Adam S. Helms

Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy: A Randomized Clinical Trial

Importance Formulating exercise recommendations for patients with hypertrophic cardiomyopathy is challenging because of concern about triggering ventricular arrhythmias and because a clinical benefit has not been previously established in this population. Objective To determine whether moderate-intensity exercise training improves exercise capacity in adults with hypertrophic cardiomyopathy. Design, Setting, and Participants A randomized clinical trial involving 136 patients with hypertrophic cardiomyopathy was conducted between April 2010 and October 2015 at 2 academic medical centers in the United States (University of Michigan Health System and Stanford University Medical Center). Date of last follow-up was November 2016. Interventions Participants were randomly assigned to 16 weeks of moderate-intensity exercise training (n = 67) or usual activity (n = 69). Main Outcomes and Measures The primary outcome measure was change in peak oxygen consumption from baseline to 16 weeks. Results Among the 136 randomized participants (mean age, 50.4 [SD, 13.3] years; 42% women), 113 (83%) completed the study. At 16 weeks, the change in mean peak oxygen consumption was +1.35 (95% CI, 0.50 to 2.21) mL/kg/min among participants in the exercise training group and +0.08 (95% CI, −0.62 to 0.79) mL/kg/min among participants in the usual-activity group (between-group difference, 1.27 [95% CI, 0.17 to 2.37]; P = .02). There were no occurrences of sustained ventricular arrhythmia, sudden cardiac arrest, appropriate defibrillator shock, or death in either group. Conclusions and Relevance In this preliminary study involving patients with hypertrophic cardiomyopathy, moderate-intensity exercise compared with usual activity resulted in a statistically significant but small increase in exercise capacity at 16 weeks. Further research is needed to understand the clinical importance of this finding in patients with hypertrophic cardiomyopathy, as well as the long-term safety of exercise at moderate and higher levels of intensity. Trial Registration clinicaltrials.gov Identifier: NCT01127061

Sarcomere Mutation-Specific Expression Patterns in Human Hypertrophic Cardiomyopathy

Background—Heterozygous mutations in sarcomere genes in hypertrophic cardiomyopathy (HCM) are proposed to exert their effect through gain of function for missense mutations or loss of function for truncating mutations. However, allelic expression from individual mutations has not been sufficiently characterized to support this exclusive distinction in human HCM. Methods and Results—Sarcomere transcript and protein levels were analyzed in septal myectomy and transplant specimens from 46 genotyped HCM patients with or without sarcomere gene mutations and 10 control hearts. For truncating mutations in MYBPC3, the average ratio of mutant:wild-type transcripts was ≈1:5, in contrast to ≈1:1 for all sarcomere missense mutations, confirming that nonsense transcripts are uniquely unstable. However, total MYBPC3 mRNA was significantly increased by 9-fold in HCM samples with MYBPC3 mutations compared with control hearts and with HCM samples without sarcomere gene mutations. Full-length MYBPC3 protein content was not different between MYBPC3 mutant HCM and control samples, and no truncated proteins were detected. By absolute quantification of abundance with multiple reaction monitoring, stoichiometric ratios of mutant sarcomere proteins relative to wild type were strikingly variable in a mutation-specific manner, with the fraction of mutant protein ranging from 30% to 84%. Conclusions—These results challenge the concept that haploinsufficiency is a unifying mechanism for HCM caused by MYBPC3 truncating mutations. The range of allelic imbalance for several missense sarcomere mutations suggests that certain mutant proteins may be more or less stable or incorporate more or less efficiently into the sarcomere than wild-type proteins. These mutation-specific properties may distinctly influence disease phenotypes.

