Nonobstructive Hypertrophic Cardiomyopathy Research Articles

Sacubitril/valsartan for the treatment of non-obstructive hypertrophic cardiomyopathy: An open label randomized controlled trial (SILICOFCM).

Sacubitril/valsartan treatment reduces mortality and hospitalizations in heart failure with reduced ejection fraction but has limited application in hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the effect of sacubitril/valsartan on peak oxygen consumption (VO2) in patients with non-obstructive HCM. This is a phase II, randomized, open-label multicentre study that enrolled adult patients with symptomatic non-obstructive HCM (New York Heart Association class I-III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103 mg) or control for 16 weeks. The primary endpoint was a change in peak VO2. Secondary endpoints included echocardiographic measures of cardiac structure and function, natriuretic peptides and other cardiac biomarkers, and Minnesota Living with Heart Failure quality of life. Between May 2018 and October 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years, 37% female) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (n = 79) or control (n = 36). At 16 weeks, there was no significant change in peak VO2 from baseline in the sacubitril/valsartan (15.3 [4.3] vs. 15.9 [4.3] ml/kg/min, p = 0.13) or control group (p = 0.47). No clinically significant changes were found in blood pressure, cardiac structure and function, plasma biomarkers, or quality of life. In patients with HCM, a 16-week treatment with sacubitril/valsartan was well tolerated but had no effect on exercise capacity, cardiac structure, or function.

The effect of bachmann bundle pacing on diastolic function in patients with non-obstructive HCM

Abstract Background and Objective Patients with non-obstructive HCM (nHCM) have advanced diastolic dysfunction and atrial remodeling, leading to increased heart failure hospitalisations. The objective of this study was to evaluate the role of Bachmann bundle pacing (BBP) in diastolic filling compared to right atrial appendage pacing (RAAP). Methods Forty patients with symptomatic nHCM and normal LV function were prospectively enrolled from January 2021 to June 2023. Inclusion criteria included electrocardiographic evidence of inter-atrial delay, E/e’ > 15, and an indication for ICD implantation. BBP was attempted in twenty patients, others underwent RAAP. A Biotronik Selectra 3D 40-S sheath was used for BBP in patients in whom initial lead implantation was unsuccessful. BBP was defined based on P-wave morphology and fluoroscopic lead position. The RV lead was implanted in the RV apex in all patients and the AV delay was optimized based on diastolic filling period and E/e’. Devices were programmed in DDD mode. During follow up, diastolic function, functional capacity, atrial fibrillation, and heart failure hospitalisations were assessed in both groups. Results Among the forty patients (age 48.2+7.8 yrs, males 75%, ESC-SCD Risk 4.3+0.6%), the baseline P wave duration, E/A, E/e’ were 138.4+16.4 ms, 2.5+0.5, and 17.5+2.4, respectively. Six patients (15%) had a history of paroxysmal AF (3 each in BBP and RAAP groups). Of the 16 patients (80%) who underwent successful BBP, the Selectra 3D 40-S sheath was used in 8 patients (Figure 1, Panel A). During BBP, a bachmann bundle potential was recorded in 7 of 16 patients (43.8%) (Figure 1, Panel C). The pacing threshold (1.5+0.5@0.4ms vs. 0.9+0.3@0.4ms, p=0.026) was higher and the atrial sensing (1.8+0.4 vs. 3.3+0.6, p=0.002) was lower in the BBP group compared to the RAAP group at 4 weeks and 6 months of follow up. There was an acute rise in threshold (2.1@0.4 ms) in 1 BBP patient at 4 weeks of follow up. Patients in the BBP group had a reduction in P wave duration compared to the patients in the RAAP group (-22.5 + 5.4 vs. +5.6 + 3.2 ms, p<0.001). During follow up (11.4 + 3.4 months), there was a significant improvement in diastolic function (E/e’), functional capacity (NYHA Class) and reduction in NT-proBNP in the BBB group compared to the RAAP group (Figure 1). The percentage of atrial pacing was similar in both groups (BBP 73.2 + 7.8 vs. RAAP 78.5 + 9.1 %, p=0.219). The risk of atrial fibrillation/tachycardia (12.5% vs. 35.0%, p=0.022) and heart failure hospitalisations (6.3% vs. 20%, p=0.042) was lower in the BBP group compared with RAAP during follow up. Conclusions BBP is safe and effective in improving diastolic function, functional capacity and heart failure hospitalizations in patients with nHCM.BBP Pacing using Selectra 3D 40-S SheathChange in E/e', NYHA, and NT-pro BNP

