitral valve towards the hypertrophied septum; Doppler echocardiography shows left ventricular outflow tract obstruction, dynamic outflow tract obstruction, and mitral regurgitation.

4. Cardiac MRI detects fibrosis (i.e. late gadolinium enhancement).

5. Genetic testing is recommended for 1st degree relatives.

6. Cardiac catheterization.

7. Holter monitoring.

Treatment:-
1. Screen all 1st degree relatives with genetic testing or cardiac imaging.
2. Counsel the patients to avoid dehydration, medications (e.g. inotropes, vasodilators), competitive sports and strenuous activity.
3. Medical therapy includes:-

1. Beta blockers (e.g. metoprolol) reduces heart rate, contractility and LVOT gradient.

2. Non-dihydropyridine CCBs (e.g. verapamil, diltiazem) improves diastolic filling, reduces heart rate and contractility. 

3. Disopyramide (Class Ia antiarrhythmic)is combined with beta blockers for refractory symptoms. It possesses negative inotropic and antiarrhythmic properties.

4. Cardiac myosin inhibitor (e.g. mavacametan) is indicated in symptomatic obstructive HCM (NYHA Class II-III) as it reduces contractility and LVOT obstruction. Monitor LVEF as it increases risk of systolic dysfunction (VALOR-HCM trial). Mavacamten significantly reduces septal reduction therapy eligibility and improves symptoms in obstructive HCM but needs regular LVEF monitoring as it increases risk of systolic dysfunction.

4. Surgical management (If symptoms are refractory to adequate medical therapy or significant LVOT obstruction i.e. ≥ 50 mmHg despite adequate medical therapy):-

1. Surgical myectomy.

2. Alcohol septal ablation.

Indications of Implantable Cardioverter Defibrillator (ICD) in HCM:-

1. Personal history of SCD or VT.

2. Family history of SCD in 1st degree relative.

3. Unexplained Syncope.

4. Massive (>30mm) LVH.

5. Repetitive NSVT or failure to augment SBP by 20 mmHg with exercise.

6. Late gadolinium enhancement on Cardiac MRI.

Unstable angina

Vignette says a 50 year old male presents to the emergency department with chief complaints of acute onset chest pain, that started 30 minutes ago; The pain is  sudden in onset, substernal, tight, and crushing in nature, severe in intensity with radiation to the left arm, jaw and neck; He also reports of shortness of breath, diaphoresis and vomiting;  He has a history of hypertension, diabetes mellitus and hyperlipidemia, but is not compliant with his medication; He is active smoker and drinks alcohol occasionally; The patient appears anxious; Vital signs show blood pressure of 130/90 mm of Hg, pulse rate of 98 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 97.9 F; ECG shows ST-segment depression in the anterior leads (V1-V4) and T-wave inversion; Cardiac troponins are negative; Echocardiography is normal; Diagnosis?

Diagnosis is Unstable angina.

Pathogenesis of unstable angina involves formation of nonocclusive thrombus over disrupted atherosclerotic plaques (MCC); Other mechanisms are coronary artery vasospasm, oxygen supply demand imbalance, and gradual narrowing of an epicardial coronary artery caused by progressive atherosclerosis or restenosis after stenting.

 

Presents with chest pain or heaviness or tightness with radiation to the left arm, jaw and neck, SOB, diaphoresis, nausea, vomiting.

 

Diagnosis:-

1. ECG shows ST depression and/or T-wave inversion.

2. Cardiac biomarkers (e.g. CK-MB, troponins) are negative.

3. Echocardiography is often normal in unstable angina.

4. Coronary angiography 

 

TIMI scores:-

1. Age > 65 years 

2. ≥ 3 risk factors for CAD 

3. Known stenosis > 50% % by prior angiography

4. ASA < 7 days 

5 ≥ 2 episodes of retrosternal chest pain within 24 hours

6. ST depression ≥ 0.5 mm 7) 

7. Elevated serum troponin or CK-MB

Early invasive strategy is deployed if the TIMI score ≥ 3; the patient is managed with urgent coronary revascularization. 

Conservative approach is deployed if the TIMI score is 0-1; the patient is managed with medical therapy.

 

Management:-

1. Oxygen supply to maintain saturation >90%. 

2. Anti ischemic therapy (e.g. nitrates, beta blockers, CCBs).

3. Anti platelet therapy (e.g. aspirin, P2Y12 inhibitors, GPIIb/IIIa inhibitors).

4. Anticoagulants therapy (e.g. UFH, LMWH).

5. Adjunctive therapy (e.g. statins, ACE inhibitors).

6. Percutaneous coronary intervention (PCI).

REMEMBER THROMBOLYTICS ARE CONTRAINDICATED IN UNSTABLE ANGINA.