Genotype-Dependent and Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy

Background: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. Methods: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). Results: Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban, calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM samples compared with controls. CaMKII protein abundance was increased only in sarcomere-mutation HCM (P<0.001). The CaMKII target pT17-phospholamban was 5.5-fold increased only in sarcomere-mutation HCM (P=0.01), as was autophosphorylated CaMKII (P<0.01), suggestive of constitutive activation. Calcineurin (PPP3CB) mRNA was not increased, nor was RCAN1 mRNA level, indicating a lack of calcineurin activation. Furthermore, myocyte enhancer factor 2 and nuclear factor of activated T cell transcription factor activity was not increased in HCM, suggesting that calcineurin pathway activation is not an upstream cause of increased CAMKII protein abundance or activation. SERCA2A mRNA transcript levels were reduced in HCM regardless of genotype, as was sarcoplasmic endoplasmic reticular calcium ATPase 2/phospholamban protein ratio (45% reduced; P=0.03). 45Ca sarcoplasmic endoplasmic reticular calcium ATPaseuptake assay showed reduced uptake velocity in HCM regardless of genotype (P=0.01). The cardiac ryanodine receptor was not altered in transcript, protein, or phosphorylated (pS2808, pS2814) protein abundance, and [3H]ryanodine binding was not different in HCM, consistent with no major modification of the ryanodine receptor. Conclusions: Human HCM demonstrates calcium mishandling through both genotype-specific and common pathways. Posttranslational activation of the CaMKII pathway is specific to sarcomere mutation–positive HCM, whereas sarcoplasmic endoplasmic reticular calcium ATPase 2 abundance and sarcoplasmic reticulum Ca uptake are depressed in both sarcomere mutation–positive and –negative HCM.

Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup

PurposeHypertrophic cardiomyopathy (HCM) is considered a hereditary autosomal dominant condition, but genetic testing is positive in only half of patients. In patients with negative genetic tests, the inheritance pattern and utility of family screening are unclear.MethodsSubjects with HCM were prospectively enrolled in a registry. A survey at a median follow-up of 4 years determined the yield of family screening.ResultsThe outcome of cardiac screening on 267 family members was reported by 120 survey respondents. Subjects with positive genetic test or family history (n=74, 62%) reported an HCM diagnosis in 34 of 203 first-degree relatives who were screened (17%). Affected family members were diagnosed at a mean age of 30–39 years, and 22 of 34 experienced HCM-related adverse events (65%). Gene test–negative subjects with no prior family history of HCM (n=46, 38%) reported an HCM diagnosis in only 2 of 64 first-degree relatives who were screened (3%, p<0.001). These two individuals were diagnosed at age >40 years without HCM-related adverse events.ConclusionHypertrophic cardiomyopathy is a heterogeneous disorder, only half of which tracks with a Mendelian inheritance pattern. Negative genetic testing and family history indicates a more complex genetic basis corresponding to low risk for family members.

Deficient cMyBP-C protein expression during cardiomyocyte differentiation underlies human hypertrophic cardiomyopathy cellular phenotypes in disease specific human ES cell derived cardiomyocytes

AIMS Mutations of cardiac sarcomere genes have been identified to cause HCM, but the molecular mechanisms that lead to cardiomyocyte hypertrophy and risk for sudden death are uncertain. The aim of this study was to examine HCM disease mechanisms at play during cardiac differentiation of human HCM specific pluripotent stem cells. METHODS AND RESULTS We generated a human embryonic stem cell (hESC) line carrying a naturally occurring mutation of MYPBC3 (c.2905 +1 G >A) to study HCM pathogenesis during cardiac differentiation. HCM-specific hESC-derived cardiomyocytes (hESC-CMs) displayed hallmark aspects of HCM including sarcomere disarray, hypertrophy and impaired calcium impulse propagation. HCM hESC-CMs presented a transient haploinsufficiency of cMyBP-C during cardiomyocyte differentiation, but by day 30 post-differentiation cMyBP-C levels were similar to control hESC-CMs. Gene transfer of full-length MYBPC3 during differentiation prevented hypertrophy, sarcomere disarray and improved calcium impulse propagation in HCM hESC-CMs. CONCLUSION(S) These findings point to the critical role of MYBPC3 during sarcomere assembly in cardiac myocyte differentiation and suggest developmental influences of MYBPC3 truncating mutations on the mature hypertrophic phenotype.

Hypertrophic cardiomyopathy: single gene disease or complex trait?

