Geske, Jeffrey B.

Importance Sleep disordered breathing (SDB) is a well-established contributor to cardiovascular morbidity, mediated by intermittent hypoxemia, autonomic dysregulation, and endothelial dysfunction. Patients with hypertrophic cardiomyopathy (HCM) may be especially at risk for SDB, but the clinical impact of SDB in this population remains unclear. Objective To define the prevalence and subtypes of SDB in HCM and examine their association with echocardiographic parameters and cardiac biomarker expression. Design, Setting, and Participants A prospective cohort study was conducted between April 18, 2018, and January 15, 2024, at a single tertiary referral center specializing in HCM care. Adults with HCM (left ventricular wall thickness ≥15 mm or pathogenic variants) were recruited from an institutional registry. Patients diagnosed with SDB or current pregnancy were excluded. Patients underwent polysomnography, with comparative assessment of echocardiographic, electrocardiographic, and biomarker indices. Observers were blinded to polysomnographic results. Data analysis was performed from April 11, 2024, to July 25, 2024. Exposures SDB classified via polysomnography using apnea-hypopnea index thresholds, with subtypes including obstructive sleep apnea and central sleep apnea and with event severity, hypoxemia, and sleep architecture disruption quantified. Main Outcomes and Measures Echocardiographic indices, cardiac biomarker expression, functional status, apnea-hypopnea index, and overnight hypoxemia. Results Among 154 patients (median [IQR] age, 60 [48-68] years; 102 [66.2%] male), 91 (59.1%) were diagnosed with SDB. Those with SDB, compared with those without SDB, had higher left ventricular mass index (median [IQR], 128 [107-161] vs 109 [96-134] g/m 2 ; P = .03), E/e′ ratio (median [IQR], 12.5 [10.0-15.0] vs 10.0 [8.3-14.5]; P = .04), and baseline troponin-T level (median [IQR], 0.013 [0.009-0.022] vs 0.011 [0.007-0.015] ng/mL [to convert to micrograms per liter, multiply by 1]; P = .04) and greater overnight troponin-T level increases (change in median [IQR], 0.0021 [−0.0029 to 0.0062] vs 0.0002 [−0.0022 to 0.0026] ng/mL; P = .02). New York Heart Association class II or III symptoms were more common in those with SDB (48 [52.7%] vs 17 [27.0%]; P = .005). Hypertension and diabetes were more prevalent among patients with SDB than without SDB (hypertension: 67 [73.6%] vs 36 [57.1%]; P = .03; diabetes: 14 [15.4%] vs 3 [4.8%]; P = .04), whereas rates of atrial fibrillation and prior myectomy did not differ significantly between groups. Conclusions and Relevance This study suggests that undiagnosed SDB is highly prevalent in patients with HCM and that SDB is associated with adverse myocardial remodeling, greater diastolic dysfunction, and elevated troponin-T levels, indicating subclinical myocardial injury. SDB may contribute to HCM pathophysiology and symptom burden, supporting the rationale for randomized clinical trials to determine the impact of treating SDB on symptoms and clinical outcomes in patients with HCM.

Abstract Aims Significant advancements have been made in the management of obstructive hypertrophic cardiomyopathy (oHCM), yet the extent of left ventricular outflow tract (LVOT) gradient reduction achieved with commonly used pharmacological therapies [beta-blockers (BBs), calcium channel blockers (CCBs), disopyramide, and cardiac myosin inhibitors (CMIs)] relative to each other is still unclear. Methods and results PubMed and Scopus were searched up to September 2024. Clinical trials or observational studies that assessed the changes associated with BBs, CCBs, disopyramide, or CMIs in LVOT gradient at rest or with provocation in patients with oHCM were included. Mean changes in LVOT gradients were pooled as mean differences (MD) with 95% confidence intervals (CIs) in a random-effects model. Thirty-seven studies, with 44 arms and 1898 patients, were included in the analysis. At the therapeutic class level, pooled analysis showed that disopyramide was associated with the highest reduction in LVOT gradient at rest [MD: −43.5 (95% CI, −51.6 to −35.3)], followed by CMIs [MD: −34.8 (95% CI, −40.6 to −29.0)], BBs [MD: −20.7 (95% CI, −29.4 to −12.0)], and then CCBs [MD: −14.7 (95% CI, −23.3 to −6.1)], inter-action P < 0.01. Within CMIs, mavacamten had a higher effect than aficamten on gradient reduction; among the included BBs, metoprolol showed the highest gradient reduction, while among CCBs, verapamil was the most effective (inter-action P < 0.01). Similar results were observed for provocable LVOT gradients. Conclusion Pharmacological therapies effectively reduced LVOT gradients in oHCM patients to varying degrees, with disopyramide and CMIs showing the highest effect, followed by BBs and CCBs.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy marked by increased left ventricular wall thickness, leading in some cases to left ventricular outflow tract (LVOT) obstruction, heart failure, and arrhythmias. Mavacamten, a selective allosteric inhibitor of cardiac myosin, has demonstrated benefits in improving hemodynamics and reducing LVOT obstruction. However, its impact on arrhythmic burden remains unclear, with reports of early atrial fibrillation (AF) risk contrasting with long-term reductions in arrhythmias. This study assesses the temporal patterns of Holter-detected arrhythmias in HCM patients treated with mavacamten. Methods: This retrospective study included HCM patients from three Mayo Clinic sites. Baseline demographic, clinical, and echocardiographic data were collected. Holter monitoring was performed at baseline, short-term (<6 months), and long-term (>6 months) follow-up. Arrhythmic events, including premature atrial contractions (PACs), premature ventricular contractions (PVCs), and supraventricular tachycardia (SVT), were analyzed using standardized rates per 24 h. Statistical comparisons utilized the Wilcoxon signed-rank test. Results: Twenty-seven patients (56% female, median age 66 years) were included. PACs, PVCs, and SVT duration transiently but not significantly increased at short-term follow-up but returned to baseline at long-term follow-up. No sustained or high-risk ventricular arrhythmias were observed. Conclusions: Mavacamten is associated with transient arrhythmic fluctuations early in treatment, followed by stabilization. These findings support its long-term electrophysiological safety and underscore the need for early rhythm monitoring. Further research should explore its role in arrhythmic risk stratification in HCM patients.

