Preclinical Hypertrophic Cardiomyopathy Research Articles

Use of advanced echocardiographic modalities to discriminate preclinical HCM mutation carriers from non-carriers

Abstract Background It is a challenging goal to identify which family members of patients with hypertrophic cardiomyopathy (HCM) will subsequently develop HCM. Previous studies evaluating the utility of two-dimensional conventional Doppler echocardiography in HCM families with a known pathogenic variant identified on genetic testing have been unable to reliably distinguish preclinical genotype-positive, phenotype-negative (G+P−) individuals from their healthy genotype-negative, phenotype-negative (G−P−) relatives. Purpose To determine if advanced echocardiographic modalities can discriminate preclinical HCM mutation carriers (G+P−) from non-carriers (G−P−). Methods A total of 199 participants who had undergone genetic testing from HCM families with a known pathogenic variant were included in the study: 39 G−P−; 58 G+P− and 102 overt HCM patients (G+P+). Speckle tracking echocardiography (STE) and colour M-mode were performed on all participants and longitudinal, circumferential and radial strain, and torsion were compared. Results Patients with overt HCM had the highest septal, posterior wall thickness, septum/posterior wall (Sep/PW) thickness ratio and left ventricular outflow tract (LVOT) gradient and lowest global longitudinal, circumferential and radial strain, and tissue Doppler-derived myocardial systolic and diastolic velocities. Comparing G−P− and G+P− individuals, there were no significant differences in LV cavity size, wall thickness, LVOT gradient, LVEF and tissue Doppler-derived myocardial systolic and diastolic velocities. However, G+P− individuals had significantly higher peak apical rotation, peak twist and colour M-mode flow propagation velocity (Vp). Multivariate linear regression identified two independent predictors (peak apical rotation and Vp), and a regression equation (using multivariate linear regression) {Mutation carrier prediction value = (0.210×peak apical rotation) − (0.002×Vp) + 0.156; r=0.655)} was derived which allowed reliable discrimination of G+P- individuals with a sensitivity of 95.2% and specificity of 94.1% at the optimal cut-off. Conclusion In HCM family members without overt HCM, peak apical rotation and Vp provide good sensitivity and specificity for identifying mutation carriers and may be a clinically useful early marker of HCM before the onset of hypertrophy. Future longitudinal studies involving larger cohorts are required to validate these findings. Funding Acknowledgement Type of funding sources: None.

Use of Advanced Echocardiographic Modalities to Discriminate Preclinical HCM Mutation Carriers From Non-Carriers

It is a challenging goal to identify which family members of patients with hypertrophic cardiomyopathy (HCM) will subsequently develop HCM. Conventional and tissue Doppler echocardiography are unable to reliably detect preclinical mutation carriers (G+P−).

Use of Advanced Echocardiographic Modalities to Discriminate Preclinical Hypertrophic Cardiomyopathy Mutation Carriers From Non-Carriers

Use of Advanced Echocardiographic Modalities to Discriminate Preclinical Hypertrophic Cardiomyopathy Mutation Carriers From Non-Carriers

Prognostic implications of different clinical profiles in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a myocardial genetic disease relatively common in the general population with heterogenous clinical presentation, natural history and prognosis. About 60% of HCM patients have a stable clinical course, while others may experience a variety of HCM-related complications which follows relatively independent pathways, and that can be distinguished in different subgroups. These subgroups are represented by patients with left ventricular outflow tract obstruction; patients with end-stage disease and reduced or preserved systolic function; patients with apical hypertrophy; patients with apical aneurysm; patients with atrial fibrillation, patients at high risk of sudden death and patients with preclinical HCM. The purpose of this review was to describe each of these clinical profiles with its prognostic implications.

