The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect.

The conserved C-terminal end segment of troponin I (TnI) plays a critical role in regulating muscle relaxation. This function is retained in the isolated C-terminal 27 amino acid peptide (residues 184-210) of human cardiac TnI (HcTnI-C27): When added to skinned muscle fibers, HcTnI-C27 reduces the Ca2+-sensitivity of activated myofibrils and facilitates relaxation without decreasing the maximum force production. However, the underlying mechanism of HcTnI-C27 function is unknown. We studied the conformational preferences of HcTnI-C27 and a myopathic mutant, Arg192His, (HcTnI-C27-H). Both peptides were mainly disordered in aqueous solution with a nascent helix involving residues from Trp191 to Ile195, as shown by NMR analysis and molecular dynamics simulations. The population of nascent helix was smaller in HcTnI-C27-H than in HcTnI-C27, as shown by circular dichroism (CD) titrations. Fluorescence and isothermal titration calorimetry (ITC) showed that both peptides bound tropomyosin (αTm), with a detectably higher affinity (∼10 µM) of HcTnI-C27 than that of HcTnI-C27-H (∼15 µM), consistent with an impaired Ca2+-desensitization effect of the mutant peptide on skinned muscle strips. Upon binding to αTm, HcTnI-C27 acquired a weakly stable helix-like conformation involving residues near Trp191, as shown by transferred nuclear Overhauser effect spectroscopy and hydrogen/deuterium exchange experiments. With the potent Ca2+-desensitization effect of HcTnI-C27 on skinned cardiac muscle from a mouse model of hypertrophic cardiomyopathy, the data support that the C-terminal end domain of TnI can function as an isolated peptide with the intrinsic capacity of binding tropomyosin, providing a promising therapeutic approach to selectively improve diastolic function of the heart.

Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis.

RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.

Echocardiographic findings in acromegaly: prevalence of concentric left ventricular remodeling in a large single-center cohort.

PURPOSE: Acromegaly is a rare disease and is associated with increased cardiovascular (CV) morbidity and mortality, especially in patients with uncontrolled disease. We aimed to analyze the prevalence and severity of cardiomyopathy and valvular heart disease in a large cohort of patients with a confirmed acromegaly diagnosis, at baseline and after treatment. METHODS: We retrospectively reviewed an institutional approved database; 190 patients with confirmed acromegaly and follow-up data available (years 2006-2018). Patients with at least one baseline echocardiogram, were included. Demographic, disease control and echocardiogram variables were collected for analysis. RESULTS: Of the 190 patients 110 (58%) had a baseline echocardiogram and 43 (39.1%) had at least one follow-up echocardiogram after surgical, medical or multimodal treatment. Baseline left ventricular hypertrophy (LVH) prevalence was 17.8% (64.7% concentric; 35.3% eccentric), diastolic and systolic dysfunction, and overt cardiomyopathy with heart failure were 15.8, 7.9, and 3.0%, respectively. Concentric remodeling of the left ventricle (LV) was noted in 31.4% of patients without LVH. Valve defects were found in 87.3% of patients (14.6% with significant valvular heart disease). CONCLUSION: Early diagnosis of acromegaly and disease control should be attempted to prevent LVH/LV dysfunction and development of valvular heart disease. Concentric LV remodeling develops prior to obvious LV hypertrophy in almost a third of patients with acromegaly, which is a novel finding. Similar to other epidemiological studies, we found a high prevalence of LVH/LV dysfunction. Although possible, reversal of systolic and diastolic dysfunction is sporadic after treatment of acromegaly.

Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.

BACKGROUND: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive. METHODS: We performed chromatin immunoprecipitation-coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA ( HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN-BoxB tethering-based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress-induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell-derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy. RESULTS: HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks-enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca2+-sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase-related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival. CONCLUSIONS: HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation.

Uptake of Predictive Genetic Testing and Cardiac Evaluation for Children at Risk for an Inherited Arrhythmia or Cardiomyopathy.

