Childhood-onset RASopathy-associated hypertrophic cardiomyopathy, diastolic dysfunction, and arrhythmias

Introduction: Hypertrophic cardiomyopathy (HCM) can lead to heart failure with preserved ejection fraction (HFpEF) due to left ventricular outflow tract obstruction (LVOTO). Septal myectomy can relieve LVOTO leading to resolution of HFpEF. However, some patients have persistent HFpEF even after myectomy without LVOTO. We aimed to characterize HCM patients with HFpEF post myectomy compared to those without HFpEF post myectomy and those with HFpEF and non-obstructive HCM. Hypothesis: There are distinct features of HCM patients with HFpEF after myectomy, no HFpEF after myectomy, and non-obstructive HCM with HFpEF. Methods: In this retrospective study, patients over age 18 were screened for HCM diagnosis between years 2003 and 2020, HCM was confirmed with echocardiogram and chart review. HFpEF was defined as use of loop diuretic for decongestion, with a left ventricular ejection fraction 50% or greater. Patients with septal myectomy were identified. Analysis of variance and chi-squared tests were performed. Results: Of 2571 patients with HCM diagnosis, there were 194 patients with HCM and HFpEF, 27 patients had HFpEF after myectomy (30%) compared to 61 patients without HFpEF after myectomy. 106 patients had nonobstructive HCM with HFpEF. A significant number of patients identifying as black or African American were in the nonobstructive HFpEF group. Hypertension was more prevalent in those with HFpEF after myectomy and non-obstructive HCM with HFpEF. Stroke was increased in the non-obstructive HCM with HFpEF (Table). Conclusions: 30% of HCM patients develop HFpEF post myectomy, with a higher incidence of hypertension compared to those without HFpEF. Non-obstructive HCM patients, more frequently black and African American, had higher rates of hypertension and diabetes, and higher risk of ischemic stroke and mortality. These phenotypes of HCM represent an important area of investigation to assess risk for stroke and development of HFpEF after myectomy.

Background: Reduced myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) in the absence of epicardial coronary artery stenosis are commonly attributed to microvascular dysfunction, a key pathophysiological feature of hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Conventional vasodilator stress may not adequately reflect exercise capacity or the hemodynamic responses characterizing these conditions. To better understand exercise-induced myocardial perfusion response, we performed quantitative myocardial perfusion in conjunction with exercise stress cardiovascular magnetic resonance imaging (Ex-CMR). Methods: A total of 108 patients (59±13 years, 43 male) with HCM, HFpEF, or non-cardiac dyspnea (NCD) were prospectively recruited for Ex-CMR at 3T using a CMR-compatible supine ergometer. Diagnoses of HCM and HFpEF were made according to current guidelines. Dyspneic patients without cardiac abnormalities were classified as NCD. Patients with obstructive coronary artery disease were excluded. Ex-CMR was performed using a standardized protocol (Fig. 1A) , hemodynamic responses and symptoms were recorded ( Fig. 1B and C) . Quantitative CMR perfusion was acquired at three short-axis slice positions at rest and after peak exercise ( Fig. 2A) . Results: Acquisitions with impaired image quality and segments with late gadolinium enhancement were excluded. The final cohort comprised 97 patients ( Table 1). No significant differences in MBF during exercise or MPR were observed between patients with and without subjective symptoms or perceived high exertion ( Fig. 1D ). MBF at rest did not differ among the three groups (p=0.266) ( Fig. 2B ). Post-exercise MBF was higher in HFpEF patients, compared to NCD and HCM patients, while MPR was similar between HFpEF and NCD patients (1.41 vs.1.44, p=0.686), but lower in HCM compared to NCD (1.27 vs.1.44, p=0.005) and HFpEF (1.27 vs.1.41, p=0.019). Using multivariable linear regression, a higher exercise-induced heart rate was independently associated with both higher post-exercise MBF and MPR. Conclusion: Ex-CMR identified distinct responses of MBF and MPR among patients with HCM compared to HFpEF and NCD. Post-exercise MBF is lower and MPR substantially worse when compared to NCD, as well as patients with HFpEF. These data show promise in defining abnormalities in exercise performance and the mechanism for functional limitations in HCM.