First experiences with protected VT ablation using surgical Impella 5.5

Abstract Introduction Ablation of ventricular arrhythmias (VA) is still challenging due to the complex substrate of the underlying heart disease. Depending on specific risk factors acute hemodynamic decompensation during or after VT ablation procedures may occur and hemodynamic support may be required. Protected VA ablation with different devices has been evaluated but associated complications like bleeding, vascular closure or weaning from the device have been restrictive. We present data on a dedicated approach to patients with anticipated hemodynamic deterioration using preventive surgical Impella support. Method 5 patients (2 female) underwent protected VT ablation under our standardized protocol. Indication for Impella support was severely impaired left ventricular function and multiple medical therapy refractory ventricular arrhythmias. 4 patients had conventional VT ablation before. Mean age was 66,8 years, mean CHADSVASC 4,4, 1 patient with non-ischemic cardiomyopathy (CMP), 1 with hypertrophic non-obstructive CMP, 3 patients with ischemic CMP. Mean EF was 20%, mean mixed venous saturation was 36 %, mean PAINESD score 27. In all patients a 5.5. Impella was implanted surgically 1 day before planned VT ablation via the right subclavian artery. VT ablation procedure started with substrate mapping, VT induction and activation mapping of the inducible VT to identify the critical VT isthmus. Ablation was directed to dissection of the critical isthmus of inducible VAs and elimination of all late potentials within low voltage areas. The Impella device was explanted after weaning off the hemodynamic support. Results Implantation of Impella 5.5 was successfully performed in all patients in general anesthesia without any complication via surgical approach. Specifically, no access site vascular complications were noted. In 4 patients the VT ablation procedure was performed in analgosedation, 1 patient in GA as this patient was intubated due to recurrent VA requiring defibrillation. Mean procedure time was 125 min, radiation time 1,3 min, inducible VTs 1,3 , median 2 morphologies. In all patients all inducible VTs could be eliminated, in 1 patient polymorphic VA was still inducible at the end of the procedure. Impella was explanted after mean 5,2 days (3-11 days). No complications occurred. All patients were discharged alive on heart failure medication and in 2 patients with amiodaron. At a mean follow up of 3.5 months, all patients are alive without VA recurrence and heart failure decompensation. Conclusion Surgical Impella implantation for protected VT ablation in severe heart failure patients is feasible and allows for effective VT mapping and ablation. Access site safety and protection for heart failure decompensation in addition to the possibility of individually mobilisation and weaning after the procedure make this protocol an attractive option. Prospective evaluation of standardized indication is needed.

Diagnostic value of LGE and T1 mapping in multiple myeloma patients’heart

BackgroundUnidentified heart failure occurs in patients with multiple myeloma when their heart was involved. CMR with late gadolinium enhancement (LGE) and T1 mapping can identify myocardial amyloid infiltrations.PurposeTo explore the role of CMR with late gadolinium enhancement (LGE) and T1 mapping for detection of multiple myeloma patients’heart.Material and methodsA total of 16 MM patients with above underwent CMR (3.0-T) with T1 mapping (pre-contrast and post-contrast) and LGE imaging. In addition, 26 patients with non-obstructive hypertrophic cardiomyopathy and 26 healthy volunteers were compared to age- and sex-matched healthy controls without a history of cardiac disease, diabetes mellitus, or normal in CMR. All statistical analyses were performed using the statistical software GraphPad Prism. The measurement data were represented by median (X) and single sample T test was adopted. Enumeration data were represented by examples and Chi-tested was adopted. All tests were two-sided, and P values < 0.05 were considered statistically significant.ResultsIn MM group, LVEF was lower than healthy controls and higher than that of non-obstructive hypertrophic cardiomyopathy group, but without statistically significant difference (%: 49.1 ± 17.5 vs. 55.6 ± 10.3, 40.4 ± 15.6, all P > 0.05). Pre-contrast T1 values of MM group were obviously higher than those of healthy controls and non-obstructive hypertrophic cardiomyopathy group (ms:1462.0 ± 71.3vs. 1269.3 ± 42.3, 1324.0 ± 45.1, all P < 0.05). 16 cases (100%) in MM group all had LGE.ConclusionLGE joint T1 mapping wider clinical use techniques and follow-up the patients’disease severity.

