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This study shows that myocardial fibrosis is an early characteristic of hypertrophic cardiomyopathy caused by sarcomere mutations. The C-terminal propeptide of procollagen type I was shown to be a serum biomarker of early myocardial fibrosis. Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomere proteins. 1 , 2 With a prevalence of approximately 1 case per 500 persons in the general population, hypertrophic cardiomyopathy is the most common monogenic cardiac disorder. 3 The clinical diagnosis depends on the identification of unexplained left ventricular hypertrophy, but this finding is present only in persons with established disease and is typically absent in childhood. 4 In contrast, genetic diagnosis identifies pathogenic sarcomere mutations in persons at any age, including mutation carriers with overt hypertrophic cardiomyopathy and mutation carriers without hypertrophy who are at high risk for the development of disease. Studying . . .

Echocardiographic Strain Imaging to Assess Early and Late Consequences of Sarcomere Mutations in Hypertrophic Cardiomyopathy Carolyn Y. Ho, MD ; Christian Carlsen, MD ; Jens Jakob Thune, MD, PhD ; Ole Havndrup, MD, PhD ; Henning Bundgaard, MD, PhD ; Faranak Farrohi, BS ; Jose Rivero, MD ; Allison L. Cirino, MS, CGC ; Paal Skytt Andersen, MS, PhD ; Michael Christiansen, MD ; Barry J. Maron, MD ; E. John Orav, PhD and Lars Køber, MD, DSci From the Cardiovascular Division (C.Y.H., J.J.T., F.F., J.R., A.L.C.), Brigham and Women’s Hospital, Boston, Mass; Department of Cardiology (C.C., J.J.T., O.H., H.B., L.K.), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Biochemistry (P.S.A., M.C.), Statens Serum Institut, Copenhagen, Denmark; Minneapolis Heart Institute Foundation (B.J.M.), Minneapolis, Minn; and Brigham and Women’s Hospital (E.J.O.), Harvard Medical School, Boston, Mass. Correspondence to Carolyn Y. Ho, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail cho{at}partners.org Received March 2, 2009; accepted June 19, 2009. Background— Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear. Methods and Results— Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH–), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (–) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain ( sys ) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal sys and systolic strain rate, respectively, compared with both preclinical HCM and controls ( P <0.013 for all comparisons), and a 33% reduction in Ea. Conclusions— Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention. Key Words: genetics • cardiomyopathy • contractility • hypertrophy • echocardiography   CLINICAL PERSPECTIVE The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.109.862128/DC1. Home | Subscriptions | Archives | Feedback | Authors | Help | Circulation Journals Home | AHA Journals Home | Search Copyright © 2009 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. var _rsCI=\"us-lippincott\"; var _rsCG=\"0\"; var _rsDN=\"//secure-us.imrworldwide.com/\"; var _rsSE=1; var _rsSM=1.0;

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80–160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z -score as the primary outcome. Valsartan ( n  = 88) improved cardiac structure and function compared to placebo ( n  = 90), as reflected by an increase in the composite z -score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P  = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication. In a randomized phase 2 clinical trial, the angiotensin receptor blocker valsartan improved cardiac structure and function in patients with early-stage hypertrophic cardiomyopathy, a condition for which there are no effective therapies for modifying disease progression.