Abstract Background Transthoracic echocardiography is the primary modality used for the assessment of the pericardial space. Guidelines recommend semi-qualitative assessment of the size of a pericardial effusion with characterization as trace, small, moderate or large. The reproducibility and association of this characterization is variable. Whether simple 2D-based quantitative measures of effusion size better associate with pericardial volumes is unclear. An accurate measure of pericardial volume would be helpful for tracking patients over time. Purpose To test whether 2D-based measures of the pericardial space could accurately predict pericardial volumes. Methods We retrospectively assessed a series of echos performed immediately prior to pericardiocentesis. 2D-based area tracings from the parasternal long and short axis at the papillary muscle level as well as 2D volumetric tracings from the apical 4 chamber view using the Simpson's method were tested with the operator blinded to the true pericardial volume (recorded at pericardiocentesis). Patients who underwent pericardiocentesis in setting of acute perforation were excluded as were patients where pericardiocentesis was unsuccessful or incomplete. Pericardial fluid area or volume was calculated by taking the difference between the measures obtained by tracing the epicardial border of the heart and pericardium (figure 1). Results The median pericardiocentesis (n=118) fluid volume was 500 mL (IQR 350 – 750 mL) with a range, 95–2300 mL. The pericardial fluid was serous (22%), sero-sanguineous (37%) and sanguineous in 41%. The effusion was malignant in 24 cases and due to inflammation in 42 cases. Pericardial area traces from either the parasternal short (r=0.56, p&lt;.0001) or long axis (r=0.62, p&lt;.0001) correlated modestly with measured pericardial volume. The average volume estimated echocardiographically by the Simpson’s method was 580 ± 359 mL (range, 85.8–2419 mL). There was stronger linear correlation between echocardiographic (apical 4-chamber measurement) and pericardiocentesis-derived volumes (r=0.92, p &lt; 0.0001; figure 2A). Etiology of the pericardial effusion was not associated with estimates of pericardial volumes. There was a large overlap in pericardial volume amongst the reading physician qualitative grading of effusion size (figure 2B). Categorization of pericardial effusion size was improved when based on volumetric estimates (Kappa 0.65) rather than physician estimates (Kappa 0.32; Figure 2B). Variation between measured pericardial volume and actual pericardial volume was most related to the quality of the image and the likely extent to which the pericardial fluid was not entirely captured in the image window. Conclusion Two-dimensional transthoracic echocardiography using biplane Simpson’s method of disks can simply and reasonably accurately estimate the pericardial effusion volume. This technique may add value in the serial assessment of pericardial effusions. Figure 2

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), VALOR-HCM trial (Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy [URL: https://clinicaltrials.gov ; Unique identifier: NCT04349072]) reported that mavacamten reduced the short-term need for septal reduction therapy (SRT). The current report examined the longer-term effect of mavacamten through end of treatment at week 128. METHODS: A double-blind randomized placebo-controlled multicenter trial at 19 sites in the United States included symptomatic obstructive HCM patients referred for SRT (enrollment July 2020 through October 2021). The group initially randomized to mavacamten continued the drug for 128 weeks and the placebo to mavacamten group from week 16 to 128 (112-week exposure). Dose titrations were performed using echocardiographic left ventricular outflow tract gradient and left ventricular ejection fraction measurements. The principal end point was proportion of patients proceeding with SRT or remaining guideline-eligible at week 128. RESULTS: At week 128, 17 of 108 (15.7%) patients in the total study sample met the composite end point (7 underwent SRT, 1 was SRT-eligible, and 9 SRT-status unevaluable). Additionally, 87 of 108 (80.5%) patients demonstrated ≥1 New York Heart Association class improvement by week 128, and 52 of 108 (48.1%) demonstrated ≥2, with a sustained reduction in resting and Valsalva left ventricular outflow tract gradients of 38.2 mm Hg and 59.4 mm Hg, respectively. Ninety-five of 108 (88%) patients transitioned to commercial mavacamten. Overall, 15 of 108 (13.8%) patients (5.41 per 100 patient-years) had an left ventricular ejection fraction <50% (2 with left ventricular ejection fraction ≤30%; 1 death). Of these, 12 of 15 (80%) continued treatment. New-onset atrial fibrillation occurred in 11 (10.2%) patients (4.55 per 100 patient-years). CONCLUSIONS: In severely symptomatic obstructive HCM patients, sustained freedom from SRT was observed at 128 weeks, with nearly 90% patients remaining on long-term mavacamten. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