Benefits of ninerafaxstat in non-obstructive hypertrophic cardiomyopathy.

Benefits of ninerafaxstat in non-obstructive hypertrophic cardiomyopathy.

Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy

BackgroundIn nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. ObjectivesThis study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. MethodsPatients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. ResultsA total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of −2.1 (95% CI: −3.6 to −0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: −2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). ConclusionsIn symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

Individual Approach to Prescribing Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common hereditary disease of the myocardium. Sodium-glucose co-transporter 2 inhibitors are recognized as first-line drugs for the treatment of heart failure, but at the moment there is little known about their use in HCM.&#x0D; The aim. To assess the possibility of using an acute test with empagliflozin in patients with HCM with echocardiographic assessment of left ventricular outflow tract (LVOT) obstruction.&#x0D; Materials and methods. Twenty-six non-obstructive HCM patients were examined. All the patients underwent an acute test with sodium-glucose co-transporter 2 inhibitor using 10 mg of empagliflozin and echocardiographic examination before and 3 hours after administration. Twenty-four patients were included in the further analysis (2 patients were excluded due to arrhythmia). The patients were divided into two groups: group 1 included subjects with an increase in LVOT pressure after empagliflozin (12 patients), group 2 included those without an increase in the gradient (12 patients).&#x0D; Results. During the acute test, an increase in LVOT gradient occurred in 12 patients, and in 6 patients the gradient increased significantly and reached more than 30 mm Hg. The indicator at rest in patients before the test was 11.2 (10.1-19), after the test it was 12.45 (8.9-17) mm Hg (p = 0.042). The indicator at the height of the Valsalva test also increased from 15 (11-29) to 15.45 (10.4-33) mm Hg (p=0.29). Comparative analysis of clinical and echocardiographic data did not show significant difference between the groups.&#x0D; Conclusions. In some patients with HCM without signs of overt or latent obstruction at the baseline, a significant increase in LVOT pressure was noted after acute test with empagliflozin. Conducting an acute test in patients with HCM is appropriate to determine the possibility of the development of LVOT obstruction while taking the drug.

Systemic Vascular Resistance and Myocardial Work Analysis in Hypertrophic Cardiomyopathy and Transthyretin Cardiac Amyloidosis with Preserved Left Ventricular Ejection Fraction.

Background: The pathophysiological impact of systemic vascular resistance (SVR) and pressure-strain loop-derived global myocardial work index (GWI) in hypertrophic cardiomyopathy (HCM) and transthyretin cardiac amyloidosis (ATTR) has been randomly investigated. Methods: Both SVR and GWI were assessed in outpatients consecutively referred at two Italian cardiology departments for heart failure with preserved left ventricular ejection fraction (LVEF), affected by either nonobstructive HCM or wild-type ATTR. Based on relevant cross-tabulations, the patients were gathered into 4 functional classes according to cut-off values of 1440 dyne/s/cm-5 for SVR, and 1576 mm Hg% for GWI, as suggested by previous studies. Results: A total of 60 patients, 30 in each group, aged 61 ± 16 years, with 78% males, were studied. HCM patients were younger than those with ATTR and in a better clinical condition (23% HCM vs. 77% ATTR were NYHA class II-III, p < 0.001). Overall, 51 patients (85%) showed a high SVR, 21/30 HCM (70%), and 30 ATTR (100%) (p < 0.005). Both SVR and GWI (expressions of ventricular-arterial coupling) were impaired in 43% of HCM patients (showing greater LV concentric hypertrophy) and 93% of ATTR patients (in advanced NYHA functional class) (p < 0.001). Conclusions: A substantial percentage of present study population showed impaired SVR and/or GWI, despite preserved LVEF. The proposed classification may shed further light on the pathophysiological and clinical characteristics of such hypertrophic phenotypes.

