Pathophysiology Of Hypertrophic Cardiomyopathy Research Articles

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.

1181 A novel insight into pathophysiology of hypertrophic cardiomyopathy using simultaneous three-dimensional volume-strain loops

Abstract Funding Acknowledgements Supported with a scholarship by the Greek State Scholarship Foundation (IKY). Background Strain assessment offers a robust evaluation of myocardial mechanics and systolic function, however reporting only peak strain values in hypertrophic cardiomyopathy (HCM) may impose limitations in the conception of its complex remodeling. Therefore, combined plotting of deformation parameters against other indices [e.g. arterial pressure, left ventricular (LV) volume] might offer additional insights into the pathophysiology of the disease. Purpose Aim of this study was i) to apply strain-volume loops in HCM based on simultaneous frame-by-frame strain and volume changes’ recordings acquired by means of three-dimensional (3D) speckle tracking imaging and ii) to take advantage of the previous methodology to gain further insights into HCM pathophysiology. Methods We included 40 HCM patients (54.1 ± 14.3 years, 82.5% male, maximum wall thickness 19.3 ± 4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build a strain–volume loop. Peak of radial, longitudinal, and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), and strain to end-diastolic volume (EDV) ratio (Rs/V, Ls/V, Cs/V) were computed for the analysis (panel A). Additionally, burden of fibrosis (percentage of LV mass) was defined by LGE extent (>5 standard deviations compared to nulled myocardium) in CMR slices. Results All HCM patients had preserved EF (60.5 ± 5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO > 30 mm Hg at rest). Mean LV mass index was 78.9 ± 14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2 ± 4.5% of LV mass. Concerning strain-volume loops the following values were recorded for radial (Rsp 30.8 ± 9.8%, RsSl 0.4 ± 0.13 and Rs/V 0.25 ± 0.09), longitudinal (Lsp -9.4 ± 3.7%, LsSl 0.12 ± 0.06 and Ls/V 0.08 ± 0.04) and circumferential deformation (Csp -14.2 ± 3.5%, CsSl 0.18 ± 0.05 and Cs/V 0.11 ± 0.03). Among typical HCM characteristics tested (LV mass, LVOTO and LGE), only LV mass presented significant correlations with LsSl (r=-0.41, p < 0.01). Interestingly, HCM patients with smaller LVMI and without LGE presented steeper and narrower (difference between systolic and diastolic strain for the same volume) longitudinal strain-volume loops compared to patients with larger LVMIs and fibrosis (panel B). Conclusions Strain-volume loop is an innovative application of 3D deformation imaging in HCM. According to this new non-invasive method, increase of LVMI in HCM is accompanied by less longitudinal contribution to stroke volume, whereas absence of fibrosis and severe hypertrophy is accompanied by better systolic-diastolic coupling. Abstract 1181 Figure.

Abstract 339: Biomechanics and Calcium Handling of Thin Filament Hypertrophic Cardiomyopathy Variants

The mechanism by which genetic variants of the thin filament cause hypertrophic cardiomyopathy (HCM) has not been fully elucidated. Induced pluripotent stem cell (iPSC)-derived cardiomyocytes can provide a rapidly generatable disease modeling tool to study HCM in these variants. While variants in the thick and thin filament both cause HCM, cardiomyocytes that harbor pathogenic variants in the thin filament genes troponin I ( TNNI3 ) and troponin T ( TNNT2 ) display a distinct molecular phenotype, which we hypothesize differs from the thick filament HCM phenotype. Both thin and thick filament mutant cardiomyocytes display increased measured oxygen consumption rate assessed by metabolic assays, however we hypothesize that the mechanism that drives metabolic change is not common between thick and thin filament variants. Mutations in the thick filament typically shift myosin conformations during relaxion towards a higher energy utilizing a disordered relaxed state (DRX) that enables ATP hydrolysis with more free myosin heads, and this likely accounts for their increased oxygen consumption. However thin filament mutations cause myosin heads to preferentially adopt a conformation in which the myosin heads are sequestered and unable to bind actin. This super relaxed state (SRX) is associated with energy conservation, which would predict reduced contractility. Yet contractility data from thin filament mutants replicate the classic HCM phenotype of hypercontractility and disturbed sarcomere relaxation. To further probe the mechanism by which thin filament variants drive HCM pathophysiology we have employed methodologies to assess calcium transients in iPSC-derived cardiomyocytes harboring thin filament variants. TNNT2 variants recapitulate this disrupted calcium handling.

