The diagnosis is symptomatic obstructive hypertrophic cardiomyopathy with resting left ventricular outflow tract obstruction.
The exertional syncope, premature sudden death in the patient's father, and myocardial fibrosis on cardiac MRI require comprehensive sudden cardiac death risk stratification. These findings should not automatically be interpreted as establishing a definite high-risk category or an automatic indication for an implantable cardioverter-defibrillator.
1. Definition
Hypertrophic cardiomyopathy, or HCM, is a myocardial disorder characterized predominantly by increased left ventricular wall thickness that is not explained solely by another cardiac, systemic, or metabolic condition capable of producing the observed magnitude of hypertrophy.
In adults, HCM is generally diagnosed when the maximal end-diastolic left ventricular wall thickness is 15 mm or greater in the absence of another sufficient cause.
A wall thickness of 13 to 14 mm requires additional supporting features, such as:
1. A family history of HCM
2. A pathogenic or likely pathogenic HCM-associated genetic variant
3. Characteristic ECG abnormalities
4. Other supportive clinical or imaging findings
Obstructive HCM is present when dynamic left ventricular outflow tract obstruction is demonstrated, usually through the interaction of septal hypertrophy and systolic anterior motion of the mitral valve.
2. Etiology and Genetics
1. HCM is frequently a genetic myocardial disease.
2. When caused by a pathogenic sarcomeric variant, inheritance is typically autosomal dominant with age-dependent and variable penetrance.
3. Disease-causing variants are identified in approximately:
o 30% of apparently sporadic cases
o 60% of familial cases
4. The most commonly implicated genes are:
o MYBPC3, encoding cardiac myosin-binding protein C
o MYH7, encoding beta-myosin heavy chain
5. Other established sarcomeric genes include:
o TNNT2
o TNNI3
o TPM1
o ACTC1
o MYL2
o MYL3
6. A substantial proportion of clinically diagnosed patients have no currently identifiable pathogenic variant.
7. Conditions that may mimic HCM include:
o Fabry disease
o Danon disease
o Cardiac amyloidosis
o Glycogen storage disorders
o RASopathies
o Mitochondrial disorders
Secondary causes of left ventricular hypertrophy, including hypertension and aortic stenosis, should also be considered and excluded when appropriate.
3. Pathophysiology
3.1 Myocardial Hypertrophy
Sarcomeric dysfunction and myocardial remodeling produce increased ventricular wall thickness, often involving the interventricular septum.
The hypertrophied myocardium is frequently stiff and poorly compliant.
3.2 Diastolic Dysfunction
Diastolic dysfunction results from:
1. Impaired myocardial relaxation
2. Increased ventricular stiffness
3. Myocardial hypertrophy
4. Interstitial and replacement fibrosis
Consequences include:
1. Elevated left ventricular filling pressures
2. Exertional dyspnea
3. Reduced exercise tolerance
4. Left atrial enlargement in some patients
3.3 Dynamic Left Ventricular Outflow Tract Obstruction
Dynamic LVOT obstruction typically results from the interaction between:
1. Septal hypertrophy
2. Systolic anterior motion of the mitral valve
During systole, the anterior mitral leaflet moves toward the hypertrophied septum, narrowing the outflow tract.
An LVOT peak instantaneous gradient of 30 mmHg or greater at rest or with physiologic provocation defines obstruction.
A resting or provoked gradient of 50 mmHg or greater is clinically important and represents the conventional hemodynamic threshold used when considering advanced therapy, particularly septal reduction therapy in an appropriately symptomatic patient.
A gradient of 50 mmHg or greater does not by itself mandate intervention.
3.4 Dynamic Nature of LVOT Obstruction
LVOT obstruction generally increases with:
1. Reduced preload
2. Reduced afterload
3. Increased myocardial contractility
4. Tachycardia
Examples include:
1. Standing
2. Valsalva maneuver
3. Dehydration
Obstruction generally decreases with:
1. Increased preload
2. Increased afterload
3. Reduced myocardial contractility
3.5 Mitral Regurgitation
Systolic anterior motion can impair mitral leaflet coaptation and produce mitral regurgitation.
3.6 Myocardial Ischemia
Myocardial ischemia may occur even without obstructive epicardial coronary artery disease because of:
1. Increased myocardial oxygen demand
2. Reduced coronary flow reserve
3. Coronary microvascular dysfunction
4. Increased intramyocardial pressure
5. Reduced diastolic perfusion time during tachycardia
3.7 Myocardial Fibrosis and Arrhythmias
Myocyte disarray and myocardial fibrosis create an arrhythmogenic substrate.
Clinically important arrhythmias include:
1. Atrial fibrillation
2. Nonsustained ventricular tachycardia
3. Sustained ventricular tachycardia
4. Ventricular fibrillation
Ventricular tachyarrhythmias are an important mechanism of sudden cardiac death in HCM.