Detection of congestive heart failure by mitral annular displacement in cats with hypertrophic cardiomyopathy – concordance between tissue Doppler imaging–derived tissue tracking and M-mode

IntroductionThe left ventricular systolic longitudinal function, traditionally measured by M-mode–derived mitral annular plane systolic excursion (MAPSE), is reduced in feline hypertrophic cardiomyopathy (HCM) and further reduced in cats with left-sided congestive heart failure (CHF). The objectives of this study were to compare longitudinal displacement measured by tissue tracking (TT-LD) and MAPSE in feline HCM and assess these methods’ ability to differentiate CHF from preclinical HCM. A further objective was to provide preliminary reference intervals for TT-LD. AnimalsEighty-five client-owned cats. MethodsA retrospective case–control study. Anatomical M-mode was used to record MAPSE, and TT-LD was recorded by tissue tracking. ResultsReduced longitudinal displacement measured by either MAPSE or TT-LD was significantly associated with CHF in cats with HCM (p < 0.036). Receiver-operating characteristic analysis indicated that TT-LD (AUC: 92.9%–97.9%) was more sensitive and specific than MAPSE (AUC: 85.8%–89.1%) for the detection of CHF. A diagnostic cut-off of 2.89 mm for maximal TT-LD in the left ventricular septum resulted in a sensitivity and specificity of 100% and 83.3%, while a diagnostic cut-off of 2.41 mm in the left ventricular posterior wall resulted in a sensitivity of 100% and a specificity of 90%. ConclusionsM-mode–derived mitral annular plane systolic excursion and TT-LD were strongly correlated, but not interchangeable. Longitudinal displacement measured by tissue tracking decreased more with disease severity than traditional MAPSE. Longitudinal displacement may help detect CHF in cats with HCM – with the maximal TT-LD of the left ventricular posterior wall achieving the highest AUC value.

Description and Clinical Implications of Myocardial Clefts Using Echocardiography.

BackgroundMyocardial clefts (MCs) are rare anomalies with debatable clinical significance. Increased use of cardiac magnetic resonance (CMR) has led to the appreciation of subtle left ventricular (LV) wall structural defects, and studies showed varying clinical significance, ranging from asymptomatic incidental findings to being considered a novel imaging marker of hypertrophic cardiomyopathy. Sparse data are available about the utility of two-dimensional echocardiography (2DE) to visualize these anomalies. We describe our institutional experience categorizing MCs using 2DE.MethodsThe echocardiography database was retrospectively queried for diagnosing MCs using Synapse® Cardiovascular Picture Archiving and Communication System (PACS) (Fujifilm, Tokyo, Japan). Identified patients were admitted to Detroit Medical Center (DMC) between January 2012 and May 2019. MCs were defined as recesses filled with luminal blood, obliterate during systole, and have U, wedge, and tunnel shapes. Images were interpreted by a cardiologist blinded to the data. Baseline demographics and clinical characteristics were documented. The study was descriptive; no intervention was done.ResultsSixteen patients with a mean age of 62.43 were included; 68.75% were women, and 81.25% were African American. The prevalence of cardiac comorbidities was primary hypertension 12 (75%), coronary artery disease 5 (31.25%), heart failure with reduced ejection fraction (HFrEF) 4 (25.0%), valvular heart disease 4 (25.0%), arrhythmia/heart block 4 (25.0%), and heart failure with preserved ejection fraction (HFpEF) 2 (12.5%). The indications for 2DE evaluation were heart failure/cardiogenic shock 2 (12.5%), acute coronary syndrome 2 (12.5%), syncope/presyncope 2 (12.5%), atypical chest pain 2 (12.5%), and others 8 (50.0%). Twenty-one MCs were visualized in eight segments of LV walls and septum as follows: basal inferior 7, mid inferoseptal 6, mid inferior 3, mid anteroseptal 2, mid inferolateral 1, mid anterolateral 1, basal inferoseptal 1, apical inferoseptal 1, and apical septal 1. Morphology was classified as tunnel in 66.66%, wedge in 23.8%, and U in 9.5%.ConclusionIn various LV and septal walls, MCs detected on 2DE were benign and incidental findings without significant implications for preclinical hypertrophic cardiomyopathy (HCM).

Cardiac extracellular volume fraction in cats with preclinical hypertrophic cardiomyopathy.