Predictive genetic testing in minors should be considered when clinical intervention is available. Children who carry a pathogenic variant for an inherited arrhythmia or cardiomyopathy require regular cardiac screening and may be prescribed medication and/or be told to modify their physical activity. Medical genetics and pediatric cardiology charts were reviewed to identify factors associated with uptake of genetic testing and cardiac evaluation for children at risk for long QT syndrome, hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. The data collected included genetic diagnosis, clinical symptoms in the carrier parent, number of children under 18 years of age, age of children, family history of sudden cardiac arrest/death, uptake of cardiac evaluation and if evaluated, phenotype for each child. We identified 97 at risk children from 58 families found to carry a pathogenic variant for one of these conditions. Sixty six percent of the families pursued genetic testing and 73% underwent cardiac screening when it was recommended. Declining predictive genetic testing was significantly associated with genetic specialist recommendation (p < 0.001) and having an asymptomatic carrier father (p = 0.006). Cardiac evaluation was significantly associated with uptake of genetic testing (p = 0.007). This study provides a greater understanding of factors associated with uptake of genetic testing and cardiac evaluation in children at risk of an inherited arrhythmia or cardiomyopathy. It also identifies a need to educate families about the importance of cardiac evaluation even in the absence of genetic testing.

Ultrasound biomicroscopy validation of a murine model of cardiac hypertrophic preconditioning: comparison with a hemodynamic assessment.

In mice, myocardial hypertrophic preconditioning (HP), which is produced by the removal of short-term transverse aortic constriction (TAC), was recently reported to render the heart resistant to hypertrophic responses induced by subsequent reconstriction (Re-TAC). However, there is no efficient noninvasive method for ensuring that the repeated aortic manipulations were successfully performed. We previously demonstrated that ultrasound biomicroscopy (UBM) is a noninvasive and effective approach for predicting TAC success. Here, we investigated the value of UBM for serial predictions of load conditions in establishing a murine HP model. C57BL/6J mice were subjected to a sham operation, TAC, or Re-TAC, and the peak flow velocity at the aortic banding site (PVb) was measured by UBM. Left ventricular end-systolic pressure (LVESP) was examined by micromanometric catheterization. The PVb was positively associated with LVESP (R2 = 0.8204, P < 0.001, for TAC at 3 days and R2 = 0.7746, P < 0.001, for Re-TAC at 4 wk). PVb and LVESP values were markedly elevated after aortic banding, became attenuated to the sham-operated level after debanding, and increased after aortic rebanding. The cardiac hypertrophic responses were examined by UBM, histology, RT-PCR, and Western blot analysis. Four weeks after the last operation, with PVb ≥ 3.5 m/s as an indicator of successful aortic constriction, Re-TAC mice showed less cardiac hypertrophy, fetal gene expression, and ERK1/2 activation than TAC mice. Therefore, we successfully established a UBM protocol for the serial assessment of aortic flow and the prediction of LVESP during repeated aortic manipulations in mice, which might be useful for noninvasive evaluations of the murine HP model.NEW & NOTEWORTHY We successfully developed an ultrasound biomicroscopy protocol for the serial assessment of aortic bandings and the relevant left ventricular pressure in a murine model of cardiac hypertrophic preconditioning. The protocol may be of great importance in the successful establishment of the hypertrophic preconditioning model for further mechanistic and pharmacological studies.

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients.

Everolimus (EVL), one of the mammalian targets of rapamycin, is a next generation immunosuppressant that may have accessory anti-proliferative effects in heart transplant (HTx) recipients. However, little is known about the clinical relationship between EVL and regression of cardiac hypertrophy. A total of 42 HTx recipients received EVL therapy at post-HTx 150 days on median and had been followed at our institute for > 1 year between 2008 and 2014 [EVL (+) group]. We also observed 18 patients without EVL from post-HTx 150 days for 1 year [EVL (-) group]. There were no significant differences in baseline variables between the two groups. Left ventricular mass index (LVMI) and the ratio of early transmitral filling velocity to the peak early diastolic mitral annular motion velocity (E/e') decreased significantly during 1-year EVL treatment compared with the EVL (-) group. There were no differences in blood pressure and medications between the 2 groups. Improvement of LVMI and the E/e' ratio was not associated with trough levels of calcineurin inhibitors or EVL, but correlated with each baseline value. In conclusion, this EVL-incorporated immunosuppressant regimen attenuated cardiac hypertrophy as well as diastolic dysfunction in HTx recipients.