4. Clinical Features
4.1 Common Symptoms
1. Exertional dyspnea
2. Chest pain
3. Palpitations
4. Fatigue
5. Reduced exercise tolerance
6. Presyncope
7. Syncope
Some patients are asymptomatic and are identified through family screening, abnormal ECG findings, cardiac imaging, or detection of a murmur.
4.2 Syncope
Syncope in HCM has several potential mechanisms, including:
1. Ventricular arrhythmia
2. Dynamic LVOT obstruction
3. Abnormal vascular response to exercise
4. Supraventricular tachyarrhythmia
5. Vasovagal mechanisms
For sudden cardiac death risk assessment, particular concern is attached to recent unexplained syncope suspected to be arrhythmic and not clearly attributable to vasovagal mechanisms or LVOT obstruction.
Therefore, this patient's exertional syncope requires careful investigation rather than automatic classification as an arrhythmic risk marker.
4.3 Family History
A family history of premature sudden death raises concern for inherited HCM.
For contemporary sudden cardiac death risk assessment, greater significance is attached to sudden death that is definitely or probably attributable to HCM, particularly in a first-degree or close relative aged 50 years or younger.
The cause of the father's sudden death should therefore be clarified if medical records or postmortem information are available.
5. Physical Examination
5.1 Systolic Murmur
Obstructive HCM typically produces a harsh crescendo-decrescendo systolic ejection murmur, commonly heard at the left lower sternal border.
The murmur generally becomes louder when LVOT obstruction increases.
Maneuvers that increase the murmur include:
1. Valsalva maneuver
2. Standing
These maneuvers reduce ventricular preload and decrease left ventricular cavity size, thereby increasing dynamic obstruction.
Maneuvers that generally decrease the LVOT murmur include:
1. Squatting
2. Sustained handgrip
Squatting increases preload and afterload. Sustained handgrip increases systemic vascular resistance and generally reduces the dynamic LVOT gradient.
An associated mitral regurgitation murmur may respond differently to handgrip.
5.2 Other Findings
1. S4 heart sound
o Reflects atrial contraction against a stiff, poorly compliant left ventricle
2. Forceful or sustained apical impulse
3. Bifid arterial pulse or pulsus bisferiens
o May occur in obstructive disease
4. A systolic murmur related to mitral regurgitation may also be present
6. Diagnosis and Evaluation
6.1 Electrocardiography
ECG abnormalities may include:
1. Left ventricular hypertrophy
2. Deep, narrow Q waves in inferior and lateral leads
3. ST-segment abnormalities
4. T-wave inversion
5. Left atrial enlargement
6. Supraventricular or ventricular arrhythmias
The characteristic narrow, dagger-like Q waves reflect abnormal ventricular activation associated with hypertrophy and should not automatically be interpreted as evidence of previous myocardial infarction.
6.2 Transthoracic Echocardiography
Transthoracic echocardiography is the primary initial cardiac imaging modality in suspected HCM.
Important findings include:
1. Maximal left ventricular wall thickness
2. Distribution of hypertrophy
3. Asymmetric septal hypertrophy
4. Left ventricular systolic and diastolic function
5. Systolic anterior motion of the mitral valve
6. Mitral regurgitation
7. Resting and provocable LVOT gradients
8. Left atrial size
9. Presence of an apical aneurysm
In this patient, the maximal wall thickness of 18 mm satisfies the morphologic threshold for HCM in the absence of another adequate explanation.
6.3 Assessment of LVOT Obstruction
LVOT obstruction is defined by a peak instantaneous gradient of 30 mmHg or greater at rest or with physiologic provocation.
If the resting gradient is below 50 mmHg, provocative maneuvers such as Valsalva should be performed.
If a clinically important gradient cannot be demonstrated despite exertional symptoms, exercise echocardiography can be used to identify exercise-induced obstruction.
This patient has a resting LVOT gradient of 60 mmHg, establishing significant resting obstructive physiology.
6.4 Cardiac Magnetic Resonance Imaging
Cardiac MRI provides complementary information and is useful for:
1. Defining the distribution of hypertrophy
2. Measuring maximal wall thickness
3. Identifying apical hypertrophy
4. Detecting an LV apical aneurysm
5. Evaluating the mitral and subvalvular apparatus
6. Identifying alternative causes of hypertrophy
7. Assessing myocardial fibrosis using late gadolinium enhancement
Late gadolinium enhancement represents myocardial replacement fibrosis and has prognostic significance.
However, the presence of patchy LGE alone is not an automatic ICD indication.
When conventional risk assessment leaves the ICD decision uncertain, extensive LGE may support consideration of an ICD. A threshold around 15% or more of left ventricular mass has commonly been used in research, but quantification methods vary and this value should not be applied as an inflexible cutoff.