BackgroundCardiac magnetic resonance imaging (CMR) allows for detection of fibrosis in hypertrophic cardiomyopathy (HCM) by quantification of the extracellular volume fraction (ECV).Hypothesis/ObjectivesTo quantify native T1 mapping and ECV in cats. We hypothesize that native T1 mapping and ECV will be significantly increased in HCM cats compared with healthy cats.AnimalsSeventeen healthy and 12 preclinical HCM, age‐matched, client‐owned cats.MethodsProspective observational study. Tests performed included indirect blood pressure, CBC, biochemical analysis including total thyroid, urinalysis, transthoracic echocardiogram, and CMR. Cats were considered healthy if all tests were within normal limits and a diagnosis of HCM was determined by the presence of left ventricular concentric hypertrophy ≥6 mm on echocardiography.ResultsThere were statistically significant differences in LV mass (healthy = 5.87 g, HCM = 10.3 g, P < .0001), native T1 mapping (healthy = 1122 ms, HCM = 1209 ms, P = .004), and ECV (healthy = 26.0%, HCM = 32.6%, P < .0001). Variables of diastolic function including deceleration time of early diastolic transmitral flow (DTE), ratio between peak velocity of early diastolic transmitral flow and peak velocity of late diastolic transmitral flow (E : A), and peak velocity of late diastolic transmitral flow (A wave) were significantly correlated with ECV (DTE; r = 0.73 P = .007, E : A; r = −0.75 P = .004, A wave; r = 0.76 P = .004).Conclusions and Clinical ImportanceQuantitative assessment of cardiac ECV is feasible and can provide additional information not available using echocardiography.

Importance of Vector Velocity Echocardiography and NT-proBNP in Identifying Individuals with Preclinical Hypertrophic Cardiomyopathy

Background and aim: Familial HCM gene mutation carriers without overt left ventricular hypertrophy (gene positive/phenotype negative G+/P-) can harbor subclinical changes in cardiovascular structure and function that precede the development of Hypertrophic Cardiomyopathy (HCM). Conventional echocardiography parameter ejection fraction is normal in HCM patients. We sought to investigate whether Velocity Vector Imaging (VVI) and NT-proBNP are more sensitive to evaluate heart function.

Risk indictors in cats with preclinical hypertrophic cardiomyopathy: a prospective cohort study.

This study aimed to identify indicators of the risk of progression of preclinical hypertrophic cardiomyopathy (HCM). This was a prospective cohort study following a population of cats with preclinical HCM. Cats serially underwent physical examination, blood pressure measurement, blood sampling and echocardiography. Development of congestive heart failure (CHF), arterial thromboembolism (ATE) or sudden death (SD) were considered cardiac-related events. Associations between factors recorded at baseline, and on revisit examinations, and the development of a cardiac-related event were explored using receiver operator characteristic (ROC) analysis. Forty-seven cats were recruited to the study and were followed for a median period of 1135 days. Fifteen cats (31.9%) experienced at least one cardiac-related event; six CHF, five ATE and five SD. One cat experienced a cardiac-related event per 10.3 years of patient follow-up. Cats with increased left atrial (LA) size and higher concentrations of N-terminal pro B-type natriuretic peptide (NTproBNP) at baseline were more likely to experience an event. Cats with a greater rate of enlargement of LA size between examinations were also more likely to experience an event. Factors easily measured, either once or serially, in cats with preclinical HCM can help to identify those at greater risk of going on to develop clinical signs.