[Heart and liver fibrosis: the components of a single equation].

Myocardial fibrosis plays a key role in the pathogenesis of cardiovascular diseases. The chronic pressure overload of the heart activates collagen that leads to its excessive accumulation, fibrosis and cardiac hypertrophy. Myocardial injury is often accompanied by liver damage. These two processes are closely linked. One of the links of this chain is the activation of the renin-angiotensin-aldosterone system (RAAS). There is impressive evidence base for drugs that block the RAAS, and thus break the vicious cycle of cardiovascular continuum. Fibrogenesis is nonspecific process and prospect of drug application affecting the activity of the RAAS may be useful for fibrosis prevention not only for the heart and liver, but also for other organs.

Long-term follow-up impact of dual-chamber pacing on patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Pacing has been proposed as a treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM), but there are few studies with long-term follow-up. We evaluated the long-term effects of dual-chamber pacing therapy for patients with HOCM, and to identify the most prognosis-specific factors for predicting outcome in such treating methods. METHODS: A total of 37 HOCM patients implanted with dual-chamber pacemakers were enrolled consecutively and followed-up. Thirty-seven cases were followed for 1 year, 26 cases for 2 years, 10 cases for 3 years, and eight cases for 4 years. At each annual point of follow-up after pacemaker implantation, the pacing frequency, pacing threshold, impedance, atrioventricular delay, and cumulative percentage of atrial and ventricular pacing were tested, respectively. In addition, left atrial dimension (LAD), left ventricular end diastolic dimension (LVEDd), left ventricular posterior wall thickness (LVPW), interventricular septum thickness (IVS), left ventricular outflow tract dimension (LVOTd), peak velocity of left ventricular outflow tract (VLVOT), left ventricular outflow tract pressure gradient (LVOTPG), left ventricular ejection fraction (LVEF), and pulmonary artery systolic pressure (PASP) were measured. Mitral valve systolic anterior motion (SAM) was also observed. Pacing parameters and echocardiography indexes before and after pacemaker implantation were dynamically compared. RESULTS: Pacing frequency and atrioventricular delay were adjusted to 60-70 beats per minute and 90-180 ms, respectively, in order to ensure the ratio of ventricular pacing was more than 98%. Pacing threshold and pacing impedance were kept in normal ranges. The differences of various pacing parameters were of no statistical significance within the 4 years of follow-up (P > 0.05). Compared with prior to pacing, it was observed that the IVS, VLVOT, and LVOTPG declined significantly (P < 0.01), the LVOTd widened significantly (P < 0.01), and the SAM phenomenon improved obviously (P < 0.01) at 1, 2, 3, and 4 years after pacemaker implantation. Additionally, the changes in LAD, LVEDd, LVPW, LVEF, and PASP were statistically insignificant (P > 0.05). CONCLUSIONS: The cardiac structural reconstruction in patients with HOCM can be chronically improved by dual-chamber pacing therapy. The IVS, LVOTd, VLVOT, and LVOTPG can be used as sensitive and specific factors in evaluating the long-term effects of dual-chamber pacing therapy for HOCM.

The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling.

