Nonobstructive Hypertrophic Cardiomyopathy Research Articles

Advancements in the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Comprehensive Review.

Hypertrophic cardiomyopathy (HCM) is characterized by excessive growth of myocardial tissue, most commonly due to genetic mutations in sarcomere proteins. This can lead to complications such as heart failure, mitral regurgitation, syncope, arrhythmias, sudden cardiac death, and myocardial ischemia. While we have come a long way in our understanding of the pathophysiology, genetics, and epidemiology of HCM, the past 10 years have seen significant advancements in diagnosis and treatment. As the body of evidence on hypertrophic cardiomyopathy continues to grow, a comprehensive review of the current literature is an invaluable resource in organizing this knowledge. By doing so, the vast progress that has been made thus far will be widely available to all experts in the field. This review provides a comprehensive analysis of the scientific literature, exploring both well-established and cutting-edge diagnostic and therapeutic options. It also presents a unique perspective by incorporating topics such as exercise testing, genetic testing, radiofrequency ablation, risk stratification, and symptomatic management in non-obstructive HCM. Lastly, this review highlights areas where current and future research is at the forefront of innovation in hypertrophic cardiomyopathy.

Ninerafaxstat in the Treatment of Diabetic Cardiomyopathy and Nonobstructive Hypertrophic Cardiomyopathy.

Ninerafaxstat is a novel mitotrope under investigation in 2 large clinical trials: IMPROVE-DiCE (a phase IIa trial investigating ninerafaxstat) and IMPROVE-hypertrophic cardiomyopathy (HCM). IMPROVE-DiCE is a single-center, open-label, phase 2a trial investigating the effectiveness of ninerafaxstat in diabetic cardiomyopathy. Ninerafaxstat significantly improved phosphocreatine/adenosine triphosphate median by 32% (P < 0.01) and reduced myocardial triglyceride content by 34% (P = 0.026). Magnetic resonance imaging (MRI) analysis showed improved left ventricular peak circumferential diastolic strain rate by 15% (P < 0.047) and peak left ventricular filling rate by 11% (P < 0.05). Pyruvate dehydrogenase flux was increased in 7 of 9 patients (P = 0.08), consistent with improved glucose utilization. IMPROVE-HCM (ninerafaxstat safe, effective for nonobstructive hypertrophic cardiomyopathy patients) is a phase 2, multicenter, randomized controlled and double-blinded study. From baseline to 12 weeks, ninerafaxstat was associated with a significantly improved ventilatory efficiency slope compared with placebo (P = 0.006). In a post hoc analysis with 35 patients with baseline Kansas City Cardiomyopathy Questionnaire score ≤80, changes in ventilatory efficiency slope favored ninerafaxstat versus placebo (P = 0.02). Left atrial size, a surrogate marker of diastolic dysfunction, was significantly decreased in patients on ninerafaxstat versus placebo (P = 0.01). These findings support a larger phase 3 study in symptomatic nonobstructive HCM patients to further investigate ninerafaxstat. Several drugs that also improve glucose utilization including fatty acid oxidation inhibitors, carnitine palmitoyltransferase I inhibitors, and glucagon-like peptide-1 receptor agonists are presently under investigation in clinical trials.

Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: A 36-week analysis from FOREST-HCM.

The aim of this study was to report safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST-HCM trial. Patients were started on aficamten 5 mg daily, with doses adjusted in 5-mg increments (5-20 mg) at ≥2-week intervals according to site-read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50-54%, decreased if LVEF 40-<50%, and temporarily interrupted if LVEF <40%. Safety and efficacy were assessed over 36 weeks. Overall, 34 patients were enrolled (mean age 57.2 ± 15.3 years, 62% female, 41% in New York Heart Association [NYHA] class III). Over 36 weeks, 82.3% achieved 15-20 mg daily dose and there was a modest reduction in LVEF by -4.3% ± 5.2 from 70% ± 6.1 (p < 0.0001). At Week 36, NYHA class improved by ≥1 class in 27 (79.4%) patients. Mean Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 13.8 ± 12.5 points relative to baseline. Median (interquartile range) levels of N-terminal pro-B-type natriuretic peptide were significantly improved from baseline (-665.5 pg/ml [-1244.0, -232.0]; p < 0.0001), while high-sensitivity cardiac troponin I was unchanged (-2.7 ng/L [-11.3, 1.6]; p = 0.25). There were no drug discontinuations due to adverse events. LVEF <50% occurred in 2 (5.9%) patients, one following pulmonary vein isolation and one associated with atrial fibrillation. Over 36 weeks, aficamten appeared safe and effective in the studied patients with nHCM.