Cardiac Remodeling Following High Intensity Exercise Training In A Preclinical HCM Mouse Model

Participation in high intensity exercise for individuals with hypertrophic cardiomyopathy (HCM) remains controversial. Retrospective data has suggested that HCM patients who participate in lifetime vigorous exercise can have favorable cardiac remodeling that resembles that which occurs in healthy athletes. Cardiac hypertrophy is highly variable in HCM patients and may mask physiologic hypertrophy induced by exercise. PURPOSE: Evaluate the effects of high intensity interval training (HIIT) on cardiac hypertrophy in a preclinical transgenic cardiac troponin T delta160E (TG) HCM mouse model. METHODS: C57BL/6J non-transgenic (NTG) (n=6 F, n=5 M) and TG (n=4 F, n=8 M) mice (13-16mos) underwent a translationally parallel cardiac rehabilitation HIIT protocol. One treadmill training bout included 4-4 minute high intensity intervals (~80% preVO2 max speed) interspersed by 5-3 minute recovery intervals (~50% preVO2 max speed) for 31 total minutes. Exercise compliance was measured as percent of total training time completed. Bouts were repeated 3 times/wk for 10wks. Pre and post HIIT murine echocardiography (ECHO) was recorded and analyzed by a blinded technician. Unpaired and paired t-tests were used for data analysis. RESULTS: Training compliance between TG and NTG did not differ (921.90min ± 4.24, 99.13% vs 928.95min ± 1.05, 99.90%; p=0.14). Pre and post HIIT left ventricular (LV) mass was significantly greater in both NTG (Mean difference & SEM: 23.04mg, 6.23; p=0.0042) and TG (Mean difference & SEM: 17.56mg, 6.31; p =0.019) mice. Body weights measured prior to pre and post HIIT ECHOs did not differ in NTG (Mean difference & SEM: 0.473g, 0.8370; p=0.585) or TG (Mean difference & SEM: 1.354g, 0.819; p=0.129) mice. CONCLUSION: In a preclinical HCM mouse model that doesn’t demonstrate pathologic hypertrophy, HIIT training resulted in LV hypertrophy in both NTG and TG mice. Our data provides initial evidence that high intensity exercise training may result in physiologic hypertrophy. Biochemical analyses are underway to elucidate the underlying type of cardiac remodeling.

Detection of congestive heart failure by Doppler echocardiography in cats with hypertrophic cardiomyopathy.

BackgroundLeft‐sided congestive heart failure (CHF) is characterized by increased filling pressures and related Doppler echocardiographic (DE) filling patterns.HypothesisDoppler echocardiographic variables of left ventricular filling derived from transmitral flow, pulmonary vein flow, and tissue Doppler can be used to detect CHF in cats with hypertrophic cardiomyopathy (HCM).AnimalsForty‐seven client‐owned cats.MethodsProspective clinical cohort study. Cats underwent physical examination, thoracic radiography, analysis of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), and transthoracic echocardiography and were divided into 3 age‐matched groups: Group 1 (apparently healthy control), Group 2 (preclinical HCM), and Group 3 (HCM and CHF). Measured and calculated variables included respiratory rate, DE estimates, serum NT‐proBNP concentration, and radiographic CHF score. Groups were compared using ANOVA, and receiver operating characteristic (ROC) curve and multivariate analyses were used to identify diagnostic cutoffs for the detection of CHF.ResultsFifteen cats were in Group 1, 17 in Group 2, and 15 in Group 3. The ROC analysis indicated that the ratio of peak velocity of early diastolic transmitral flow to peak velocity of late diastolic transmitral flow (area under the curve [AUC], 1.0; diagnostic cutoff, 1.77; P = .001), ratio of left atrial size to aortic annular dimension (AUC, 0.91; diagnostic cutoff, 1.96; P = .003), left atrial diameter (AUC, 0.89; cutoff, 18.5 mm; P = .004), diastolic functional class (AUC, 0.89; cutoff, class 2; P = .005), respiratory (AUC, 0.79; cutoff, 36 breaths per minute [brpm]; P = .02), and the ratio of the peak velocity of fused early and late transmitral flow velocities to the peak velocity of the fused early and late diastolic tissue Doppler waveforms (AUC, 0.74; cutoff, 15.1; P = .05) performed best for detecting CHF.Conclusions and Clinical ImportanceVarious DE variables can be used to detect CHF in cats with HCM. Determination of the clinical benefit of such variables in initiating treatments and assessing treatment success needs further study.

Long-term incidence and risk of noncardiovascular and all-cause mortality in apparently healthy cats and cats with preclinical hypertrophic cardiomyopathy.