Wellens syndrome

Vignette says a 50 year old male presents to the emergency department with an episode of chest pain induced by excretion 1 hour back, currently he doesn't complain of chest pain; He has a history of hypertension for which he takes amlodipine; Vital signs show blood pressure of 130/80 mm of Hg, pulse rate of 88 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 98% in RA and temperature of 96.9 F; ECG shows biphasic T wave in lead V2; Cardiac biomarkers (i.e. troponins) are normal; Diagnosis?

Diagnosis is a type A wellens syndrome.

Wellens syndrome is characterized by biphasic T waves or deeply inverted T waves in leads V2-V3, that is highly specific for critical stenosis of the proximal left anterior descending coronary artery, usually pain free at presentation to the emergency department with normal or mild elevated cardiac biomarkers; Require immediate percutaneous coronary intervention (PCI) to relive the occlusion.

 Figure:- ECG showing biphasic T wave in lead V2 suggestive of type A wellens syndrome.

Thrombotic thrombocytopenic purpura (TTP)

Vignette says a 35 year old female presents with a 3 day history of fatigue, headaches and confusion; She also reports small purple spots on her legs; On examination, she has pallor, petechiae on her legs, and mild jaundice; Vital signs show blood pressure of 130/80 mm of Hg, pulse rate of 98 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 99.9 F; Examination shows pale bulbar conjunctiva and palms; Laboratory studies show hemoglobin of 8.0 mg/dL, platelet count of 30K, LDH of 600 U/L (normal range is 135-225 U/L), serum creatinine levels of 1.8 (normal range is 0.7-1.3 mg/dL), indirect bilirubin of 1.8 mg/dL (normal range is 0.2 to 0.8 mg/dL) and low haptoglobin levels; PBS shows schistocytes; Coombs test is negative; ADAMTS13 assay activity is decreased (i.e. <10% of ADAMTS13 activity; Diagnosis?

Diagnosis is Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia
(MAHA) characterized by the pentad of fever, hemolytic anemia, thrombocytopenia, and
renal and neurologic dysfunction.

Pathophysiology:- Inhibition or deficiency of ADAMTS13 activity (a protease that cleaves von Willebrand factor); It leads to decreased degradation of large vWF multimers; persistence of large vWF multimers on the endothelial surface causes platelet adhesion, aggregation and subsequent thrombus formation.

Clinical features:-
1. MAHA
2. Thrombocytopenia
3. Acute renal failure
4. Altered mental status
5. Fever

Diagnosis:-
1. CBC shows decreased platelet count, decreased hemoglobin, increased reticulocyte count.
2. Coagulation profile shows normal PT and aPTT.
3. PBS analysis shows schistocytes (>2–3/hpf).
4. Increased LDH, increased indirect bilirubin, decreased haptoglobin, Coombs negative
hemolytic anemia.
5. Deranged RFT.
6. ADAMTS13 assay detects auto antibody against ADAMTS13.
7. ADAMTS13 assay activity is decreased (i.e. <10% of ADAMTS13 activity).

Treatment:-
1. Plasmapheresis and high dose steroids are the mainstay of therapy.
2. Rituximab (i.e. Anti-CD20 monoclonal antibody).
3. No platelet transfusions (may cause thrombus formation).
4. Splenectomy if refractory to plasmapheresis & steroids.

Wolff parkinson white syndrome

Vignette says a 25 year old male presents to the emergency department with sudden onset of palpitations that started 30 minutes back while he was exercising; He also reports of lightheadedness, chest discomfort and shortness of breath; There is no significant medical history; Vital signs show blood pressure of 110/70 mm of Hg, pulse rate of 158 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 98% in RA and temperature of 96.9 F; Examination findings are normal; ECG shows short PR interval (<120ms), prolonged QRS complex (> 120ms) and delta wave (a slurred upstroke on the QRS complex); Diagnosis?

Diagnosis is Wolff parkinson white syndrome with supraventricular tachycardia.

Wolff parkinson white syndrome (WPW) is characterized by preexcitation of the ventricles via the accessory pathway between atria and the ventricles; WPW syndrome is characterized by the presence of abnormal accessory electrical pathway between atria and ventricle (i.e. bundle of kent); The ECG findings of wolff parkinson white syndrome are short PR interval (<120ms), prolonged QRS complex (> 120ms) and delta wave (a slurred upstroke on the QRS complex). 