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4

This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM). Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤30 mmHg, left ventricular ejection fraction [LVEF] ≥60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] >300 pg/mL) received aficamten 5-20 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. 41 patients were enrolled (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF <50% (range: 41-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. Aficamten administration for symptomatic nHCM was generally safe and associated with improvements in heart failure symptoms and cardiac biomarkers. ClinicalTrials.gov Identifier: NCT04219826 LAY SUMMARY: Non-obstructive hypertrophic cardiomyopathy (nHCM) is a disease in which the heart muscle becomes abnormally thickened. There are no proven medical therapies. Aficamten is a new cardiac myosin inhibitor designed to target the underlying cause of HCM. REDWOOD-HCM Cohort 4 was the first study exploring the efficacy and safety of aficamten in people with symptoms from nHCM. Most patients reported improved health and functional status. There was also significant decrease in blood levels of biomarkers indicating excessive pressure within the heart and damage to heart muscle cells. These results support a larger placebo-controlled study of aficamten for people with nHCM (ACACIA-HCM).

Cumulative long-term efficacy and safety of mavacamten treatment in nonobstructive hypertrophic cardiomyopathy: updated interim analysis from the MAVERICK cohort of the MAVA-long-term extension (LTE) study up to 120 weeks

Cumulative long-term efficacy and safety of mavacamten treatment in nonobstructive hypertrophic cardiomyopathy: updated interim analysis from the MAVERICK cohort of the MAVA-long-term extension (LTE) study up to 120 weeks

A systematic review and meta-analysis of the efficacy and safety of Mavacamten therapy in international cohort of 524 patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common heritable myocardial disorder worldwide. Current pharmacological treatment options are limited. Mavacamten, a first-in-class cardiac myosin inhibitor, targets the main underlying pathology of HCM. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Mavacamten in patients with HCM. PRISMA flow chart was utilized using PubMed, SCOPUS, and Cochrane databases for all up-to-date studies using pre-defined keywords. Pre-specified efficacy outcomes comprised several parameters, including an improvement in peak oxygen consumption (pVO2) and ≥ 1 NYHA class, the need for septal reduction therapy (SRT), change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ), changes in biochemical markers and LVEF, along with peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Safety outcomes included morbidity and serious adverse events. This systematic review included five studies, four RCTs and one non-randomized control trial comprised a total of 524 (Mavacamten [273, 54.3%] vs placebo [230, 45.7%] adult (≥ 18 years) patients with a mean age of 56 years. The study. comprised patients with Caucasian and Chinese ethnicity and patients with obstructive (oHCM) and non-obstructive (nHCM) HCM. Most baseline characteristics were similar between the treatment and placebo groups. Mavacamten showed a statistically significant increase in the frequency of the primary composite endpoint (RR = 1.92, 95% CI [1.28, 2.88]), ≥ 1 NYHA class improvement (RR = 2.10, 95% CI [1.66, 2.67]), a significant decrease in LVEF, peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Mavacamten also showed a significant reduction in SRT rates (RR = 0.29, 95% CI [0.21, 0.40], p < 0.00001), KCCQ clinical summary scores (MD = 8.08, 95% CI [4.80, 11.37], P < 0.00001) troponin levels and N-terminal pro-B-type natriuretic peptide levels. However, there was no statistically significant difference between Mavacamten and placebo regarding the change from baseline peak oxygen consumption. Mavacamten use resulted in a small increase in adverse events but no statistically significant increment in serious adverse events.Our study showed that Mavacamten is a safe and effective treatment option for Caucasian and Chinese patients with HCM on the short-term. Further research is needed to explore the long-term safety and efficacy of Mavacamten with HCM. In addition, adequately powered studies including patients with nHCM is needed to ascertain befits of Mavacamten in those patients.