Background Individuals with hypertrophic cardiomyopathy (HCM), even when asymptomatic, are at‐risk for sudden cardiac death and stroke from arrhythmias, making it imperative to identify individuals affected by this familial disorder. Consensus guidelines recommend that first‐degree relatives (FDRs) of a person with HCM undergo serial cardiovascular evaluations. Methods We determined the uptake of family screening in patients with HCM and developed an online video intervention to facilitate family communication and screening. Family screening and genetic testing data were collected through a prospective quality improvement initiative, a standardized clinical assessment and management plan (SCAMP), utilized in an established cardiovascular genetics clinic. Patients were prescribed an online video if screening of their FDRs was incomplete and a pilot study on video utilization and family communication was conducted. Results Two‐hundred and sixteen probands with HCM were enrolled in SCAMP Phase I and 190 were enrolled in SCAMP Phase II. In both phases, probands reported that 51% of FDRs had been screened (382/749 in Phase I, 258/504 in Phase II). Twenty patients participated in a pilot study on video utilization and family communication. Nine participants reported watching the video and six participants reported sharing the video with relatives; however only one participant reported sharing the video with relatives who were not yet aware of the diagnosis of HCM in the family. Conclusion Despite care in a specialized cardiovascular genetics clinic, approximately one half of FDRs of patients with HCM remained unscreened. Online interventions and videos may serve as supplemental tools for patients communicating genetic risk information to relatives. We prospectively determined the uptake of family screening in patients with hypertrophic cardiomyopathy (HCM) and assessed the impact of an online video intervention on family communication and screening. Approximately half of the first‐degree relatives fail to pursue potentially life‐saving screening that is recommended when HCM is diagnosed in a family, and the uptake of screening is correlated with the proband's decision to pursue genetic testing and genetic test results. At least 82 patients were prescribed the educational video and 20 patients participated in a pilot study on video utilization; participants identified multiple motivators and few barriers to sharing an educational video with their relatives.

Purpose of Review Preimplantation genetic testing for monogenic conditions (PGT-M) is an increasingly utilized reproductive technology for patients with inherited heart disease (IHD). In this article, we provide an overview of the PGT-M process, including current guidance about its use, and review recent data about the perspectives and experiences of patients considering the use of PGT-M. Recent Findings PGT-M is used for a variety of IHDs; however, there is evidence that providers do not consistently raise this topic with patients, which may be due to a lack of knowledge about PGT-M. Regardless of the condition, patients report similar motivations for using PGT-M, such as the desire for a healthy child and the wish to save offspring from suffering. Patients make individualized decisions that are influenced by their lived experience with the diagnosis, a sense of responsibility to prevent disease transmission and other personal and logistical considerations. The PGT-M process can be challenging and each patient requires comprehensive information and support throughout. Summary PGT-M is a complex multi-step process whereby individual decision-making is influenced by various intrinsic and extrinsic factors. Adequate information and support are necessary for individual decision-making and expectation-setting. This is best accomplished by a multidisciplinary collaboration including cardiology, genetics, reproductive endocrinologists, and obstetric providers.

Genetic counselors (GCs) typically provide short-term counseling and assess patient needs, including the need for ongoing psychosocial support. While some patients may benefit from a referral to a mental health provider (MHP), previous research identified barriers to this process due to patient characteristics, the GC work environment, and MHP availability. Adoption of interprofessional collaborative practice (IPCP), a model where multiple healthcare professionals from diverse training disciplines collaborate to deliver patient care, may mitigate these barriers. Evidence suggests that IPCP both increases patient satisfaction and reduces healthcare spending. Anecdotal evidence suggests that GCs and MHPs may use IPCP in select institutions, but there is limited research examining these relationships. This study aims to characterize the benefits, barriers, and limitations of current IPCP practice between GCs and MHPs. Six semi-structured interviews with GCs and MHPs were completed and analyzed thematically. Four themes emerged: (1) mental health concerns in GC sessions and GC scope of practice; (2) establishing and maintaining IPCP between GCs and MHPs; (3) benefits, barriers, and limitations of IPCP; and (4) next steps to develop future IPCP. The findings suggest that there are varying approaches to IPCP that are influenced by perceptions of provider scope of practice. IPCP may mitigate some previously described referral barriers related to logistics, and the availability of trusted MHPs with knowledge of a GCs specialty, thereby improving patient and provider satisfaction.

