Highlights
Patients with obstructive hypertrophic cardiomyopathy (oHCM) demonstrate chronic activation of the Anrep response—a compensatory mechanism characterized by elevated afterload, hypercontractility, and increased myocardial workload. This study demonstrates that mavacamten, a cardiac myosin inhibitor, achieves hemodynamic corrections comparable to alcohol septal ablation through identical reversal of this maladaptive state. Both treatment approaches reduced afterload and contractility, shortened systolic ejection time, and decreased myocardial energetic demands while preserving stroke volume. The findings establish the Anrep response as a central therapeutic target in oHCM management.
Background: The Anrep Response in Obstructive Hypertrophic Cardiomyopathy
Obstructive hypertrophic cardiomyopathy represents a significant clinical challenge, affecting approximately 1 in 500 individuals and representing the most common genetic cardiomyopathy. The pathophysiology centers on left ventricular outflow tract (LVOT) obstruction, which creates a state of elevated afterload that the heart must continuously overcome to maintain systemic perfusion.
The Anrep response, first described over a century ago, represents a fundamental compensatory mechanism in which the myocardium adapts to increased afterload through a state of hyperdynamic systole. In oHCM, this chronic response manifests as prolonged systolic ejection time, elevated end-systolic pressure, and heightened contractility—all serving to maintain cardiac output against the increased resistance. However, this compensatory state comes at substantial energetic cost, increasing myocardial oxygen demand and mechanical workload.
Prior to this study, the therapeutic implications of Anrep activation in oHCM remained incompletely characterized. While anatomical interventions such as alcohol septal ablation (ASA) directly relieve the obstructive lesion, the hemodynamic consequences of this mechanical correction had not been systematically compared against pharmacologic approaches targeting contractile function.
Study Design
This prospective comparative study enrolled two distinct patient cohorts for parallel analysis. The primary cohort consisted of 36 patients with symptomatic obstructive HCM who received mavacamten therapy. Treatment response was assessed at 3 months, with responders defined as those achieving a resting LVOT gradient below 50 mmHg. Of these, 29 patients met responder criteria and underwent comprehensive echocardiography-derived pressure-volume analysis before and after therapy.
For direct comparison, a separate cohort of 13 patients with oHCM underwent identical pressure-volume analysis before and 3 months following alcohol septal ablation. All participants in the ASA cohort demonstrated sufficient gradient reduction to qualify as procedural responders.
Pressure-volume analysis quantified multiple indices of cardiac function and energetic status. Afterload was assessed through left ventricular end-systolic pressure and effective arterial elastance. Contractility measures included end-systolic elastance and end-systolic volume at 150 mmHg. Systolic ejection time was recorded as an indicator of Anrep activation. Myocardial workload was quantified through stroke work, potential energy, and pressure-volume area. Diastolic function was evaluated via left ventricular end-diastolic pressure, end-diastolic volume, and the volume at 15 mmHg LV end-diastolic pressure.
Key Findings
At baseline, all enrolled patients exhibited the hallmark signatures of chronic Anrep activation. Compared to normal reference values, this population demonstrated elevated afterload indices, with increased LV end-systolic pressure and effective arterial elastance reflecting the hemodynamic burden of LVOT obstruction. Contractility measures confirmed hyperdynamic function, with elevated end-systolic elastance and characteristically low end-systolic volume at 150 mmHg. Systolic ejection time was prolonged, consistent with the delayed aortic valve closure observed in states of increased afterload.
Myocardial workload indices confirmed the energetic consequences of these hemodynamic alterations. Stroke work, potential energy, and pressure-volume area were all elevated, indicating that the Anrep-compensated heart expends substantially more energy to maintain equivalent forward flow.