The significance of the progression of systolic and diastolic dysfunctions in hypertrophic cardiomyopathy (HCM) is still an open issue. We sought to evaluate the clinical and prognostic implications of the progression of left ventricular systolic and diastolic dysfunction in HCM. One hundred one HCM patients were studied by echo-Doppler at baseline and during follow-up. During a follow-up of 109 + or - 67 months, 28% of patients showed a progression to left ventricular diastolic dysfunction, defined as restrictive filling pattern (RFP), and 16% to left ventricular systolic dysfunction (left ventricular ejection fraction <50%). The 10-year heart transplant-free survival rate was 45% in patients with RFP at follow-up vs. 82% in the patients without RFP (P < 0.001), and 52% in patients with left ventricular systolic dysfunction at follow-up vs. 75% in the patients with left ventricular ejection fraction of at least 50% (P = 0.001). Baseline predictors of death/transplantation were New York Heart Association class III-IV, indexed left atrial diameter, and RFP. When RFP and left ventricular systolic dysfunction were added at follow-up, both emerged as prognostic predictors (RFP: hazard ratio 8.92, 95% confidence interval 2.5-31.86; systolic dysfunction: hazard ratio 25.35, 95% confidence interval 3.57-179.88) with a significant increase of area under the receiver-operating characteristic curves (0.81 vs. 0.70, P = 0.03) with respect to the baseline model. Left ventricular diastolic and/or systolic dysfunction at follow-up are relatively frequent in HCM and are associated with a poor prognosis.

Background Considerable data are available concerning improvements in diagnostic approaches over recent years for the treatment of heart failure with reduced ejection fraction (HFrEF). Conversely, regarding heart failure with preserved ejection fraction (HFpEF), there has been relatively little change in terms of therapy and prognostic stratification. Many efforts have been made to phenotype HFpEF spectrum, aiming to identify simple and reliable tools for recognizing patients at high risk for mortality. Purpose The aim of the present study is to identify a prognostic tool for all-cause mortality in patients with HFpEF. Methods From 2013 to 2024 thirty-eight HFpEF patients who underwent both transthoracic echocardiography at rest and cardiopulmonary exercise test (CPET) combined with echocardiography have been enrolled. Patients with established cardiomyopathy, such as hypertrophic cardiomyopathy and cardiac amyloidosis, have been excluded from the analysis. Mean follow-up period was 3,7 years. Primary outcome was all-cause mortality. Results Sixteen patients (42%) died during the study's follow-up period. No statistically significant differences were found for clinical, demographic, and therapeutic variables. Among all echocardiographic parameters, both at rest and during exertion, E/e' at rest (12 [8.9-19] vs. 17 [12-33], p-value 0.023), SPAP at rest and during exertion (31 ± 7 vs. 43 ± 16, p-value 0.021 and 51 ± 10 vs. 66 ± 17, p-value 0.019), TAPSE/SPAP at rest and during exertion (0.67 ± 0.15 vs. 0.47 ± 0.20, p-value 0.005 and 0.48 ± 0.15 vs. 0.33 ± 0.12, p-value 0.019), and left atrial reservoir function (22 [15-29] vs. 9.4 [6-15], p-value 0.001) were significantly associated with all-cause mortality (Table 1). Among CPET variables, respiratory exchange rate and oxygen pulse were associated with all-cause mortality (1.1 ± 0.13 vs. 1.18 ± 0.15, p-value 0.021 and 10 [7-11] vs. 8.1 [5.4-8.7], p-value 0.008) (Table 1). In multivariate analysis, the only independent predictor of mortality was left atrial reservoir function (p-value 0.026, OR 1.17 [1.02-1.35]). The optimal cutoff was identified using the Youden Index analysis (cut-off: 16.4%, sensitivity 85%, specificity 68%; AUC 0.839 [0.710-0.969]) (Figure 1). Survival curves based on the optimal cutoff are reported in Figure 1. Conclusions In a cohort of patients with HFpEF the left atrial reservoir function remains an important prognostic determinant for all-cause mortality. These results highlight the importance of estimating left ventricular filling pressures which are higher in patients diagnosed with HFPEF due to diminished ventricular compliance. Further studies with a larger cohort are needed to confirm these preliminary data.

