Non-obstructive hypertrophic cardiomyopathy

Article written and reviewed by Dr Luca Moretti

Non-obstructive hypertrophic cardiomyopathy includes patients in whom no significant outflow tract gradient is documented either at rest or during adequate physiologic provocation. The definition therefore assumes that obstruction has been sought correctly, not merely that it is absent on the first echocardiogram. A maximum gradient below 30 mmHg after appropriate Valsalva, standing and exercise supports the classification. Non-obstruction is a hemodynamic finding and not a measure of overall disease severity.

The absence of the gradient removes an important mechanism of symptoms, but leaves stiffness, impaired relaxation, microvascular ischemia, fibrosis, arrhythmias and reduced ability to increase cardiac output intact. Some patients are asymptomatic and stable, whereas others develop severe limitation despite a normal ejection fraction. The non-obstructive form should therefore not be described as a mild variant. Its functional burden depends on mechanisms that resting echocardiography may underestimate.

The group is morphologically heterogeneous. It includes septal forms without SAM, concentric, apical and focal hypertrophy, and phenotypes with a small cavity or advanced remodeling; the midventricular form with an intracavitary gradient requires separate description. Etiology may also be sarcomeric, infiltrative, metabolic or unresolved. The term nHCM does not replace the anatomic and etiologic characterization required for prognosis and treatment.

An ejection fraction above 60% does not guarantee normal function, because a small cavity may eject a high percentage of a small volume. Longitudinal strain, cardiac output and exercise reserve may be reduced before the ejection fraction falls. In HCM, a value below 50% already defines the systolic phase and signals important progression. Ventricular function should be interpreted through volumes and the ability to generate flow, not as an isolated percentage.

Management is made difficult by the scarcity of therapies specifically validated to improve symptoms and prognosis when there is no gradient to reduce. Drugs used to control heart rate, ischemia or congestion have less robust evidence than strategies for obstruction. The ODYSSEY-HCM trial showed that mavacamten did not significantly improve the two primary endpoints of exercise capacity and health status in the population studied. Targeted therapy therefore remains an unmet clinical need.

Hemodynamic definition and mechanisms of symptoms

The first requirement for classifying a form as non-obstructive is an adequate search for a gradient. At rest, the outflow tract and cavity are assessed, followed by Valsalva and standing; if the result remains below threshold and the patient is symptomatic, exercise completes the evaluation. Dobutamine does not reproduce everyday loading and is not the standard test. A missed latent obstruction would place the patient in the wrong group and deny potentially effective therapies.

Diastolic dysfunction combines slow relaxation and increased stiffness. The ventricle accommodates a small increase in volume with a large rise in pressure, especially during tachycardia, when diastole shortens. Atrial contribution becomes essential and fibrillation may precipitate congestion. Exercise filling pressures may be elevated even when resting Doppler findings and natriuretic peptides do not appear proportionate to symptoms.

Reduced cardiac output reserve results from a small cavity, reduced filling, chronotropic incompetence and abnormal longitudinal mechanics. During exercise, the ventricle may fail to increase stroke volume and arterial pressure adequately, causing fatigue or presyncope without obstruction. Excessive beta-blockade may worsen chronotropic limitation. Cardiovascular reserve should be measured because resting values do not describe its failure.

Intramural arteriolar disease, capillary rarefaction and increased myocardial mass reduce coronary reserve. High diastolic pressures compress the microcirculation and tachycardia reduces perfusion time, causing pain, dyspnea or troponin release. Repeated episodes promote scar formation and worsening function. Microvascular ischemia is distinct from epicardial coronary artery disease, which may nevertheless coexist and requires age-appropriate assessment.

Interstitial fibrosis increases stiffness, whereas replacement fibrosis creates electrical heterogeneity. LGE mainly visualizes focal scars, while T1 and extracellular volume estimate a more diffuse component. Fibrotic burden may explain symptoms, arrhythmias and progression, but it is not the only determinant. Tissue characterization helps distinguish sarcomeric HCM from amyloidosis or Fabry disease and place the patient along a biologic trajectory.