Hemodynamic Corrections with Mavacamten
Among the 29 mavacamten responders, 3 months of therapy produced comprehensive hemodynamic improvements that paralleled those achieved through surgical intervention. Afterload reduction was evident, with decreased LV end-systolic pressure and effective arterial elastance. Contractility indices improved, with reduced end-systolic elastance and appropriate increases in end-systolic volume at 150 mmHg, indicating regression toward normal contractile states. Systolic ejection time shortened, reflecting reduced Anrep activation.
Critically, these improvements occurred without compromising forward flow. Stroke volume was preserved throughout treatment, indicating that the hemodynamic benefits did not come at the cost of reduced cardiac output. Myocardial workload decreased substantially, with reductions in stroke work, potential energy, and pressure-volume area reflecting improved cardiac efficiency. Diastolic function also improved, evidenced by increased end-diastolic volume and volume at 15 mmHg LV end-diastolic pressure, alongside decreased LV end-diastolic pressure.
Comparison with Alcohol Septal Ablation
The 13 patients who underwent alcohol septal ablation demonstrated hemodynamic changes of similar magnitude and direction to those observed with mavacamten treatment. The parallel improvements across all measured indices—afterload, contractility, systolic ejection time, myocardial workload, and diastolic function—indicate that the two therapeutic approaches achieve their clinical benefits through identical physiologic mechanisms.
Mavacamten Nonresponders
Seven patients in the mavacamten cohort did not achieve the prespecified response threshold (persistent LVOT gradient ≥50 mmHg at 3 months). Notably, these nonresponders showed no significant changes in Anrep-related indices or myocardial workload despite continued therapy. This observation suggests that incomplete gradient reduction leaves the Anrep response chronically activated, maintaining elevated energetic demands and potentially perpetuating disease progression.
Expert Commentary
These findings carry significant implications for understanding oHCM pathophysiology and guiding therapeutic decision-making. The demonstration that pharmacologic therapy can achieve hemodynamically equivalent outcomes to invasive intervention challenges the historical emphasis on purely anatomical approaches to obstruction relief.
The Anrep response, while initially compensatory, represents a maladaptive state when chronically sustained. The energy-intensive nature of hypercontractile function, combined with impaired diastolic filling, creates a cascade of progressive cardiac dysfunction. By demonstrating that both mavacamten and ASA reverse this state, the study provides mechanistic validation for current guideline-recommended treatment algorithms while identifying a framework for monitoring therapeutic efficacy.
Several limitations warrant consideration. The relatively small sample sizes (29 mavacamten responders, 13 ASA patients) limit statistical power for detecting subtle between-group differences. The single timepoint assessment at 3 months does not address longer-term outcomes or the durability of hemodynamic corrections. Additionally, the definition of mavacamten response (resting gradient <50 mmHg) represents a surrogate endpoint, and the relationship between Anrep reversal and hard clinical outcomes requires further investigation.
The nonresponder analysis provides important mechanistic insight, suggesting that therapeutic success in oHCM may be more appropriately defined by reversal of the Anrep state than by arbitrary gradient thresholds alone. Future studies should explore whether optimization of mavacamten dosing or duration could convert nonresponders to this favorable hemodynamic profile.
Conclusion
This pressure-volume analysis establishes that mavacamten and alcohol septal ablation achieve comparable hemodynamic corrections in obstructive HCM through identical reversal of chronic Anrep activation. Both interventions reduce afterload and contractility, shorten systolic ejection time, and decrease myocardial energetic demands while preserving stroke volume. The findings identify the Anrep response as a central mechanistic target and suggest that pharmacologic myosin inhibition may provide a non-invasive alternative to surgical intervention for appropriate patients. Future research should investigate whether early Anrep reversal prevents progressive cardiac dysfunction and improves long-term outcomes in this population.
References
Reil JC, Sequeira V, Coppée C, Peters K, Federspiel JM, Steendijk P, Maack C, Waddingham MT, Rudolph V, Reil GH, Scholtz S. Mavacamten Versus Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: An Echocardiography-Derived Pressure-Volume Analysis. Circulation. Heart failure. 2026-04-13:e013392. PMID: 41969098.