BackgroundEpidemiologic knowledge regarding noncardiovascular and all‐cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence‐based healthcare guidelines.ObjectivesTo characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all‐cause mortality in AH and pHCM cats.AnimalsA total of 1730 client‐owned cats (722 AH, 1008 pHCM) from 21 countries.MethodsRetrospective, multicenter, longitudinal, cohort study. Long‐term health data were extracted by medical record review and owner/referring veterinarian interviews.ResultsNoncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P = .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight‐loss‐vomiting‐diarrhea‐anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All‐cause death proportions were greater in pHCM than AH (65% versus 40%, respectively; P < .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years; P = .10), but all‐cause survival was significantly shorter in pHCM (P = .0001).Conclusions and Clinical ImportanceAll‐cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death.

Could two-dimensional radial strain be considered as a novel tool to identify pre-clinical hypertrophic cardiomyopathy mutation carriers?

Treatment of overt form of hypertrophic cardiomyopathy (HCM) is often unsuccessful. Efforts are focused on a possible early identification in order to prevent or delaying the development of hypertrophy. Our aim was to find an echocardiographic marker able to distinguish mutation carriers without left ventricular hypertrophy (LVH) from healthy subjects. We evaluated 28 patients, members of eight families. Three types of mutation were recognized: MYBPC3 (five families), MYH7 (two families) and TNNT2 (one family). According to genetic (G) and phenotypic (Ph) features, patients were divided in three groups: Group A (10 patients), mutation carriers with LVH (G+/Ph+); Group B (9 patients), mutation carriers without LVH (G+/Ph-); Group C (9 patients), healthy subjects (G-/Ph-). Echocardiography examination was performed acquiring standard 2D, DTI and 2D-strain imaging. Global longitudinal strain (GLS) and global radial strain (GRS) at basal and mid-level were measured. GRS was significantly different between group B and C at basal level (32.18% ± 9.6 vs. 44.59% ± 12.67 respectively; p-value < 0.0001). In basal posterior and basal inferior segments this difference was particularly evident. ROC curves showed for both the involved segments good AUCs (0.931 and 0.861 for basal posterior and inferior GRS respectively) with the best predictive cut-off for basal posterior GRS at 43.65%, while it was 38.4% for basal inferior GRS. Conversely, GLS values were similar in the three group. 2D longitudinal strain is a valid technique to study HCM. Radial strain and particularly basal posterior and inferior segmental reduction could be able to identify mutation carriers in a pre-clinical phase of disease.

Speckle tracking echocardiography in cats with preclinical hypertrophic cardiomyopathy

BackgroundCats with hypertrophic cardiomyopathy (HCM) have decreased left ventricular (LV) longitudinal deformation detected by mitral annular plane systolic excursion (MAPSE) and speckle tracking echocardiography. People with preclinical HCM have decreased systolic LV longitudinal and radial strain (S) and strain rate (SR), with preserved circumferential S and SR.Hypothesis/ObjectivesCats with preclinical HCM have decreased systolic LV deformation compared to normal cats.AnimalsSeventy‐three client‐owned cats with (n = 37) and without (n = 36) preclinical HCM.MethodsRetrospective echocardiographic study. Left and right ventricular longitudinal S and SR, LV radial and circumferential S and SR were calculated by STE. Left ventricular mass was also calculated. Correlation between STE variables and LV hypertrophy was determined and receiver‐operating characteristic (ROC) curves were plotted for prediction of HCM.ResultsCats with HCM had smaller absolute longitudinal S (−14.8 ± 3.3% vs −19.7 ± 2.7%, P < .001), longitudinal SR (−2.36 ± 0.62 vs −2.95 ± 0.68 second−1, P < .001), radial S (46.2 ± 21.3% vs 66.7 ± 17.6%, P < .001), and radial SR (5.60 ± 2.08 vs 6.67 ± 1.8 second−1, P < .001) compared to healthy controls. No difference was observed for circumferential S and SR. Cats with HCM had greater LV mass (13.2 ± 3.7 g vs 8.6 ± 2.7 g, P < .001). The ROC with the greatest area under the curve (AUC) for the identification of HCM (0.974) was plotted from a logistic regression equation combining LV mass, MAPSE at the free wall, and LV internal diameter in diastole (LVIDd).Conclusions and clinical importanceCats with preclinical HCM have decreased long axis and radial deformation. Decreased longitudinal deformation and decreased LVIDd are factors that would support a diagnosis of HCM.