Atrial fibrillation reduces functional capacity through irregular rate and loss of atrial systole. Even brief episodes may be poorly tolerated in a stiff cavity, whereas a persistently rapid rhythm may contribute to systolic dysfunction. Atrial dilation reflects chronic pressure exposure but does not perfectly predict the time of onset. Atrial monitoring becomes particularly important when episodic dyspnea or palpitations are not explained during scheduled examination.

Comorbidities may dominate the limitation. Obesity, hypertension, sleep apnea, anemia, lung disease, renal dysfunction and deconditioning increase pressures and ventilatory demand. Attributing every symptom to HCM leads to ineffective polypharmacy, whereas ignoring the cardiac substrate leads to undue reassurance. Symptom phenotyping distinguishes the myocardial component from correctable conditions that amplify the clinical picture.

In the advanced phenotype, restrictive physiology may develop with markedly enlarged atria, cavities that are not necessarily large and reduced output. This does not convert the diagnosis into primary restrictive cardiomyopathy; it represents a hemodynamic stage of HCM. Pulmonary pressure and right ventricular function become prognostic determinants and influence transplantation. Low output may be more important than overt congestion and requires functional or invasive testing in selected cases.

Ventricular-arterial coupling may be inefficient even without a gradient. High afterload from hypertension or vascular stiffness reduces reserve, whereas excessive vasodilation may cause hypotension in patients with a small stroke volume. Blood pressure reserve is therefore interpreted together with output and comorbidities without applying the logic of obstruction to every non-obstructive patient.

Skeletal muscle and peripheral oxygen extraction contribute to capacity. Sedentary behavior, obesity and hospitalizations cause deconditioning that may persist even after good cardiac optimization. Cardiopulmonary exercise testing and rehabilitation distinguish a recoverable component. Peripheral limitation does not make the symptom less real and represents a therapeutic target different from the myocardium.

Clinical assessment, imaging and differential diagnosis

History defines actual activity, progression, pain, palpitations, syncope and factors that modify symptoms. A person who has stopped walking uphill may describe themselves as asymptomatic because they no longer encounter their limit. NYHA class, questionnaires and daily activities provide complementary perspectives. Functional quantification prevents a therapeutic strategy from being judged on general impression alone.

Echocardiography documents hypertrophy distribution, volumes, function, atrium, valves and pulmonary pressure. The examination must seek gradients in the outflow tract and at midventricular level using color and Doppler because an intracavitary signal is not equivalent to LVOTO. Strain may reveal regional dysfunction but depends on image quality and software. Absence of SAM supports the non-obstructive form but does not exclude a provocable gradient under different conditions.

Exercise echocardiography answers two questions: whether obstruction appears and how blood pressure, regurgitation and function change. Acquisition during peak exercise is preferable when possible because the gradient may fall rapidly during recovery. Exercise should be symptom-limited rather than stopped by an overly short protocol. Reliable classification requires a test intense enough to reproduce the situation reported by the patient.

Cardiopulmonary exercise testing measures oxygen consumption, ventilatory efficiency, heart rate, blood pressure and oxygen pulse. A reduced peak may result from low output, deconditioning or a peripheral component; the VE/VCO2 slope rises with ventilatory inefficiency and pressure elevation. Repetition documents a trend more objectively than NYHA class alone. The cardiopulmonary profile is particularly important when transplant referral is considered in the absence of an available obstructive procedure.

Magnetic resonance defines the apex, anterolateral wall, volumes and scar without geometric assumptions. An apparently non-obstructive form may reveal apical obliteration, aneurysm or midventricular hypertrophy that changes classification. LGE, T1 and extracellular volume help distinguish cause and burden. Serial remodeling is assessed when a new CMR can change risk or treatment, not through repetitions without a clinical question.

ECG monitoring searches for NSVT and fibrillation, with duration proportional to symptom frequency. A loop recorder may be useful for rare unexplained syncope or palpitations that are difficult to document. Nonsustained tachycardia is described by frequency, duration and rate. Arrhythmic risk stratification follows the same principles as in obstructive HCM and cannot be omitted because a gradient is absent.