Characterization of atrial histology in a patient with hypertrophic cardiomyopathy: Possible evidence of a primary atrial myopathy

Introduction: Mavacamten is a cardiac myosin inhibitor that has been approved for obstructive hypertrophic cardiomyopathy (oHCM). The CardioMEMS PA (pulmonary artery) sensor allows remote pulmonary artery diastolic (PAD) pressure monitoring to adjust diuresis in heart failure with preserved ejection fraction (HFpEF). We present the case of a patient with oHCM and HFpEF where data extrapolated from CardioMEMS provided valuable insight to the hemodynamic impact of cardiac myosin inhibitors. Case: A 66-year-old female with hypertension, obesity and oHCM presented with worsening dyspnea and was evaluated for septal myectomy. However, surgery was deferred because of decompensated HFpEF, as evidenced by significant leg edema on exam, and severely elevated left and right-side filling pressure, with restrictive physiology on right heart catheterization. A CardioMEMS PA sensor was implanted to guide decongestion, however, escalation of diuresis was limited due to severe left ventricular outflow tract (LVOT) obstruction. PAD remained elevated at 20-30 mmHg. Due to the refractory LVOT obstruction and despite the use of maximally tolerated beta blockers, Mavacamten was initiated and escalated according to protocol. LVOT obstruction resolved on follow up echocardiogram. Without any adjustment in her diuretic regimen, her PAD decreased to 15-20 mmHg. On follow-up visit, the patient reported improvement in dyspnea and reduction in lower extremity edema. Discussion: Managing oHCM is challenging, particularly when complicated by HFpEF. Mavacamten has shown promise in reducing LVOT gradients and improving symptoms in oHCM. However, managing fluid status in these patients can be difficult due to the risk of exacerbating LVOT obstruction while optimizing filling pressures. Our case provides direct evidence that treating LVOT obstruction with a cardiac myosin inhibitor leads to improvement in decompensated heart failure, as evidenced by the reduction in PAD. Conclusion: Addressing LVOT obstruction is key to decongesting and managing heart failure in oHCM patients. In our case, the use of CardioMEMS PA sensor system allowed a novel perspective of assessing hemodynamic impact of cardiac myosin inhibitors.

Left Ventricular Torsion by Two-Dimensional Speckle Tracking Echocardiography in Patients with Diastolic Dysfunction and Normal Ejection Fraction

Clinical value of the tissue Doppler derived index of myocardial performance (Tei index) in cats with hypertrophic cardiomyopathy.

To clarify the histopathologic influence on diastolic function in the hypertrophied heart, we compared the echocardiographic and histopathologic findings in 9 controls, 10 patients with hypertrophic cardiomyopathy (HCM), and 8 hypertensive patients with asymmetric septal hypertrophy (HT-ASH). M-mode echocardiography was used to determine the left ventricular diastolic function. Mean diameter of myocytes, percentage of fibrosis and disarrangement were quantitatively calculated from right ventricular endomyocardial biopsy specimens. In both HT-ASH and HCM, the isovolumic relaxation time was significantly longer and the rapid filling volume tended to be smaller than in the controls. Histopathologically, the mean diameter of myocytes and percentage of myocardial interstitial fibrosis did not differ significantly between HT-ASH and HCM. However, quantitative disarrangement of myocytes in HCM was significantly greater than that in HT-ASH. Multiple regression analysis showed that the percentage of fibrosis was the most significant factor related to diastolic left ventricular dysfunction in HT-ASH, while disarrangement of myocytes was the most significant in HCM. We conclude that diastolic dysfunction in HT-ASH can be attributed to the percentage of fibrosis, and to disarrangement of myocytes in HCM.