Left Ventricular Strain Is Abnormal in Preclinical and Overt Hypertrophic Cardiomyopathy: Cardiac MR Feature Tracking.

Purpose To evaluate myocardial strain and circumferential transmural strain difference (cTSD; the difference between epicardial and endocardial circumferential strain) in a genotyped cohort with hypertrophic cardiomyopathy (HCM) and to explore correlations between cTSD and other anatomic and functional markers of disease status. Left ventricular (LV) dysfunction may indicate early disease in preclinical HCM (sarcomere mutation carriers without LV hypertrophy). Cardiac MRI feature tracking may be used to evaluate myocardial strain in carriers of HCM sarcomere mutation. Materials and Methods Participants with HCM and their family members participated in a prospective, multicenter, observational study (HCMNet). Genetic testing was performed in all participants. Study participants underwent cardiac MRI with temporal resolution at 40 msec or less. LV myocardial strain was analyzed by using feature-tracking software. Circumferential strain was measured at the epicardial and endocardial surfaces; their difference yielded the circumferential transmural strain difference (cTSD). Multivariable analysis to predict HCM status was performed by using multinomial logistic regression adjusting for age, sex, and LV parameters. Results Ninety-nine participants were evaluated (23 control participants, 34 participants with preclinical HCM [positive for sarcomere mutation and negative for LV hypertrophy], and 42 participants with overt HCM [positive for sarcomere mutation and negative for LV hypertrophy]). The average age was 25 years ± 11 and 44 participants (44%) were women. Maximal LV wall thickness was 9.5 mm ± 1.4, 9.8 mm ± 2.2, and 16.1 mm ± 5.3 in control participants, participants with preclinical HCM (P = .496 vs control participants), and participants with overt HCM (P < .001 vs control participants), respectively. cTSD for control participants, preclinical HCM, and overt HCM was 14% ± 4, 17% ± 4, and 22% ± 7, respectively (P < .01 for all comparisons). In multivariable models (controlling for septal thickness and log-transformed N-terminal brain-type natriuretic peptide), cTSD was predictive of preclinical and overt HCM disease status (P < .01). Conclusion Cardiac MRI feature tracking identifies myocardial dysfunction not only in participants with overt hypertrophic cardiomyopathy, but also in carriers of sarcomere mutation without left ventricular hypertrophy, suggesting that contractile abnormalities are present even when left ventricular wall thickness is normal. © RSNA, 2018 Online supplemental material is available for this article.

International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: The REVEAL Study.

BackgroundHypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved.Hypothesis/ObjectivesObservational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH).AnimalsOne thousand seven hundred and thirty client‐owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH).MethodsRetrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long‐term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death.ResultsDuring the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean ± standard deviation, 1.3 ± 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9‐15 years.Conclusions and Clinical ImportancePreclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality.

Biomarkers of cardiovascular stress and fibrosis in preclinical hypertrophic cardiomyopathy

ObjectiveSarcomeric gene mutation carriers without overt left ventricular hypertrophy (G+/LVH−) can harbour subclinical changes in cardiovascular structure and function that precede the development of hypertrophic cardiomyopathy (HCM). We sought to...