Neonatal hypertrophic cardiomyopathy with dyspnoea as the first symptom: a case report

Neonatal hypertrophic cardiomyopathy (HCM) is an idiopathic disease characterised by myocardial hypertrophy with normal or small ventricular chambers, a systolic hyperdynamic state and diastolic dysfunction. The etiology, pathogenesis and clinical manifestations of HCM are diverse, and it is likely to progress to sudden cardiac death. The highly heterogeneous nature of this disease determines the difficulty of its diagnosis, and it is especially rare to report that can be diagnosed conclusively in the neonatal period. However, when it does occur, the younger the age of onset is, the higher the mortality rate and the worse the prognosis. The genetic variants and diagnostic timing can affect the life course of the patient. This case report describes a neonate with a family history of HCM who was diagnosed with hypertrophic non-obstructive cardiomyopathy by echocardiography shortly after birth. At 4 years of age, the patient presented with slow weight gain, feeding difficulties, tachypnoea and diaphoresis, and cardiac ultrasound findings suggesting progression to severe hypertrophic obstructive cardiomyopathy, with a high likelihood of arrhythmias, heart failure, pulmonary hypertension, syncope and even sudden death. Neonatal congenital hypertrophic cardiomyopathy is extremely rare and difficult to diagnose before the onset of symptoms. Echocardiography has a definite diagnostic value in hypertrophic cardiomyopathy and helps in early detection and treatment. At the time of clinical diagnosis, children with hypertrophic cardiomyopathy should be asked about their family history and, if necessary, a survey of family members should be conducted for the early detection of mildly ill patients and gene carriers to enable timely intervention and treatment, which remains the focus of our research and efforts.

Non-obstructive hypertrophic cardiomyopathy exhibit subclinical abnormalities in systolic and diastolic ventricular kinetic energy and systolic haemodynamic forces on 4D flow CMR

Abstract Background Patients with non-obstructive hypertrophic cardiomyopathy (nHCM) exhibit a range of anatomical variations including septal, reverse septal, apical, and concentric hypertrophy. Cardiovascular magnetic resonance imaging (CMR) with 4D flow permits assessment of haemodynamic forces (HDF) and kinetic energy (KE) of intraventricular blood flow (1,2). These parameters may indicate subclinical flow inefficiencies which may not be detectable on routine transthoracic echocardiography (3,4). The aim of this study was therefore to investigate if left ventricular (LV) HDF and KE differ between nHCM and controls, and between subgroups of nHCM. Methods Patients with nHCM (n=71) and age- and sex-matched controls (n=20) underwent CMR at 3T (Trio, Siemens) (Table 1). Patients were categorised as phenotype positive (P+) based on presence of hypertrophy (maximum wall thickness ≥15mm, or ≥13mm with a positive family history), and as phenotype negative (P-) referring to pre-hypertrophic sarcomeric variant carriers. Patients with P+ nHCM were classified into subgroups based on the pattern of hypertrophy. Left ventricular HDF and KE were computed over the cardiac cycle using validated modules (1) (Figure 1). Measurements of HDF were based on the Navier-Stokes equations (1), and analysed in three orthogonal directions as root mean square and peak values for systole and diastole. Force ratio was calculated as the sum of the two transverse components divided by the longitudinal component. The Mann-Whitney U test was used for group comparisons, Pearson analysis for correlations, and Fisher’s exact test for binary categorical data. Results P+, P- patients and controls had comparable LV ejection fraction from CMR, LV outflow tract pressure gradients, and diastolic parameters on echocardiography (Table 1). Systolic HDF and force ratio were increased, primarily in the lateral wall-septum direction in septal and reverse septal P+ patients compared to controls, but did not differ in any other directions in P+ compared to P- patients and to controls (Table 1, Figure 1). Diastolic HDF and force ratio did not differ between groups. Systolic KE was increased in P+ patients compared to P- and to controls (Table 1, Figure 1), mainly through increased KE in patients with septal and reverse septal hypertrophy. P+ patients also had increased late diastolic (A-wave) KE relative to P- patients and to controls (Table 1). Both systolic KE and force ratio correlated with maximum wall thickness in patients (r=0.31, p=0.005; r=0.43, p&amp;lt;0.0001). Conclusion In non-obstructive hypertrophic cardiomyopathy, left ventricular HDF and KE analysis from 4D flow CMR detect subclinical flow abnormalities. Increased systolic HDF and KE are linked to the extent and pattern of hypertrophy. Late diastolic A-wave KE was also abnormal in P+ patients despite normal diastolic velocities on echocardiography.Table 1Figure 1