In patients with disproportionate symptoms, catheterization during exercise may demonstrate increased pressures and distinguish cardiac from pulmonary limitation. Invasive measurement should be performed at expert centers and interpreted with output, pulmonary pressure and response to load. It is not required in routine assessment. Exercise hemodynamics becomes useful when an important decision depends on a mechanism that noninvasive tests have not clarified.

The differential diagnosis includes hypertension, athlete's heart, amyloidosis, Fabry disease and other storage disorders. Absence of obstruction makes some clinical signs less discriminating and increases the value of tissue characterization and extracardiac findings. An older patient with concentric hypertrophy and low voltages requires a different strategy from a young patient with familial disease. Etiologic diagnosis takes precedence over hemodynamic classification when it identifies a specific therapy.

Natriuretic peptides may be elevated because of atrial pressure, renal function or fibrillation and have prognostic value, but they are not specific to the mechanism. Chronic troponin elevation may reflect microvascular stress, whereas an acute change requires the appropriate ischemia pathway. Biomarkers support a trajectory and do not replace imaging or coronary assessment.

An apical or midventricular form may be incorrectly classified as non-obstructive if Doppler assesses only the outflow tract. Color, contrast and magnetic resonance show compartmentalization. Intracavitary assessment is particularly important when obliteration, pain and aneurysm are present because treatment and risk differ from nHCM with no gradient at any level.

Treatment of symptoms and trial results

Treatment aims to reduce excessive heart rate, ischemia, congestion and arrhythmias because there is no gradient to eliminate. Beta-blockers may improve palpitations and pain and prolong filling, but an excessively high dose reduces chronotropic response and worsens fatigue. Response should be verified with activity or testing rather than assumed from a lower heart rate. The chronotropic balance is particularly delicate in patients whose limitation already results from insufficient augmentation of cardiac output.

Verapamil or diltiazem may improve relaxation and rate control when blood pressure and conduction permit. Combination with a beta-blocker increases the risk of bradycardia, block and hypotension and requires caution. There is no robust evidence that these drugs modify the natural history of the non-obstructive form. Conventional therapy should be maintained only if it provides symptomatic benefit or addresses a concomitant indication.

Low-dose diuretics may reduce congestion and pressures, but excessive diuresis reduces filling of an already small cavity and may cause hypotension or renal injury. Weight, blood pressure, renal function and symptoms guide titration. Edema does not always result from HCM and requires assessment of veins, medications, kidneys and liver. Fluid management is not a uniform restriction but a balance adapted to the disease stage.

MAVERICK-HCM, a phase 2 study, showed reductions in NT-proBNP and troponin with mavacamten but was not powered to demonstrate a definitive clinical benefit; some participants had a reversible reduction in ejection fraction. The biologic signal justified the phase 3 study. This progression illustrates why favorable biomarkers do not automatically equal better symptoms. Clinical validation requires patient-perceived endpoints and functional capacity in addition to laboratory changes.

ODYSSEY-HCM randomized 580 symptomatic adults and compared mavacamten with placebo for 48 weeks. Differences in the two primary endpoints, peak oxygen consumption and KCCQ score, did not reach statistical significance; reductions in ejection fraction and treatment discontinuations were more frequent with the drug. The result does not prove that every form of myosin modulation is ineffective, but it does not support routine use of mavacamten in the non-obstructive population studied.

Management of atrial fibrillation prioritizes timely diagnosis and anticoagulation, rate control and, when appropriate, maintenance of sinus rhythm. Ablation and drugs have higher recurrence rates than in hearts without HCM but may substantially improve tolerance. Anticoagulation for clinical fibrillation is indicated regardless of CHA2DS2-VASc unless contraindicated. Thromboembolic prevention is a more firmly established prognostic therapy than many symptomatic interventions.

Hypertension, obesity, sleep apnea and diabetes should be treated because they increase the burden of heart failure and fibrillation. In truly non-obstructive disease, antihypertensive drugs should not be avoided because of an abstract fear of an absent gradient, but blood pressure and possible phenotypic evolution are monitored. Weight loss and physical activity may improve capacity and metabolic risk. Management of comorbidities offers concrete benefit even when it does not directly modify the sarcomeric variant.