Energetic drain driving hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins. HCM is characterized by hypertrophy of the left ventricle, frequently involving the septum, that is not explained solely by loading conditions. HCM has a heterogeneous clinical profile, but diastolic dysfunction and ventricular arrhythmias represent two dominant features of the disease. Preclinical evidence indicates that the enhanced Calcium (Ca2+ ) sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric mutations, but can also result from secondary mutation-driven alterations. Here, we review experimental and clinical evidence indicating that increased myofilament Ca2+ sensitivity lies upstream of numerous cellular derangements which potentially contribute to the progression of HCM toward heart failure and sudden cardiac death.

Coronary arterial vasculature in the pathophysiology of hypertrophic cardiomyopathy.

Alterations in the coronary vascular system are likely associated with a mismatch between energy demand and energy supply and critical in triggering the cascade of events that leads to symptomatic hypertrophic cardiomyopathy. Targeting the early events, particularly vascular remodeling, may be a key approach to developing effective treatments. Improvement in our understanding of hypertrophic cardiomyopathy began with the results of early biophysical studies, proceeded to genetic analyses pinpointing the mutational origin, and now pertains to imaging of the metabolic and flow-related consequences of such mutations. Microvascular dysfunction has been an ongoing hot topic in the imaging of genetic cardiomyopathies marked by its histologically significant remodeling and has proven to be a powerful asset in determining prognosis for these patients as well as enlightening scientists on a potential pathophysiological cascade that may begin early during the developmental process. Here, we discuss questions that continue to remain on the mechanistic processes leading to microvascular dysfunction, its correlation to the morphological changes in the vessels, and its contribution to disease progression.

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca2+ sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca2+-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca2+ sensitizer. Our findings suggest that both methods of increasing myofilament Ca2+ sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (kTR); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I1,1/I1,0 ratio from X-ray diffraction. Computational modeling suggests that Ca2+ sensitization through this cTnC mutation or bepridil accelerates kTR primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in kTR, we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca2+ activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca2+ sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca2+ activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.

First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with an estimated prevalence of 1/500. More than 40 genes have been reported to cause HCM. Among them, CSRP3 is usually included on HCM gene panels used for molecular diagnosis by next-generation sequencing (NGS). To provide new insights into the pathophysiology of hypertrophic cardiomyopathy, a NGS workflow based on a panel of 48 cardiomyopathies-causing genes was analyzed on a cohort of 542 HCM patients. As expected, this molecular approach led to identify most pathogenic or likely pathogenic variants into prevalent HCM-causing genes: MYBPC3 (123/542; 22.7%), MYH7 (48/542; 8.9%), TNNT2 (12/542; 2.2%), and TNNI3 (10/542; 1.8%). Among MYBPC3 variants, 96 led to a premature stop codon (78%). More surprisingly, our molecular study led also to detect, for the first time, homozygous CSRP3 truncating variants in two unrelated HCM probands. Meta-analysis of rare previously reported CSRP3 variants on HCM probands using ACMG guidelines indicate that only one variation (p.Cys58Gly) could be considered as likely pathogen. By combining meta-analysis results and identification of two unrelated HCM patients with homozygous CSRP3 truncating variants, we suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal recessive inheritance rather than with an autosomal dominant transmission as usually reported on HCM (OMIM 612124).

Recreational Exercise in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, defined as unexplained left ventricular hypertrophy, has an estimated prevalence of at least 1 in 500 and is among the most common forms of inherited heart disease.1 The pathophysiology of hypertrophic cardiomyopathy is complex and involves the interplay between diastolic dysfunction, myocardial ischemia, systolic anterior motion of the mitral valve resulting in outflow tract obstruction, and arrhythmia.2 Clinical presentations are heterogeneous and range from asymptomatic to palpitations, dyspnea, exercise intolerance, chest pain, syncope, and sudden death. Although the absolute risk of cardiac mortality is less than 1% per year,3 hypertrophic cardiomyopathy remains a common cause of sudden cardiac death in the young, especially in competitive athletes.4,5 Since hypertrophic cardiomyopathy has autosomal dominant inheritance, relatives of affected individuals have substantial risk of disease. Clinical evaluation of family members and cascade screening with genetic testing can identify those affected, many of whom are asymptomatic. When properly treated, the majority of patients with hypertrophic cardiomyopathy will have a normal life span.3