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Prior genome-wide association studies (GWAS) identified few genomic loci and disease genes due to limited sample size. Purpose To discover novel genetic loci, genes and mechanisms implicated in HCM using a large scale GWAS and multi-trait analysis of GWAS (MTAG). Methods and results We performed the largest HCM GWAS meta-analysis and MTAG to date including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We estimated the heritability of HCM attributable to common genetic variation (h2SNP) to be 0.25±0.02 using genome-based restricted maximum likelihood (GREML), with higher h2SNP in non-sarcomeric (0.29±0.02) compared to sarcomeric HCM (0.16±0.04). We identified a total of 70 loci (50 novel) associated with HCM (Figure 1), and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin. We performed rare variant burden analysis including 1,845 clinically-diagnosed unrelated HCM cases and 37,481 controls and demonstrated a 10.5-fold (95% CI: 4.1-26.8; P=0.0000002) excess burden of SVIL loss of function (LoF) variants in HCM cases. Two-sample mendelian randomization analyses using LV contractility as exposure and obstructive (oHCM) and non-obstructive HCM (nHCM) as outcomes support a causal role of increased LV contractility in both oHCM and nHCM (Figure 2), suggesting common disease mechanisms and anticipating shared response to therapy. Conclusion We identify 50 novel genomic loci associated with HCM. Our data suggest that LoF variants in SVIL are a cause of HCM, and that increased contractility mediate both nHCM and oHCM. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.Figure 1Figure 2

Association between scar quantification and documented history of ventricular tachycardia in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a major risk factor for sudden cardiac death, and it is crucial to accurately identify patients who may benefit from implantable cardioverter defibrillator (ICD) implantation. Therefore, accurate risk stratification remains an unmet clinical need for patients with obstructive (HOCM) and non-obstructive (HNCM) hypertrophic cardiomyopathy. Methods and Aim Consecutive HCM patients were enrolled at a tertiary academic center and underwent cardiac magnetic resonance imaging. We aimed to explore risk factors for a documented history of ventricular tachycardia (VT). Results In total 246 HCM (160 HNCM, 86 HOCM) patients were included in the present analysis. Patients with HOCM and HNCM had similar rates of documented VTs (20.0% vs. 23.2%, p=0.61). However, the HCM-risk-score was significantly lower in HNCM patients (4.56% vs. 3.36%, p=0.003). There was no significant difference in age (53 vs. 57 years, p=0.65), sex (female sex 30% vs. 42%, p=0.14), or echocardiographic parameters, including the maximum outflow tract gradient (59 vs. 67 mmHg, p=0.71), the maximum wall thickness (21 vs. 20 mm, p=0.088), and the left atrial diameter (57 vs. 56 mm, p=0.59), in patients with versus without a history of documented VT. Furthermore, NT-proBNP (1040 vs. 1199 pg/mL, p=0.74) and high sensitivity troponin-T levels (22 vs. 19 ng/L, p=0.38) did not differ between groups. Patients with a history of VT were significantly more likely to have late gadolinium enhancement (LGE, 80% vs 50%, p=0.007) and had a higher percentage of LGE in relation to the left ventricular mass (9.2% vs 3.7%, p=0.001). These findings were consistent in patients with HOCM and HNCM (3.32% vs. 5.72% p=0.085). In an adjusted logistic regression model, the percentage of LGE was independently associated with the presence of VT (Odds ratio 1.27 [95%CI 1.08-1.50]). Conclusion These findings suggest that LGE may be a useful imaging marker for risk assessment in patients with HOCM and HNCM.