Rehabilitation and moderate aerobic exercise, prescribed after assessment, counter deconditioning and fear. Progressive increases in workload make it possible to recognize symptoms and chronotropic response. Indiscriminate restrictions may worsen the very capacity being preserved. Exercise prescription should be reassessed if arrhythmias, syncope or phenotypic changes develop.

Iron status is assessed when anemia or deficiency may explain fatigue, and appropriate correction may improve exercise without modifying HCM. Thyroid function, electrolytes and renal function influence rhythm and drug tolerance. Metabolic review prevents a reversible limitation from being interpreted as myocardial progression and reduces the risk of arrhythmias triggered by imbalances.

The placebo response observed in trials underscores the importance of controlled measures and a predefined objective in practice. Improvement after introduction of a drug may depend on spontaneous variation, greater activity or clinical attention. Outcome monitoring with KCCQ, testing or concrete activities allows only interventions that produce sustained benefit to be retained.

Progression, advanced therapies and prognosis

The systolic phase is defined by an ejection fraction below 50% and represents a prognostic turning point. Thinning, chamber enlargement, mitral regurgitation, scar and arrhythmias may occur, but a small cavity does not exclude advanced disease. Negative inotropic drugs are reassessed and heart failure therapy for reduced function is applied according to tolerance. Early recognition avoids waiting for a very low ejection fraction before specialist referral.

ARNI or appropriate renin-angiotensin system inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists and SGLT2 inhibitors are considered in the reduced-function phase according to general principles and individual characteristics. HCM-specific evidence is less extensive than in general populations, but the risk of leaving heart failure untreated is high. Blood pressure, renal function and cavity size sometimes limit titration. Neurohormonal therapy should not be applied automatically to patients with preserved ejection fraction and low output.

Cardiac resynchronization may be useful when reduced ejection fraction, bundle branch block and dyssynchrony coexist according to appropriate criteria. The defibrillator is indicated on the basis of arrhythmic risk and may be combined with CRT when necessary. Pacing does not correct pure stiffness and should not be used as empiric therapy for the non-obstructive form. Devices address defined electrical and synchronization problems, not the diagnostic label itself.

A patient with severe limitation, reduced peak oxygen consumption, hospitalizations or low output should be referred early for transplantation even with preserved ejection fraction. Absence of marked dilation may delay recognition compared with dilated cardiomyopathy. Catheterization, right ventricular function and pulmonary pressure define risk. Transplant assessment should precede multiorgan damage, cachexia or irreversible pulmonary hypertension.

Ventricular assist is technically difficult when the cavity is small and hypertrophied because cannula position and filling may be inadequate. In the dilated phase it becomes more feasible, but right ventricular involvement and arrhythmias remain obstacles. This limitation makes transplantation the main advanced therapy for many end-stage non-obstructive phenotypes. Advance planning prevents the lack of a practicable mechanical solution from emerging only during shock.

Prognosis depends on age at onset, genotype, fibrosis, capacity, function, fibrillation, NSVT and aneurysm. Absence of LVOTO removes one hemodynamic marker but does not automatically reduce the risk of sudden death or heart failure. HCM Risk-SCD and major markers are applied with the same cautions used for HCM as a whole. Multidimensional stratification separates risks of sudden death, thromboembolism and hemodynamic progression.

Follow-up reassesses whether a gradient appears over time, especially when symptoms, blood pressure, weight or medications change. ECG, echocardiography and monitoring are integrated with magnetic resonance and cardiopulmonary exercise testing when they can alter a decision. Stable follow-up does not remove the need for family surveillance. The dynamic nature of the phenotype means that non-obstructive is a current description, not an immutable identity.

Communication should avoid two extremes: promising a benign form because the gradient is absent or presenting every episode of dyspnea as inevitable progression. Many patients maintain a good quality of life, and modifiable factors or arrhythmias can be treated; a minority require advanced therapies. Explaining clinical uncertainty in terms of observable data and scheduled follow-up makes the pathway understandable without resorting to absolute reassurance.