Echocardiographic Assessment of Right Ventricular Size and Function in Cats With Hypertrophic Cardiomyopathy

BackgroundStudies evaluating right ventricular (RV) structural and functional abnormalities in feline hypertrophic cardiomyopathy (HCM) are limited.HypothesisRight ventricular structural and functional abnormalities are present in cats with HCM and are associated with clinical severity.AnimalsEighty‐one client‐owned cats.MethodsRetrospective 2‐dimensional (2D) echocardiographic study. Right atrial diameter (RAD), RV free wall thickness (RVFWd), RV internal dimension (RVIDd), RV fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE) were measured in control cats (n = 26), cats with subclinical HCM (subclinical HCM; n = 31), and cats with HCM and congestive heart failure (HCM + CHF; n = 24).ResultsRight heart size (RAD, RVFWd, and RVIDd) and RV function (FAC and TAPSE) significantly (all P < .05) increased and decreased, respectively, in the HCM + CHF group compared with controls. In the subclinical HCM group, only RVFWd was significantly (P < .05) higher than in controls. Compared with reference intervals derived from controls, 29% of cats with HCM had increased RVFWd. Increased left ventricular free wall thickness, increased RVIDd and decreased TAPSE independently correlated with increased left atrial size. Cats with HCM and pleural effusion were significantly more likely to have increased RVFWd and had increased RAD and decreased TAPSE compared with cats without pleural effusion.Conclusions and Clinical ImportanceRight ventricular remodeling and dysfunction occur in some cats with HCM and may be associated with clinical severity. Our results support involvement of RV in the pathophysiology of HCM in some cats and support echocardiographic assessment of the RV in cats with HCM.

Гипертрофическая кардиомиопатия и ишемическая болезнь сердца. Варианты сочетанной патологии

The issues of epidemiology and pathophysiology of hypertrophic cardiomyopathy (HCMP), as well as the search for its additional clinical-instrumental and genetic markers, environmental factors capable to influence the formation of its clinical variant and prognosis are subjects of great interest to the modern scientific community. Besides genetic markers of main neurohumoral systems, and morphofunctional parameters of intracardiac hemodynamics clinical course of the disease is influenced by a complex of concomitant pathology including ischemic heart disease (IHD), joining of which is possible in 10% of cases. IHD substantially aggravates course of HCMP and hampers selection of medical therapy. It should be noted that prognosis of primary hypertrophies is affected by episodes of ischemia of complex genesis and addition of IHD significantly increases risk of sudden death in these patients.

Speckle tracking echocardiography to assess regional ventricular function in patients with apical hypertrophic cardiomyopathy.

AIMTo explore regional systolic strain of midwall and endocardial segments using speckle tracking echocardiography in patients with apical hypertrophic cardiomyopathy (HCM).METHODSWe prospectively assessed 20 patients (mean age 53 ± 16 years, range: 18-81 years, 10 were male), with apical HCM. We measured global longitudinal peak systolic strain (GLPSS) in the midwall and endocardium of the left ventricle.RESULTSThe diastolic thickness of the 4 apical segments was 16.25 ± 2.75 mm. All patients had a normal global systolic function with a fractional shortening of 50% ± 8%. In spite of supernormal left ventricular (LV) systolic function, midwall GLPSS was decreased in all patients, more in the apical (-7.3% ± -8.8%) than in basal segments (-15.5% ± -6.93%), while endocardial GLPPS was significantly greater and reached normal values (apical: -22.8% ± -7.8%, basal: -17.9% ± -7.5%).CONCLUSIONThis study shows that two-dimensional strain was decreased mainly confined to the mesocardium, while endocardium myocardial deformation was preserved in HCM and allowed to identify subclinical LV dysfunction. This transmural heterogeneity in systolic strain had not been previously described in HCM and could be explained by the distribution of myofibrillar disarray in deep myocardial areas. The clinical application of this novel finding may help further understanding of the pathophysiology of HCM.

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02291237.