Background In patients with heart failure with preserved ejection fraction (HFpEF), studies have described different HFpEF phenogroups based on medical comorbidities and variable echocardiographic, invasive hemodynamic, and biomarker data. We hypothesized that myocardial histopathologic findings may define phenogroups with differing clinical features and outcomes in patients with HFpEF. Methods We analyzed consecutive patients with left HF and EF ≥50% who underwent right ventricular septal endomyocardial biopsy (EMB) at our institution between 2001 and 2022 to investigate HF etiology. Patients with infiltrative or hypertrophic cardiomyopathy, sarcoidosis, myocarditis, primary valvular heart disease, constrictive pericarditis, isolated right HF, or insufficient EMB samples were excluded. Clinical, echocardiographic, and invasive hemodynamic data were collected. The severity of hypertrophy and fibrosis on EMB specimens was characterized (semiquantitative grading) by experienced cardiac pathologists based on standard histologic stains. Patients were stratified into four phenogroups based on EMB findings: "mild" (none/mild hypertrophy and fibrosis), "hypertrophy" (moderate/marked hypertrophy, minimal/mild fibrosis), "fibrosis" (moderate/marked fibrosis, none/mild hypertrophy), and "severe" (moderate/marked hypertrophy and fibrosis). Results Among the 121 patients analyzed, the median age was 67 years, 50% were female and cardiovascular conditions were common (Table 1). Fibrosis was graded as minimal in 21% (n=25), mild in 64% (n=77), moderate in 12% (n=15), and marked in 3% (n=4). Hypertrophy was graded as none in 4% (n=5), mild in 41% (n=50), moderate in 40% (n=48), and marked in 15% (n=18). Only one patient had the isolated "fibrosis" phenogroup and was excluded from further analysis, while 54 had the "mild", 48 had the "hypertrophy", and 18 had the "severe" phenogroup (Table 1). The "hypertrophy" phenogroup exhibited significantly higher rates of hypertension, diabetes, RV dilation, and higher pulmonary artery pressures. Over a median follow-up of 7.9 years (3.1–13.8), mortality rate varied according to the histopathologic phenogroups (Figure 1, p=0.034) with "severe" having the worst and "mild" having the best outcomes. Survival analyses based on fibrosis grades alone, hypertrophy grades alone, or echocardiographic hypertrophy did not reveal significant differences (all p = NS). Differences in survival remained significant adjusting for age (HR 3.39, 95% CI 1.20-9.58). Conclusions The integrated severity of histopathologic hypertrophic and fibrotic remodeling defined HFpEF phenogroups with variable prognosis. Clinical features did not reliably identify histopathologic phenogroups. These data suggest that advanced myocardial phenotyping (e.g., gene, protein, metabolism) may reveal unique HFpEF myocardial subtypes in need of specific therapies.Figure 1

End stage hypertrophic cardiomyopathy occurs in an estimated 3–15 % of patients and can present as either systolic or diastolic dysfunction. Risk factors for developing end stage disease include a family history of end stage disease, younger age at initial diagnosis, increased wall thickness and persistent arrhythmia. The classic form of adverse remodeling includes left ventricular cavity dilation with regression of hypertrophy and decrease in ejection fraction. Standard medical therapy for systolic heart failure and consideration of prophylactic defibrillator is indicated when LVEF is less than 50 %. Heart transplant is a viable option for patients with end stage hypertrophic cardiomyopathy, including those with systolic heart failure, diastolic heart failure or refractory arrhythmia. Strategies used to bridge patients to transplant include continuous inotropic infusion, left ventricular assist device, intra-aortic balloon pump, and in rare cases extracorporeal membrane oxygenation. Survival after heart transplant for hypertrophic cardiomyopathy is equal to or better than survival for patients who have other types of cardiomyopathies.

Accelerated Bachmann bundle area pacing for atrial resynchronization in patients with non-obstructive hypertrophic cardiomyopathy and heart failure with preserved ejection fraction: A randomized crossover trial.

Background— Left ventricular diastolic dysfunction (DD) is a key determinant of outcomes in pediatric cardiomyopathy (CM), but remains very challenging to diagnose and classify. Adult paradigms and guidelines relating to DD are currently applied in children. However, it is unknown whether these are applicable to children with CM. We investigated the assessment of DD in children with CM using adult and pediatric echocardiographic criteria and tested whether recent adult guidelines are applicable to this population. Methods and Results— Three investigators independently classified diastolic function in 4 study groups: controls, dilated, hypertrophic, and restrictive CM. Agreement among investigators, failure to classify DD, and the reasons for diagnostic failure were determined. The usefulness of individual echo parameters to diagnose and classify DD was assessed. One hundred seventy-five children (aged 0–18 years) were studied. DD diagnostic criteria were discrepant in the majority of patients. Delayed relaxation was diagnosed in only 14% of hypertrophic CM patients and never in dilated CM and restrictive CM, with 50% of those patients having coexisting findings of elevated filling pressures. Many key parameters, such as mitral and pulmonary venous Doppler, were not informative. Agreement among investigators for grading of DD was poor (36% of CM patients). Conclusions— Assessment of DD in childhood CM seems inadequate using current guidelines. The large range of normal pediatric reference values allows diagnosis of DD in only a small proportion of patients. Key echo parameters to assess DF are not sufficiently discriminatory in this population, and discrepancies between criteria within individuals prevent further classification and result in poor interobserver agreement.