Background: Sleep disordered breathing (SDB) is frequently observed in patients with cardiovascular disease, and is associated with intermittent hypoxia, sympathetic activation, oxidative stress, and endothelial dysfunction, all of which may facilitate the development and progression of cardiovascular disease. Objectives: We sought to determine the prevalence, subtypes, and clinical implications of comorbid SDB in patients with hypertrophic cardiomyopathy (HCM). Methods: In this prospective observational study, patients with HCM without prior diagnosis of SDB were recruited to undergo inpatient polysomnography between May 1 st 2018 and October 31 st 2022. Electrocardiographic and echocardiographic parameters, cardiac biomarkers, and symptoms were comparatively assessed in patients with and without comorbid SDB. Patients were assessed for the development of major adverse cardiovascular events (MACE) during follow-up (median 29, range 3-57 months). Results Among 154 participants, 91 (59.1%) were diagnosed with SDB of whom 38 (41.8%) had mild, 22 (24.2%) moderate, 18 (19.8%) severe obstructive sleep apnea, and 13 (14.3%) had central sleep apnea. SDB was associated with greater left ventricular mass (median [IQR]) (128 [107, 161] vs. 109 [96, 134] g/m 2 , p =0.034) and E/e’ ratio (12.5 [10, 15] vs. 10.0 [8.3, 14.5], p =0.039). Patients with HCM over the age of 50 years, with body mass index ≥ 30kg/m 2 , who described their sleep as “poor” were at particularly high risk of having comorbid SDB, as were those who were diabetic, hypertensive, or described greater exertional limitation (NYHA Class ≥II 53% vs. 27%, p =0.005). Importantly, subjects with SDB had elevated baseline Troponin T levels (14 ng/L vs 11 ng/L, p =0.030), and further substantial overnight troponin increases following untreated apneic sleep (2.1ng/L vs 0.2ng/L, p =0.009). Finally, patients with comorbid SDB experienced a significantly higher proportion of incident adverse cardiovascular events (MACE hazard ratio 5.3, 95% CI, 1.6, 17.2, p =0.006) than those without SDB. Conclusions: We report a particularly high burden of previously undiagnosed SDB in patients with HCM, particularly in older, heavier, male patients. Undiagnosed SDB in HCM is not benign and is associated with symptom progression, comorbidity, and a poorer prognosis, particularly in the case of central sleep apnea. These important new findings provide rationale for heightened vigilance and routine screening for SDB in patients with HCM.

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, reduces the need for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients and symptoms. As a cardiac myosin inhibitor, mavacamten’s mechanism of action reduces myocardial hypercontractility. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function and can complement left ventricular ejection fraction (LVEF). Objective We sought to assess serial changes in LV and right ventricular (RV)-GLS in patients enrolled in the VALOR-HCM study. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean 60 years, 51% male, LVEF 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). LV and RV-GLS assessment was performed according to the current American and European guideline recommendations using a vendor-neutral post processing software. Non-foreshortened apical (4, 3 and 2-chamber) views were used to obtain peak value of LV-GLS. For RV-GLS, RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. Results Serial changes in LVEF, average LV-GLS, and RV-GLS (4-chamber and free wall) from baseline to week 56 are shown in the Figure. Despite preserved LVEF at baseline, average baseline LV-GLS was abnormal. There were significant and continued improvements in LV-GLS in the total group from baseline to week 56. 12 patients had transient reduction in LVEF (&lt;50%) requiring temporary drug interruption (permanent discontinuation in 3). The LV-GLS in this subgroup was worse at baseline compared to the total study population, with no significant worsening from baseline through week 56. In the overall population, excluding these 12 patients, LV-GLS demonstrated an improvement sustained through week 56. Both free wall and 4-chamber RV-GLS were abnormal at baseline and remained unchanged from baseline to week 56. Conclusions In the VALOR-HCM trial, despite hypercontractile LVEF at baseline, average baseline LV-GLS was worse than normal reference values. Treatment with mavacamten resulted in an improvement in LV-GLS from baseline through Week 56 (with no significant worsening of LV-GLS in the subgroup who experienced any reduction in LVEF &lt;50%), suggesting a favorable long-term impact on regional LV systolic function due to the reduction of cardiac hypercontractility. Additionally, there was no significant detrimental impact on RV systolic function on serial GLS assessment.Serial changes in LV and RV GLS in VALOR