Rising pulmonary pressure may precede right ventricular dysfunction and reduce transplant options. Echocardiography, pulmonary diffusion testing and catheterization distinguish a postcapillary component from other causes. Pulmonary vasodilator therapies are not used automatically for pressure due to left heart disease. Pulmonary hemodynamics must be defined before treatments that could increase return to a poorly compliant ventricle.

The absence of a corrective procedure may have a substantial psychological impact in symptomatic patients. A clear explanation of mechanisms, realistic goals and the possibility of advanced therapies reduces the sense of abandonment. The therapeutic alliance includes symptom management, activity, sleep and mental health without presenting psychological support as a substitute for cardiac assessment.

Specific complications and care issues

Heart failure with preserved ejection fraction is the most characteristic hemodynamic complication. High pressures may cause dyspnea and hospitalizations even when function and dimensions appear normal, making exercise testing or selective hemodynamic assessment necessary. Diuretics relieve congestion but do not correct stiffness or microvascular dysfunction. Occult congestion should be recognized before atrial remodeling and pulmonary hypertension become advanced.

Atrial fibrillation causes loss of capacity, heart failure and stroke. Silent episodes are relevant in patients with a dilated atrium or intermittent symptoms and may require prolonged monitoring. Anticoagulation markedly reduces embolic risk, whereas rhythm control may become less effective after extensive atrial remodeling. Early diagnosis of the arrhythmia is therefore one of the few interventions capable of preventing a major complication with established evidence.

Ventricular arrhythmias do not depend on the presence of a gradient. LGE, NSVT, syncope, family history, wall thickness, aneurysm and dysfunction guide the ICD decision. A non-obstructive form with extensive scar may carry greater risk than an obstructive form with few markers. The electrical substrate must be assessed directly and not inferred from the hemodynamic classification.

Microvascular dysfunction may cause pain and scar, but nitrates can produce hypotension and, if an unrecognized gradient exists, accentuate it. Ranolazine and other antianginal agents have limited data and response is individual. Epicardial coronary disease should be treated according to its indications. Ischemic pain therefore requires anatomic and physiologic distinction before chronic empiric therapy.

Chronotropic incompetence may result from the disease, medications or sinus node dysfunction. Reducing a dose may improve exercise but increase palpitations, blood pressure or ischemia; pacing is reserved for a documented indication. Exercise testing clarifies whether heart rate rises appropriately. The chronotropic response is an often neglected functional target when attention is focused only on wall thickness and ejection fraction.

Pregnancy, anemia and infections increase demand and heart rate and may unmask limited reserve. The non-obstructive form avoids some preload-related risks but not those related to stiffness, arrhythmias or function. Preconception assessment and cardio-obstetric coordination are indicated in symptomatic or advanced phenotypes. The postpartum period requires attention to rapid volume shifts and the onset of fibrillation.

The lack of a corrective procedure may generate a cycle of adding drugs without a clear hypothesis. Every change should define the target symptom, the time for reassessment and stopping criteria. Cardiopulmonary exercise testing, monitoring and questionnaires permit a more transparent assessment. Deprescribing ineffective treatments is part of safety, especially when bradycardia and hypotension worsen capacity.

The ideal pathway integrates an expert center and local cardiology. The former defines etiology, risk and advanced therapies; the latter monitors blood pressure, comorbidities, adherence and signs of progression. Serial data should be comparable and not dispersed among institutions. Continuity of care is particularly important in the non-obstructive form, where gradual change may be the only signal preceding advanced heart failure.

Pregnancy may be tolerated with good outcomes in stable forms, but severe stiffness or the systolic phase increases maternal risk. Medications, anticoagulation and mode of delivery are planned before conception. Obstetric risk depends on function and symptoms more than on the mere absence of a gradient and requires postpartum surveillance.

The family should be informed that a relative with the same variant may develop an obstructive form. The proband's hemodynamic classification does not predict the geometry of every carrier. Cascade testing identifies predisposition, whereas echocardiography and provocation define the individual phenotype during follow-up.