In this patient, patchy LGE indicates myocardial fibrosis, but its extent has not been quantified.
6.5 Ambulatory ECG Monitoring
At initial evaluation, patients with HCM should undergo 24 to 48 hours of ambulatory ECG monitoring to assess for:
1. Nonsustained ventricular tachycardia
2. Atrial fibrillation
3. Other clinically important arrhythmias
Periodic ambulatory monitoring is also part of ongoing evaluation.
Extended monitoring is appropriate when symptoms such as palpitations are intermittent or when paroxysmal atrial fibrillation is suspected.
6.6 Exercise Testing
Exercise testing can help assess:
1. Functional capacity
2. Exercise-related symptoms
3. Blood pressure response
4. Exercise-related arrhythmias
5. Exercise-induced LVOT obstruction when combined with echocardiography
6.7 Genetic Testing and Family Screening
Genetic counseling should be offered to patients with HCM.
If a pathogenic or likely pathogenic variant is identified in the proband, cascade genetic testing should be offered to first-degree relatives.
First-degree relatives should undergo clinical screening using:
1. ECG
2. Echocardiography
The frequency of subsequent screening depends on age, genotype, family history, and clinical circumstances.
7. Sudden Cardiac Death Risk Assessment
Sudden cardiac death risk assessment should be performed at diagnosis and reassessed periodically, generally every 1 to 2 years in adolescents and adults.
Risk assessment should not be reduced to a simple checklist in which every abnormality automatically mandates ICD implantation.
7.1 Secondary Prevention
An implantable cardioverter-defibrillator is recommended in patients with HCM who have experienced:
1. Previous cardiac arrest
2. Documented sustained ventricular tachycardia
7.2 Major Primary Prevention Risk Markers in Adults
It is reasonable to consider an ICD when one or more major risk markers are present, including:
1. Family history of HCM-related sudden cardiac death
o Sudden death definitely or probably attributable to HCM in a first-degree or close relative aged 50 years or younger
2. Massive left ventricular hypertrophy
o Maximal wall thickness 30 mm or greater
3. Recent unexplained syncope suspected to be arrhythmic
o Not clearly vasovagal
o Not clearly attributable to LVOT obstruction
4. Left ventricular apical aneurysm
5. Left ventricular systolic dysfunction
o LVEF below 50%
7.3 Additional Risk Modifiers
When the primary prevention ICD decision remains uncertain, additional findings may influence shared decision-making, particularly:
1. Nonsustained ventricular tachycardia on ambulatory monitoring
2. Extensive late gadolinium enhancement on cardiac MRI
Greater significance is generally assigned to NSVT that is frequent, prolonged, or rapid.
Abnormal blood pressure response during exercise is not currently treated as a standalone major AHA or ACC indication for ICD implantation.
7.4 Quantitative Risk Estimation
Estimation of a patient's 5-year risk of sudden cardiac death may provide additional information for shared decision-making.
The ESC approach incorporates the HCM Risk-SCD model in eligible adult patients.
Risk calculators should complement rather than replace individualized clinical assessment and should not serve as the sole determinant of ICD implantation.
7.5 Application to This Patient
This patient requires comprehensive sudden cardiac death risk assessment because:
1. He experienced exertional syncope.
2. His father died suddenly at age 35 years.
3. Cardiac MRI demonstrates myocardial fibrosis.
However:
1. His maximal wall thickness is 18 mm, not massive hypertrophy.
2. The mechanism of his syncope has not yet been established.
3. His resting LVOT gradient of 60 mmHg provides a potential hemodynamic mechanism for exertional symptoms or syncope.
4. The father's sudden death has not yet been documented as HCM-related.
5. The extent of LGE has not been quantified.
6. The presence or absence of nonsustained ventricular tachycardia has not yet been established.
7. His left ventricular ejection fraction and the presence or absence of an apical aneurysm should be incorporated into formal risk assessment.
Therefore, the most accurate description is symptomatic obstructive HCM with features requiring urgent comprehensive sudden cardiac death risk stratification, rather than automatically labeling the patient as definitively high risk.
8. Management
Management should ideally involve a cardiologist experienced in HCM, with referral to a specialized HCM center for complex treatment decisions.
8.1 General Measures
1. Maintain adequate hydration.
2. Avoid significant volume depletion.
3. Evaluate and treat clinically important arrhythmias.
4. Screen first-degree relatives.
5. Offer genetic counseling.
6. Reassess sudden cardiac death risk periodically.
8.2 Exercise and Sports
Patients with HCM should not automatically be prohibited from all physical activity or competitive sport.
Contemporary guidance supports:
1. Regular mild to moderate recreational exercise for most patients
2. Individualized cardiovascular evaluation before vigorous exercise
3. Shared decision-making regarding competitive sports
4. Periodic reassessment by clinicians experienced in HCM
Universal exclusion from competitive sport solely because HCM is present is no longer recommended.