Patients with WPW syndrome are predisposed to PSVTs as the accessory electrical pathway provides a potential path for a reentrant loop and may present as:- 

1. Orthodromic Atrioventricular Reentrant Tachycardia 

2. Antidromic Atrioventricular Reentrant Tachycardia 

Accessory pathway also acts as a path when the patient has concurrent AFib, as the refractory periods of the accessory pathway are less; Thus, during AFib, it may result in fast ventricular rates. ECG shows atrial fibrillation with rapid ventricular rates (>250/min) with a wide QRS complex.

Treatment:- 

1. Orthodromic AVNRT (i.e. Presents as a narrow complex SVT) is treated with vagal maneuvers (e.g. carotid massage, modified valsalva maneuver) and AV nodal blocking agents (e.g. adenosine, beta-blocker, calcium channel blocker).

2. Antidromic AVNRT (i.e. Presents as a wide complex SVT) is treated with anti arrhythmics (e.g. procainamide is DOC in antidromic AVNRT).

3. If a patient has atrial fibrillation with rapid ventricular response then procainamide and ibutilide are agents of choice. AV nodal blocking agents (e.g. adenosine, beta-blocker, calcium channel blocker) are contraindicated; Beta blockers, calcium channel blockers adenosine reduces conduction through the AV node and promotes conduction through the accessory pathway. Therefore, they are contraindicated in patients with WPW syndrome patients who develop atrial fibrillation or flutter.

4. Radiofrequency ablation of the accessory pathway is the definitive treatment.

5. DC cardioversion in hemodynamically unstable patients.

Figure:- ECG finding of Wolff-parkinson white syndrome

Acute Gout

Vignette says a 48 year old male presents to his primary case physician with sudden onset pain in his great toe of left foot for 24 hours; He describes pain sharp and severe, preventing him to bear weight and carry out his daily activities; He has a history of hypertension for which he takes losartan and hydrochlorothiazide; He doesn’t smoke but drinks alcohol regularly; Examination shows swollen tender first metatarsophalangeal joint of left foot; Laboratory studies show normal serum levels of uric acid; Synovial fluid analysis shows needle shaped negatively birefringent shaped crystals; X-ray of foot is normal; Diagnosis?

Diagnosis is acute attack of gout.

Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in joints; Risk factors are male sex, hypertension, obesity, diabetes, dyslipidemia, alcohol use; ♂ > ♀ (9:1); peak incidence in 5th decade of life.

Causes:-

1. Overproduction of uric acid (10%):- Idiopathic, Increased turnover of cells (e.g. cancer, hemolysis, psoriasis, chemotherapy), Enzyme deficiency (e.g. Lesch-Nyhan syndrome, glycogen storage disease i.e. von gierke disease), Ethanol.

2. Underexcretion of uric acid (90%):- Renal insufficiency, Ketoacidosis or lactic acidosis, drugs like thiazides, aspirin.

Diagnosis:-

1. CBC shows leukocytosis (predominantly neutrophilic leukocytosis) and inflammatory markers (i.e. ESR, CRP) are elevated during acute attacks.

2. Elevated serum uric acid levels; It is 25% normal during acute attacks.

3. Aspiration of the joint and analysis of synovial fluid, shows needle shaped and negatively birefringent urate crystals.

4. X-ray is normal in early disease; erosions of cortical bone with overhanging margins is present in later disease. 

Acute management:-

1. NSAIDs (1st line of therapy) includes indomethacin, naproxen; Avoid Aspirin (as it inhibits uric acid excretion).

2. Colchicine (2nd line of therapy); side effects are nausea or vomiting, abdominal cramps, and severe diarrhea.

3. Oral prednisone if the patient does not respond to or cannot tolerate NSAIDs and colchicine.

Chronic management:-

Management between attacks prevents recurrences.

1. Fluids, weight loss, less intake of purine rich foods (alcohol, red meat,organ meat, and seafood) and avoid fasting. 

2. Xanthine oxidase inhibitors (e.g. allopurinol, febuxostat) decrease uric acid production in the body.

3. Recombinant urate oxidase (e.g. pegloticase, rasburicase) dissolves uric acid into allantoin and increases its excretion in urine.

4. Uricosuric (e.g. probenecid and sulfinpyrazone) increases uric acid excretion in the kidney.