Diltiazem prevents stress-induced contractile deficits in cardiomyocytes, but does not reverse the cardiomyopathy phenotype in Mybpc3-knock-in mice.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac illness and can lead to diastolic dysfunction, sudden cardiac death and heart failure. Treatment of HCM patients is empirical and current pharmacological treatments are unable to stop disease progression or reverse hypertrophy. In this study, we tested if the non-dihydropyridine Ca2+ channel blocker diltiazem, which previously showed potential to stop disease progression, can improve the phenotype of a HCM mouse model (Mybpc3-targeted knock-in), which is based on a mutation commonly found in patients. Diltiazem improved contractile function of isolated ventricular cardiomyocytes acutely, but chronic application did not improve the phenotype of adult mice with a fully developed HCM. Our study shows that diltiazem has beneficial effects in HCM, but long-term treatment success is likely to depend on characteristics and cause of HCM and onset of treatment. Left ventricular hypertrophy, diastolic dysfunction and fibrosis are the main features of hypertrophic cardiomyopathy (HCM). Guidelines recommend β-adrenoceptor or Ca2+ channel antagonists as pharmacological treatment. The Ca2+ channel blocker diltiazem recently showed promising beneficial effects in pre-clinical HCM, particularly in patients carrying MYBPC3 mutations. In the present study we evaluated whether diltiazem could ameliorate or reverse the disease phenotype in cells and in vivo in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Sarcomere shortening and Ca2+ transients were measured in KI and wild-type (WT) cardiomyocytes in basal conditions (1-Hz pacing) and under stress conditions (30nm isoprenaline, 5-Hz pacing) with or without pre-treatment with 1μm diltiazem. KI cardiomyocytes exhibited lower diastolic sarcomere length (dSL) at baseline, a tendency to a stronger positive inotropic response to isoprenaline than WT, a marked reduction of dSL and a tendency towards arrhythmias under stress conditions. Pre-treatment of cardiomyocytes with 1μm diltiazem reduced the drop in dSL and arrhythmia frequency in KI, and attenuated the positive inotropic effect of isoprenaline. Furthermore, diltiazem reduced the contraction amplitude at 5Hz but did not affect diastolic Ca2+ load and Ca2+ transient amplitude. Sixmonths of diltiazem treatment of KI mice did not reverse cardiac hypertrophy and dysfunction, activation of the fetal gene program or fibrosis. In conclusion, diltiazem blunted the response to isoprenaline in WT and KI cardiomyocytes and improved diastolic relaxation under stress conditions in KI cardiomyocytes. This beneficial effect of diltiazem in cells did not translate in therapeutic efficacy when applied chronically in KI mice.

Left Atrial structure and function in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy

BackgroundImpaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH).MethodSeventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15).ResultsLA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both).ConclusionLA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.

Right ventricular involvement in feline hypertrophic cardiomyopathy

ObjectivesTo evaluate right ventricular (RV) wall thickness and chamber dimensions in cats with hypertrophic cardiomyopathy (HCM). AnimalsOne hundred fifty-one healthy control cats and 200 cats with HCM. MethodsRetrospective, observational, clinical cohort study. Two-dimensional echocardiograms from all cats were analyzed. Right atrial diameter, RV free wall thickness, and RV chamber diameter were quantified using multiple imaging views. Conventional (mean ± 2 standard deviations) and allometrically scaled (Y = a × Mb) reference values were determined in normal cats and compared to values found in cats with HCM. Linear and logistic regression, multivariate regression, and mixed model analysis were performed to identify associations between RV wall thickness and severity of left ventricular (LV) hypertrophy, clinical severity of HCM, and presence of pleural effusion. ResultsMean RV wall thickness was increased in HCM (p<0.001). Considering increased RV wall thickness in at least one segment, 94 (47%) and 112 (56%) cats with HCM had RV hypertrophy using upper reference limits based on mean + 2 standard deviations or allometric scaling, respectively. There was an association between severity of LV and RV hypertrophy (p<0.05). Left-sided congestive heart failure (n = 58) was associated with increased RV wall thickness in all segments compared to cats with preclinical HCM (p<0.001). Body weight had negligible effects on RV wall thickness (R2 0.08–0.17, p<0.001), whereas age and breed had no effect (p>0.05) in control cats. ConclusionsIncreased RV wall thickness is common in cats with HCM and relates to severity of LV hypertrophy and clinical status.