Novel Potential Treatment of Familial Hypertrophic Cardiomyopathy with Analogues of the Green Tea Polyphenol Epigallocatechin-3-Gallate

Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) directly alter regulation of cardiac contractility. We have modelled HCM in isolated guinea pig cardiomyocytes by adenoviral expression of human thin filament proteins; in addition to altered contractility, expression of HCM mutants (cTnT R92Q, cTnI R145G and α-TM D175N) results in increased myofilament Ca2+-buffering, leading to altered Ca2+ handling and stimulation of Ca2+-dependent signalling pathways that contribute to HCM pathophysiology. A promising therapeutic approach for correcting these defects is direct desensitisation of myofilament Ca2+ affinity. The green tea catechin, epigallocatechin-3-gallate (EGCg), is known to reduce myofilament Ca2+ binding via interaction with troponin C. We have analysed the effect of EGCg and a panel of analogues on in vitro actomyosin ATPase regulation and myofilament Ca2+ affinity (measured using cTnC labelled with IAANS fluorophore at Cys 35), and on cardiomyocyte contractility and Ca2+ handling. We have found that the parent ECGg compound has poor potency, requiring 30-100 μM to desensitise the myofilament, and suffers from significant off-target effects at lower concentrations (<1 μM) when applied to isolated cardiomyocytes. We have screened several panels of novel compounds and identified at least three catechins with greater efficacy and specificity than the parent compound. They desensitise the myofilament to the same or greater extent than EGCg at 10-100 fold lower concentrations (between 10 and 1 μM). Similar concentrations applied to isolated cardiomyocytes expressing the HCM troponin T mutant R92Q were sufficient to restore normal Ca2+ handling and contractility. This indicates the novel analogues have improved specificity in restoring myofilament Ca2+ buffering compared with the parent compound. This could make them more appealing therapeutically for the treatment of HCM.

Cardiac Findings in Infants of Diabetic Mothers

Hypertrophic cardiomyopathy (HCM) associated with diabetes during pregnancy has been relatively recently described. The echocardiographic findings are similar to those found in the classic sarcomeric familial HCM. In addition, the hemodynamics and clinical presentation may be significant and can include impaired cardiac output and pulmonary hypertension as a result of diastolic dysfunction, left ventricular outflow tract obstruction, and systolic dysfunction. Unlike sarcomeric HCM, neonatal HCM associated with diabetes during pregnancy is self-limited and in fact tends to resolve in weeks to months. On the other hand, in the impaired neonate, a rational management plan needs to be instituted. This article describes the history, potential causes, and pathophysiology of HCM and details a rational management plan for the treatment of these patients.

A New 4D Trajectory-Based Approach Unveils Abnormal LV Revolution Dynamics in Hypertrophic Cardiomyopathy

The assessment of left ventricular shape changes during cardiac revolution may be a new step in clinical cardiology to ease early diagnosis and treatment. To quantify these changes, only point registration was adopted and neither Generalized Procrustes Analysis nor Principal Component Analysis were applied as we did previously to study a group of healthy subjects. Here, we extend to patients affected by hypertrophic cardiomyopathy the original approach and preliminarily include genotype positive/phenotype negative individuals to explore the potential that incumbent pathology might also be detected. Using 3D Speckle Tracking Echocardiography, we recorded left ventricular shape of 48 healthy subjects, 24 patients affected by hypertrophic cardiomyopathy and 3 genotype positive/phenotype negative individuals. We then applied Generalized Procrustes Analysis and Principal Component Analysis and inter-individual differences were cleaned by Parallel Transport performed on the tangent space, along the horizontal geodesic, between the per-subject consensuses and the grand mean. Endocardial and epicardial layers were evaluated separately, different from many ecocardiographic applications. Under a common Principal Component Analysis, we then evaluated left ventricle morphological changes (at both layers) explained by first Principal Component scores. Trajectories’ shape and orientation were investigated and contrasted. Logistic regression and Receiver Operating Characteristic curves were used to compare these morphometric indicators with traditional 3D Speckle Tracking Echocardiography global parameters. Geometric morphometrics indicators performed better than 3D Speckle Tracking Echocardiography global parameters in recognizing pathology both in systole and diastole. Genotype positive/phenotype negative individuals clustered with patients affected by hypertrophic cardiomyopathy during diastole, suggesting that incumbent pathology may indeed be foreseen by these methods. Left ventricle deformation in patients affected by hypertrophic cardiomyopathy compared to healthy subjects may be assessed by modern shape analysis better than by traditional 3D Speckle Tracking Echocardiography global parameters. Hypertrophic cardiomyopathy pathophysiology was unveiled in a new manner whereby also diastolic phase abnormalities are evident which is more difficult to investigate by traditional ecocardiographic techniques.

Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy.

Mitochondrial dysfunction and oxidative stress are important players in the development of various cardiovascular diseases, but their roles in hypertrophic cardiomyopathy (HCM) remain unknown. We examined whether mitochondrial oxidative phosphorylation (OXPHOS) capacity was impaired with enhanced mitochondrial oxidative stress in HCM. Cardiac and skeletal muscles were obtained from 9 domestic cats with spontaneously occurring HCM with preserved left ventricular systolic function and from 15 age-matched control cats. Mitochondrial OXPHOS capacities with nonfatty acid and fatty acid substrates in permeabilized fibers and isolated mitochondria were assessed using high-resolution respirometry. ROS release originating from isolated mitochondria was assessed by spectrofluorometry. Thiobarbituric acid-reactive substances were also measured as a marker of oxidative damage. Mitochondrial ADP-stimulated state 3 respiration with complex I-linked nonfatty acid substrates and with fatty acid substrates, respectively, was significantly lower in the hearts of HCM cats compared with control cats. Mitochondrial ROS release during state 3 with complex I-linked substrates and thiobarbituric acid-reactive substances in the heart were significantly increased in cats with HCM. In contrast, there were no significant differences in mitochondrial OXPHOS capacity, mitochondrial ROS release, and oxidative damage in skeletal muscle between groups. Mitochondrial OXPHOS capacity with both nonfatty acid substrates and fatty acid substrates was impaired with increased mitochondrial ROS release in the feline HCM heart. These findings provide new insights into the pathophysiology of HCM and support the hypothesis that restoration of the redox state in the mitochondria is beneficial in the treatment of HCM.

Genetic Etiology of Hypertrophic Cardiomyopathy

Clarifying the genetic etiology and pathophysiology of hypertrophic cardiomyopathy (HCM), we could identify the molecular pathways how cardiac hypertrophy occurs, the mechanistic process how heart fails, consequently the specific targets for rational therapy. In a clinical setting, the genomic testing of HCM-causing mutation can help us establish the diagnosis for HCM patients, as well as assess the affection status for their family members.

153 Novel Insights into the Pathophysiology of Hypertrophic Cardiomyopathy Using Label free Quantitative Proteomics

IntroductionThe genetic background of hypertrophic cardiomyopathy (HCM) is well described; however it fails to explain the phenotypic diversity characteristic of the disease. By performing an unbiased label-free quantitative proteomics analysis...

HYPERTROPHIC CARDIOMYOPATHY: GENETIC ALTERATIONS, PATHOGENESIS AND PATHOPHYSIOLOGY

The review is dedicated to the description of genetic alterations, pathogenetic mechanisms and pathophysiology of hypertrophic cardiomyopathy, based on the analysis of current up to date information. A contemporary data is provided on the role a plenty discovered mutations of structural, contractile and regulatory sarcomere proteins in cardiomyopathy. The main hypotheses of pathogenetic processes are highlighted, especially the disordered calcium exchange. The importance of genetic testing of patients with hypertrophic cardiomyopathy and their relatives is underlined. The review concerns the basic pathophysiologic characteristics of the disease according to their diagnostic, clinical and prognostic value. Except the description of pathophysiologic properties, as a matter of fact, the obstruction of outflow in the left ventricle, diastolic dysfunction, myocardial ischemia and rhythm disorders, the contemporary instrumental diagnostic methods (positron-emission tomography, computed tomography) in early diagnostic and monitoring of the disease.

Hypertrophic cardiomyopathy: part 1 - introduction, pathology and pathophysiology.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease with many genotype and phenotype variations. Earlier terminologies, hypertrophic obstructive cardiomyopathy and idiopathic hypertrophic sub-aortic stenosis are no longer used to describe this entity. Patients present with or without left ventricular outflow tract (LVOT) obstruction. Resting or provocative LVOT obstruction occurs in 70% of patients and is the most common cause of heart failure. The pathology and pathophysiology of HCM includes hypertrophy of the left ventricle with or without right ventricular hypertrophy, systolic anterior motion of mitral valve, dynamic and mechanical LVOT obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, and fibrosis. Thorough understanding of pathology and pathophysiology is important for anesthetic and surgical management.