However, this patient has recent exertional syncope, symptomatic resting LVOT obstruction, and unresolved sudden cardiac death risk. Competitive football should therefore be stopped while he undergoes comprehensive evaluation, risk assessment, and treatment.
8.3 Pharmacologic Treatment of Symptomatic Obstructive HCM
First-line therapy
1. Nonvasodilating beta-blocker
Beta-blockers reduce heart rate and myocardial contractility, prolong diastolic filling, and may reduce the LVOT gradient and symptoms.
If beta-blockers are ineffective or not tolerated:
2. Verapamil
3. Diltiazem
Routine combination therapy with a beta-blocker plus verapamil or diltiazem is not established as standard HCM therapy and may increase the risk of excessive bradycardia or conduction disturbance.
Verapamil should be avoided or used with particular caution in patients with:
1. Severe dyspnea at rest
2. Hypotension
3. Very high resting LVOT gradients, such as greater than approximately 100 mmHg
If symptoms persist despite appropriate conventional therapy:
Options include:
1. A cardiac myosin inhibitor in eligible adults
2. Disopyramide, generally in combination with an atrioventricular nodal blocking agent
3. Septal reduction therapy at an experienced HCM center
8.4 Cardiac Myosin Inhibitors
Cardiac myosin inhibitors reduce excessive actin-myosin interaction and myocardial contractility.
Mavacamten
Mavacamten is approved in the United States for adults with symptomatic NYHA class II to III obstructive HCM to improve functional capacity and symptoms.
Because mavacamten can reduce LVEF and cause systolic heart failure:
1. Echocardiographic assessment of LVEF is required before and during therapy.
2. Important CYP-mediated drug interactions must be considered.
3. Mavacamten is available in the United States only through the CAMZYOS REMS Program.
Aficamten
Aficamten was approved by the United States FDA in December 2025 for adults with symptomatic obstructive HCM to improve functional capacity and symptoms.
Aficamten can also cause systolic dysfunction and heart failure.
Current United States labeling requires:
1. Assessment of LVEF before therapy
2. Serial echocardiographic monitoring during treatment
3. Dose adjustment or interruption when LVEF falls below specified thresholds
4. Enrollment in the MYQORZO REMS Program
Regulatory approval and availability vary by country.
8.5 Medications Requiring Caution
In symptomatic obstructive HCM, medications that substantially reduce preload or afterload can worsen dynamic LVOT obstruction.
Agents requiring caution include:
1. Potent vasodilators
2. Nitrates
3. Dihydropyridine calcium channel blockers
4. ACE inhibitors and ARBs when they worsen obstruction or symptoms
5. Excessive or high-dose diuretic therapy
6. Positive inotropic agents such as dobutamine
7. Digoxin in symptomatic obstructive physiology unless there is another compelling indication
These drugs are not universally contraindicated in every patient with HCM.
Low-dose diuretics may be used cautiously when clinically important congestion is present.
8.6 Septal Reduction Therapy
Septal reduction therapy is considered in patients who have:
1. Significant symptoms attributable to LVOT obstruction despite appropriate medical therapy
2. A resting or physiologically provoked LVOT gradient generally 50 mmHg or greater
3. Appropriate cardiac anatomy
The gradient alone is not an indication for septal reduction therapy.
Septal reduction procedures should be performed at experienced HCM centers.
Surgical septal myectomy
Surgical myectomy is particularly appropriate when:
1. Surgical anatomy favors myectomy
2. Concomitant mitral or subvalvular abnormalities require correction
3. Another cardiac condition requires surgical treatment
Alcohol septal ablation
Alcohol septal ablation is an alternative in selected adults with suitable coronary anatomy, particularly when surgical treatment is contraindicated or operative risk is considered unacceptable.
An asymptomatic patient should not undergo septal reduction solely because an LVOT gradient of 50 mmHg or greater is present.
9. Key Clinical Insight
A young patient with exertional syncope, exertional chest pain or dyspnea, a dynamic systolic murmur that becomes louder when preload decreases, asymmetric septal hypertrophy, systolic anterior motion of the mitral valve, and a resting LVOT gradient of 60 mmHg has symptomatic obstructive hypertrophic cardiomyopathy.
In this patient, the premature sudden death of his father, exertional syncope, and myocardial fibrosis make formal sudden cardiac death risk stratification essential, but the available information is insufficient to conclude automatically that he meets criteria for a primary prevention ICD.
References
1. Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(23):e1239-e1311. doi:10.1161/CIR.0000000000001250.
2. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. European Heart Journal. 2023;44(37):3503-3626. doi:10.1093/eurheartj/ehad194.
3. U.S. Food and Drug Administration. MYQORZO (aficamten) Prescribing Information. Initial U.S. approval: 2025. NDA 219083.