Flow inefficiencies in non-obstructive HCM revealed by kinetic energy and hemodynamic forces on 4D-flow CMR.

Patients with non-obstructive hypertrophic cardiomyopathy (HCM) exhibit myocardial changes which may cause flow inefficiencies not detectable on echocardiogram. We investigated whether left ventricular (LV) kinetic energy (KE) and hemodynamic forces (HDF) on 4D-flow cardiovascular magnetic resonance (CMR) can provide more sensitive measures of flow in non-obstructive HCM. Ninety participants (70 with non-obstructive HCM and 20 healthy controls) underwent 4D-flow CMR. Patients were categorized as phenotype positive (P+) based on maximum wall thickness (MWT) ≥ 15 mm or ≥13 mm for familial HCM, or pre-hypertrophic sarcomeric variant carriers (P-). LV KE and HDF were computed from 4D-flow CMR. Stroke work was computed using a previously validated non-invasive method. P+ and P- patients and controls had comparable diastolic velocities and LV outflow gradients on echocardiography, LV ejection fraction, and stroke volume on CMR. P+ patients had greater stroke work than P- patients, higher systolic KE compared with controls (5.8 vs. 4.1 mJ, P = 0.0009), and higher late diastolic KE relative to P- patients and controls (2.6 vs. 1.4 vs. 1.9 mJ, P < 0.0001, respectively). MWT was associated with systolic KE (r = 0.5, P < 0.0001) and diastolic KE (r = 0.4, P = 0.005), which also correlated with stroke work. Systolic HDF ratio was increased in P+ patients compared with controls (1.0 vs. 0.8, P = 0.03) and correlated with MWT (r = 0.3, P = 0.004). Diastolic HDF was similar between groups. Sarcomeric variant status was not associated with KE or HDF. Despite normal flow velocities on echocardiography, patients with non-obstructive HCM exhibited greater stroke work, systolic KE and HDF ratio, and late diastolic KE relative to controls. 4D-flow CMR provides more sensitive measures of haemodynamic inefficiencies in HCM, holding promise for clinical trials of novel therapies and clinical surveillance of non-obstructive HCM.

Discontinuation of afterload-reducing drugs decreases left ventricular outflow tract obstruction in hypertrophic obstructive cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), the most common genetic heart disease, is classified into hypertrophic non-obstructive and hypertrophic obstructive cardiomyopathy (HOCM). Patients with HOCM and coexisting heart failure or arterial hypertension are often prescribed afterload-reducing drugs. Although recommended in current guidelines, data on the direct effect of discontinuing afterload-reducing medication are scarce. This study aims to demonstrate the benefit of discontinuing afterload-reducing medication in HOCM patients. This monocentric retrospective analysis included 24 patients with HOCM with afterload-reducing medication, including angiotensin-converting enzyme inhibitors, angiotensin-1 receptor blocker and dihydropyridine-calcium channel blocker, at their first outpatient visit. Effects of discontinuing this medication on LVOTO were examined compared to patients with persistent use despite medical advice. 16 patients discontinued their afterload-reducing drugs, resulting in a significant decrease in median LVOT gradient from 86.5 [60.5-109.3] mmHg to 61.5 [28.3-97.50] mmHg (p = 0.0004). In 6 patients, beta-blocker therapy was initiated simultaneously, or the dose was increased. Regardless, LVOT gradient reduction was also significant in the remaining 10 patients (p = 0.001). The gradient was not changed significantly in the 8 patients continuing their afterload-reducing medication. Discontinuation of afterload-reducing drugs significantly decreases LVOTO. Our study underscores the significance of abstaining from afterload-reducing drugs in HOCM patients, particularly in patients with concomitant hypertension or heart failure. According to recently published European guidelines, HOCM patients should preferably be treated with beta-blockers or non-dihydropyridine-calcium channel blockers.