This editorial refers to ‘Hypertrophic remodelling in cardiac regulatory myosin light chain ( MYL2 ) founder mutation carriers’[†][1], by G.R.F. Claes et al ., on page 1815. Landmark genetic mapping studies beginning in the 1990s defined hypertrophic cardiomyopathy (HCM) as an autosomal dominant inherited disease caused by specific mutations in cardiac sarcomere genes.1 Certain mutations in large families were initially described as being more deleterious than others, giving hope that genetic testing would enable predictions of disease severity. However, a more complicated story emerged as extreme locus and phenotypic heterogeneity became evident as the rule rather than the exception in less select populations.2 Indeed, HCM is now recognized as a disease which is primarily caused by a single mutation but then modulated greatly by other factors. In fact, the variability in phenotype attributable to disease modifiers has confounded studies of genotype–phenotype correlations for the primary mutations themselves. Founder mutations offer a distinct advantage in studying disease variability in HCM. Not only is the mutation identical in all subjects, but so also is the surrounding genetic region (haplotype block), which includes the regulatory sequences immediately adjacent to and within the gene. Therefore, differences in disease expression must arise from either other genetic variation or environmental factors. Several previous studies of founder mutations in HCM have shown extreme disease variability, with a range of clinical expression similar to that found in studies of HCM with mixed genotypes. The study by Claes and colleagues adds to this growing evidence in the case of a founder mutation in MYL2 .3 Together, these studies provide robust evidence for the importance of additional genetic and/or environmental factors in … [1]: #fn-2

Heart Valve Disease

Heart valve disease is often characterized by a prolonged asymptomatic period that lasts for years and presents primary care physicians with an opportunity to detect disease before irreversible heart failure or other cardiac complications develop. Acute valvular disease can masquerade as respiratory illness or present with nonspecific systemic symptoms, and an astute examination by a primary care physician can direct appropriate care. Therefore, an understanding of the common pathologies and presentations of valvular heart disease is critical. This review focuses on the 2 most common valve lesions, aortic stenosis and mitral regurgitation, and provides an overview of other valve disease topics.

HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C

Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover.

Exercise hemodynamics in hypertrophic cardiomyopathy identify risk of incident heart failure but not ventricular arrhythmias or sudden cardiac death

OBJECTIVE To determine whether abnormal blood pressure response (ABPR), with or without left ventricular outflow tract obstruction (LVOTO), is associated with adverse heart failure and arrhythmia outcomes in hypertrophic cardiomyopathy (HCM). METHODS A retrospective, single-center analysis was performed for adult HCM patients who underwent exercise stress testing. RESULTS Of 589 patients included in the study, 192 (33%) demonstrated ABPR. A similar proportion of patients with ABPR had LVOTO compared to those without ABPR (56% vs 63%, p = 0.11). Patients with ABPR demonstrated lower percent predicted VO2 and METs achieved than those with LVOTO (16.9 ± 6.8 vs 21.6 ± 7.9, p = 0.002 and 5.3 ± 2.4 vs 7.4 ± 3.1, p < 0.001). In a subgroup of 17 patients with LVOTO and ABPR who subsequently underwent successful myectomy, 5 (30%) demonstrated persistent ABPR. 23 patients (3.8%) experienced sudden cardiac death or ventricular arrhythmias, which were not associated with ABPR, regardless of age group. In multivariable analysis, syncope (p = 0.04), left ventricular hypertrophy (p = 0.02) and left atrial diameter (p = 0.006) were significantly associated with the composite outcome of sudden death or severe ventricular arrhythmia, whereas ABPR was not (p = 0.38). In contrast, ABPR was associated with subsequent heart failure hospitalization (p = 0.002), regardless of presence or absence of LVOTO (p = 0.04, p = 0.02). CONCLUSIONS ABPR is associated with reduced functional capacity in HCM regardless of the presence of LVOTO but is not associated with adverse arrhythmia outcomes. Patients with ABPR have a higher incidence of subsequent heart failure hospitalization.

Information, Data Entry, and Reporting Requirements for a Resident Handoff of Care Support Tool

Physician handoff of care is a mechanism for transferring patient information, responsibility, and authority from one set of caregivers to another. At shift change at a hospital, residents going off shift handoff patients to those coming on shift. There are limited handoff of care tools that facilitate the handover process by condensing patient information in reports that can be referenced during the handoff of care and used during patient care as cognitive artifacts. This effort works to address information, data entry and reporting requirements for a resident handoff of care tool that would support transfer of information as well as patient care.