BackgroundPatients with hypertrophic cardiomyopathy may develop symptoms of shortness of breathing due to diastolic dysfunction which is not related to the severity of left ventricular outflow tract obstruction. As these patients usually develop a non-ischemic pattern of myocardial fibrosis, this may represent a mechanism for increased myocardial stiffness leading to impaired diastolic filling. The study aimed to determine the prevalence of myocardial fibrosis assessed by magnetic resonance imaging in children with hypertrophic cardiomyopathy and to evaluate its relationship with echocardiographic parameters including left ventricle diastolic dysfunction and to find echocardiographic indices which correlates with myocardial fibrosis as detected by cardiac magnetic resonance. A cross-sectional study was done for data of 50 children with hypertrophic cardiomyopathy from July 2018 to July 2021, patients were divided into (group 1) having myocardial fibrosis and (group 2) with no myocardial fibrosis, and results of echocardiographic parameters were compared between the two groups.ResultsResults showed strong relationship between presence of myocardial fibrosis and each of the following: Interventricular septum thickness, lower lateral and septal early diastolic tissue velocities (E′), E/E′ ratio, presence of left ventricular out flow tract obstruction and the grade of diastolic dysfunction.ConclusionsThe trans-mitral lateral and septal E/E′ (early mitral inflow to early diastolic mitral annular velocity ratio) allows early detection of left ventricular diastolic dysfunction in children with hypertrophic cardiomyopathy. The prevalence of diastolic dysfunction is higher in obstructive hypertrophic cardiomyopathy. The diastolic dysfunction severity is higher in patients with myocardial fibrosis.

It is known that patients with diastolic dysfunction have usually impaired left ventricular (LV) longitudinal systolic function, and the latter parameter shows strong correlation with the (tissue) Doppler parameters of the LV diastolic function. The role of non-velocity-type parameters of the global LV diastolic function have not been investigated yet. LV mass and left atrial volume, however, seem to be important factors as the former influences passive ventricular distension and the latter is established as a marker of the diastolic dysfunction's severity. The aim of our study was to investigate the relationship between LV longitudinaJ systolic function and these parameters. The same correlations were also investigated in patients with impaired systolic function. Patients: 16 healthy subjects, 29 patients suffering from hypertrophic cardiomyopathy (HCM) (ejection fraction >50%) and 24 patients with dilated cardiomyopathy (DCM) (EF< 35%) were studied. The three groups matched in age and gender. Inclusion criteria were: normal sinus rhythm, absence of moderate to severe mitraJ valve disease. Methods: In addition to the conventional transmitral flow patterns pulmonary vein Doppler parameters were measured by ATL HDI 5000 ultrasound system. Myocardial systolic velocity (S) was measured at the lateral border of the mitraJ annulus using tissue Doppler imaging. Ma~ximaJ left atrial volume (Vma~x) was measured from the apical 4and 2-chamber views using Simpson's method. The use of Devereux's mass index is probably limited in patients with HCM and DCM, so cardiac magnetic resonance imaging (1.5 T Siemens Vision plus) was used to determine the LV mass. LV mass and Vmax were normalized to body surface area (LVMI; Vma~x index). Results: In HCM patients isolated diastolic dysfunction while in DCM patients combined systolic and diastolic dysfunction were found. In HCM patients lateral S correlated negatively with LVMI (r= -0.492, p<0.01) and Vma~x index (r= -0.492, p<0.01). In DCM patients similar correlations were found with LVMI (r= -0.418, p<0.05) and Vma~x index (r=0.515, p<0.05), too. No significant correlation was found in the group of healthy volunteers. Conclusion: LV longitudinal systolic function showed a significant negative correlation with non-velocity-type parameters of the LV diastolic function such as LVMI and Vma~x index in patients with diastolic dysfunction and in patients with combined systolic and diastolic dysfunction as well.