Risk Factors of Cardiac Complications in Pregnant Women with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common inherited genetic cardiac disease during pregnancy. Studies of risk factors are of great significance for maternal and fetal outcomes. The aim of the study was to identify predictive risk factors for cardiac complications in pregnant women with HCM. One hundred patients with HCM who delivered at the Shanghai obstetrical cardiology intensive care center between January 2000 and December 2022 were retrospectively reviewed. A logistic regression model was used to identify independent risk factors for cardiac complications. Twenty-one cases were obstructive HCM (21%), 16 with cardiac function grade I and 5 with grade II; 79 cases were non-obstructive HCM (79%), 67 with cardiac function grade I, 11 with grade II, and 1 with grade III. Ninety-one cases had abnormal electrocardiogram (ECG) (91%), mainly with ST-T changes (77%). The average interventricular septum was 19.39 ± 6.13 mm by echocardiography (21.75 ± 5.86 mm for obstructive HCM and 18.73 ± 6.08 mm for non-obstructive HCM). The main cardiac complications were maternal death (n = 2, 2%), heart failure (n = 7, 7%), and sustained ventricular tachyarrhythmia (n = 1, 1%). Cardiac complications occur commonly during the third trimester and postpartum period. Three independent risk factors to predict cardiac complications in pregnant women with HCM were obstructive HCM (P = 0.036), New York Heart Association (NYHA) class ≥II (P = 0.022), and previous history of syncope (P = 0.037). HCM increases the risk of maternal death, heart failure, and malignant arrhythmia. More attention should be given to risk assessment and pregnancy management. Early detection of risk factors can reduce the incidence of maternal mortality and cardiac complications.

Changes in left ventricular-aortic angulation are associated with the development of obstruction in hypertrophic cardiomyopathy

ObjectiveTo characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy who develop left ventricular (LV) outflow tract obstruction. MethodsWe reviewed patients with hypertrophic cardiomyopathy with LV outflow tract obstruction who underwent septal myectomy from May 2012 to June 2023. Among 68 patients initially without obstruction documented up to 7.6 years (interquartile range, 6.3-9.4 years) before the operation, a comparison was made with 78 patients with nonobstructive hypertrophic cardiomyopathy over a similar period. Patients who did not develop obstruction were matched with those who did on sex, age, and maximum septal wall thickness during the initial echocardiography, identifying 41 matched pairs. Echocardiographic data, including 5 measures of angulation, were compared between the groups. ResultsThe median interval between echocardiographic assessments was 7.5 years (interquartile range, 6.3-8.1 years) among patients with obstruction versus 7.3 years (interquartile range, 6.2-9.0 years) in patients without nonobstruction. Patients with obstruction were more likely to have hypertension at both times. The maximum septal wall thickness increased within both groups (both P values < .001), but the magnitude of increase was not different between groups (P = .130). Patients with obstruction exhibited a greater increase in LV mass (P < .001) compared with patients without obstruction (P = .004). Aortic angulation significantly increased in 4 of the 5 measurements (all P values < .001) in patients with obstruction, whereas patients with no obstruction showed no change. Anterior and posterior mitral valve leaflet lengths and coaptation lengths remained similar in both groups over time. ConclusionsThe development of LV outflow tract obstruction in patients with hypertrophic cardiomyopathy was associated with progressive LV outflow tract angulation and increased LV hypertrophy, as reflected by LV mass. Progression to obstruction was not related to changes in the mitral valve leaflet morphology.

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’ &amp;gt; 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&amp;lt;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.