ObjectiveThe early natural history of sarcomere mutations and the evolution to hypertrophic cardiomyopathy (HCM) are poorly characterised. To describe phenotypic progression, we compared mutation carriers who developed HCM to those who did not during prospective longitudinal investigation.MethodsSarcomere mutation carriers without baseline left ventricular hypertrophy (LVH) were studied during participation in a pilot clinical trial testing diltiazem versus placebo. 38 participants (mean±SD age 15.8±8.6 years) were followed for a median of 2.9 years (range 1.0–5.1 years) with imaging and biomarker analysis. 4 participants (mean baseline age 13.8±3.9 years) developed HCM and were compared to those without phenotypic progression.ResultsParticipants who developed HCM were all children/adolescents and members of families with more highly penetrant mutations. At baseline, participants who developed HCM had a higher left ventricular (LV) ejection fraction (74±2% vs 69±1%, p=0.02), lower global E′ velocity (11.2±0.5 vs 14.8±0.4 cm/s, p<0.0001), higher N terminal pro peptide of B-type natriuretic peptide (NT-proBNP) values (208±72 vs 57±13 pg/mL, p=0.04), longer posterior mitral leaflets, and more prevalent ECG abnormalities. During follow-up, these parameters and cardiac troponin values continued to diverge in participants who developed HCM, although LV wall thickness stabilised.ConclusionsLV relaxation, ECG changes, mitral leaflet length, and serum NT-proBNP concentrations appeared more prominently abnormal at baseline in preclinical sarcomere mutation carriers who imminently progressed to HCM. LVH appears to stabilise within 2 years of onset. Further investigation is needed to improve our understanding of the evolution of this disease.Trial registration numberNCT00319982; Post-results.

Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained.

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 investigate if circulating biomarkers of cardiovascular stress and collagen metabolism among G+/LVH− individuals, measured at rest and following exercise provocation, yield further insights into the underlying biology of HCM.MethodsWe studied 76 individuals with overt HCM, 50 G+/LVH− individuals and 41 genotype-negative related controls enrolled in a cross-sectional, multicentre observational study (HCMNet). Biomarkers of cardiac stress (N-terminal pro-B-type natriuretic peptide, NT-proBNP; high-sensitivity troponin I, hsTnI; soluble ST2) and fibrosis (carboxy-terminal propeptide of procollagen type I; C-terminal telopeptide of type I collagen; galectin-3; periostin) were measured.ResultsIndividuals with overt HCM had elevated NT-proBNP and hsTnI compared with G+/LVH− subjects and controls at rest, along with an exaggerated increase in NT-proBNP and hsTnI in response to exercise. We found no detectable differences in resting or exercise-provoked biomarker profiles of cardiovascular stress and fibrosis among G+/LVH− individuals compared with healthy controls despite subtle echocardiographic differences in cardiac structure and function.ConclusionDynamic exercise testing exaggerated resting differences in natriuretic peptides and troponin elevations among individuals with overt HCM. In contrast, we found no differences in biomarker profiles of cardiovascular stress and fibrosis among G+/LVH− individuals compared with controls even after maximal exercise provocation. Our findings highlight the need for continued investigation into early phenotypes of sarcomeric gene mutations and the evolution of HCM.

Titin, an important protein in the sarcomere, is the largest human protein. This study identified mutations in the titin gene that result in a truncated protein as important causes of dilated cardiomyopathy. Gene mutation is an important cause of cardiomyopathy. Mutations in eight sarcomere-protein genes cause hypertrophic cardiomyopathy, detected in 40 to 70% of patients. 1 , 2 Variations in more than 40 genes, most of which encode components of the sarcomere, the cytoskeleton, or the nuclear lamina, have been shown or posited to cause dilated cardiomyopathy. 3 , 4 Clinical evaluation identifies 30 to 50% of patients with dilated cardiomyopathy as having a relative who is affected or likely to be affected, 5 – 7 implicating a genetic cause. However, pathogenic mutations have been found in only 20 to 30% of patients. 8 TTN, the gene encoding titin, . . .