Sacubitril/valsartan for treatment of symptomatic non-obstructive hypertrophic cardiomyopathy: a randomised, controlled, phase II clinical trial (SILICOFCM)

Abstract Aim To evaluate the effect of sacubitril/valsartan on exercise capacity, cardiac structure, and function in patients with hypertrophic cardiomyopathy (HCM). Methods Phase II, randomised, open-label multicentre study enrolled adult patients with symptomatic non-obstructive HCM (NYHA class I–III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103mg) or usual care for 16 weeks. Primary endpoint was a change in peak oxygen consumption (peak VO2). Secondary endpoints included echocardiography measures of cardiac structure and function, natriuretic peptides and other biomarkers, and Minnesota Living with Heart Failure quality of life (QoL). Results Between May 2018 and November 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years [SD 11], 37% women) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (N=79) or usual care (N=36). At 16 weeks, there was no significant change in peak VO2 from baseline in sacubitril/valsartan (15.3 [4.3] vs 15.9 [4.3] ml/kg/min, p=0.13), or usual care group (p=0.47). There was a significant reduction in ventilatory efficiency slope (30.1 [7] vs 28.4 [4.9], p=0.03), but not in the control group (p=0.09). No significant changes were found in systolic or diastolic function, cardiac structure, or plasma biomarkers. The QoL score decreased significantly in the sacubitril/valsartan by 6 points (p=0.005) but not in the usual care group (p=0.66). Conclusion In patients with hypertrophic cardiomyopathy, 16 weeks of treatment with sacubitril/valsartan was well tolerated and contributed to a significant improvement in ventilatory efficiency and quality of life but not in exercise capacity or cardiac function.

Abstract 16562: Subclinical Flow Inefficiencies in Non-Obstructive Hypertrophic Cardiomyopathy Subgroups Revealed by 4D Flow Cardiovascular Magnetic Resonance

Background Patients with non-obstructive hypertrophic cardiomyopathy (nHCM) may exhibit flow inefficiencies despite normal flow profiles on transthoracic echocardiogram. We investigated whether left ventricular (LV) kinetic energy (KE) and hemodynamic forces (HDF) on 4D flow CMR are abnormal in nHCM, and examined the impact of genotype and hypertrophy phenotype on flow profiles. Methods 90 participants (70 HCM without echocardiographic outflow tract obstruction and 20 healthy controls) underwent 4D flow CMR. Patients were categorized as phenotype positive (P+) if they had LV hypertrophy (≥15mm or ≥13mm with an HCM family history), or phenotype negative (P-) referring to pre-hypertrophic pathogenic sarcomeric variant carriers. LV KE, HDF and transversal/longitudinal HDF ratio were computed from 4D flow CMR. Results P+ patients and controls were of similar age, but P- were younger. P+, P- and controls had comparable LV ejection fraction on CMR, and LV outflow tract pressure gradients and diastolic velocities on echocardiography (Table 1). Systolic KE was higher in P+ compared to controls (Table 1, Figure 1). Early diastolic KE was higher in P- than P+, reflecting younger P-, but did not differ between P+ and controls. Late diastolic KE was higher in P+ versus P- and controls. Systolic HDF ratio was higher in P+ than controls (Table 1, Figure 1). Diastolic HDF and HDF ratio were similar between P+ and controls. Conclusion Despite comparable flow velocities on echocardiography, nHCM exhibited higher systolic KE and HDF ratio, and late diastolic KE on 4D flow CMR relative to controls. Both the extent and pattern of hypertrophy are important determinants of abnormalities in KE and HDF.

Abstract 14463: Beyond Sarcomere Mutations Plakophilin-2 and Familial Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder with diverse clinical presentation, course and outcomes. It is commonly caused by mutations in sarcomeric genes. Non-sarcomeric gene mutations have been associated with HCM in certain metabolic and storage diseases. Pathogenic mutations in plakophilin-2 (PKP2) gene have been associated with enhanced desmosomal protein degradation and linked to arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome and dilated cardiomyopathy. We report an association between PKP2 gene mutation and familial HCM. Case presentation: A 65-year-old man with family history of HCM (maternal grandfather, 2 aunts and an uncle) presented with dyspnea on exertion (NYHA class II-III) and pedal edema. Echo showed severe LVH, mid-cavitary obstruction and LV apical aneurysm. Cardiac MRI confirmed findings (Figure:A and B) and additionally showed significant late gadolinium enhancement (Figure:C and D, &gt;20% of LV myocardium). Extended ambulatory heart monitor detected frequent runs on non-sustained ventricular tachycardia. A primary prevention ICD was implanted. Genetic testing identified a pathogenic mutation [c.1237C&gt;T (p.Arg413*)] in exon 5 of PKP2 gene resulting in premature translational stop signal and disrupted desmosomal protein plakophilin-2. Family screening (Figure:E) identified a sister with positive results who also had non-obstructive HCM (Figure:E). Discussion: We present a family with typical presentations of HCM and no phenotypic evidence of ARVC. This novel observation provides evidence for pleiotropic model of complex genotype-phenotype interactions through nonlinear networks. Further evidence would be needed to understand potential molecular basis of hypertrophic signaling in PKP2 gene mutation.

Abstract 14636: Social Determinants of Health and Clinical Outcomes in a Diverse Hypertrophic Cardiomyopathy Cohort

Introduction: Contemporary studies are needed to evaluate impact of social determinants of health (SDH) and clinical outcomes in diverse hypertrophic cardiomyopathy (HCM) populations. Hypothesis: Among predominant Black/Hispanic minority population, HCM-related death is higher than reported literature and may be related to SDH. Methods: Data from HCM patients were obtained in a large academic safety-net hospital from 2017 to 2022. Outcomes including heart failure (HF), atrial fibrillation, stroke, ventricular arrhythmias, septal reduction therapy (SRT) and death were obtained by chart review. Zip codes were extracted using the SDH database from the Neighborhood Atlas from University of Wisconsin to determine area deprivation index (ADI 1-10, higher ADI signifies greater neighborhood disadvantage). Chi-square and binary logistic regression analyses were conducted to assess association between ADI and outcomes, adjusting for demographic data. Results: At baseline, 118 HCM patients, were 52 ± 15 years old, 44% female, 54% Black, 20% Hispanic, 10% White, BMI 31± 6 kg/m2, and ESC score 2.4 ± 1.9. Seventy-eight (82%) patients had nonobstructive HCM (22 % apical variant) with maximal wall thickness of 19 ± 6 mm; 14% had late gadolinium enhancement (LGE) &gt; 15%. Among 50% patients with genetic testing, 31% had a pathogenic/likely pathogenic sarcomere variant and 44% had variants of unknown significance. Over 6.3 years follow up (IQR 6.6), 20% patients developed incident HF, 19% AF, 8% SRT, and 6 (5%) patients suffered HCM-related death. Among the 23% of patients who had an ICD placed, 15% had appropriate ICD shock over 7 ± 7 years. Among the 105 patients with available zip codes, 44% patients had ADI &gt; 6. There was no association between ADI and global outcome (OR [95% CI] = 1.32 [0.6-2.9], p = 0.49) or HCM-related death (OR [95% CI] = 0.46 [0.7-2.9], p = 0.41). Conclusions: Compared to published literature, our cohort was mainly Black/Hispanic with high degree of apical remodeling and low frequency of obstruction, highlighting need for focused efforts to improve HCM diagnosis in this population. Further, global outcome and HCM-related death were not related to zip-code level SDH. Larger diverse cohorts are needed to include individual level SDH in relation to outcomes.