The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. Furthermore, it remains unclear how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome (also termed Noonan Syndrome with multiple lentigines), which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). In normal hearts, Shp2 controls cardiomyocyte size by regulating signaling through protein kinase B (Akt) and mammalian target of rapamycin (mTOR). We hypothesized that Shp2 LOF mutations dysregulate this pathway, resulting in HCM. For our studies, we chose the Shp2 mutation Q510E, a dominant-negative LOF mutation associated with severe early onset HCM. Newborn mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth displayed increased cardiomyocyte sizes, heart-to-body weight ratios, interventricular septum thickness, and cardiomyocyte disarray. In 3-mo-old hearts, interstitial fibrosis was detected. Echocardiographically, ventricular walls were thickened and contractile function was depressed. In ventricular tissue samples, signaling through Akt/mTOR was hyperactivated, indicating that the presence of Q510E-Shp2 led to upregulation of this pathway. Importantly, rapamycin treatment started shortly after birth rescued the Q510E-Shp2-induced phenotype in vivo. If rapamycin was started at 6 wk of age, HCM was also ameliorated. We also generated a second mouse model in which cardiomyocyte-specific Q510E-Shp2 overexpression started after birth. In contrast to the first model, these mice did not develop HCM. In summary, our studies establish a role for mTOR signaling in HCM caused by Q510E-Shp2. Q510E-Shp2 overexpression in the cardiomyocyte population alone was sufficient to induce the phenotype. Furthermore, the pathomechanism was triggered pre- but not postnatally. However, postnatal rapamycin treatment could still reverse already established HCM, which may have important therapeutic implications.

Noninvasive imaging modalities and sudden cardiac arrest in the young: can they help distinguish subjects with a potentially life-threatening abnormality from normals?

Sudden cardiac arrest (SCA) in the young is always tragic, but fortunately it is an unusual event. When it does occur, it usually happens in active individuals, often while they are participating in physical activity. Depending on the population's characteristics, the most common causes of sudden cardiac arrest in these subjects are hypertrophic cardiomyopathy, congenital coronary abnormalities, arrhythmia in the presence of a structurally normal heart (ion channelopathies or abnormal conduction pathways), aortic rupture, and arrhythmogenic right-ventricular cardiomyopathy. Two-dimensional echocardiography (2-DE) has been proposed as a screening tool that can potentially detect four of these five causes of SCA, and many groups now sponsor community-based 2-DE SCA-screening programs. "Basic" 2-DE screening may include assessment of ventricular volumes, mass, and function; left atrial size; and cardiac and thoracic vascular (including coronary) anatomy. "Advanced" echocardiographic techniques, such as tissue Doppler and strain imaging, can help in diagnosis when the history, electrocardiogram (ECG), and/or standard 2-DE screening suggest there may be an abnormality, e.g., to help differentiate those with "athlete's heart" from hypertrophic or dilated cardiomyopathy. Cardiac magnetic resonance imaging or cardiac computed tomography can be added to increase diagnostic sensitivity and specificity in select cases when an abnormality is suggested during SCA screening. Test availability, cost, and ethical issues related to who to screen, as well as the detection of those with potential disease but low risk, must be balanced when deciding what tests to perform to assess for increased SCA risk.

Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes.

RAS activation is implicated in physiologic and pathologic cardiac hypertrophy. Cross-talk between the Ras and calcineurin pathways, the latter also having been implicated in cardiac hypertrophy, has been suspected for pathologic hypertrophy. Our recent discovery that germ-line mutations in RAF1, which encodes a downstream RAS effector, cause Noonan and LEOPARD syndromes with a high prevalence of hypertrophic cardiomyopathy provided an opportunity to elaborate the role of RAF1 in cardiomyocyte biology. Here, we characterize the role of RAF1 signaling in cardiomyocyte hypertrophy with an aim of identifying potential therapeutic targets. We modeled hypertrophic cardiomyopathy by infecting neonatal and adult rat cardiomyocytes (NRCMs and ARCMs, respectively) with adenoviruses encoding wild-type RAF1 and three Noonan/LEOPARD syndrome-associated RAF1 mutants (S257L, D486N or L613V). These RAF1 proteins, except D486N, engendered cardiomyocyte hypertrophy. Surprisingly, these effects were independent and dependent of mitogen activated protein kinases in NRCMs and ARCMs, respectively. Inhibiting Mek1/2 in RAF1 overexpressing cells blocked hypertrophy in ARCMs but not in NRCMs. Further, we found that endogenous and heterologously expressed RAF1 complexed with calcineurin, and RAF1 mutants causing hypertrophy signaled via nuclear factor of activated T cells (Nfat) in both cell types. The involvement of calcineurin was also reflected by down regulation of Serca2a and dysregulation of calcium signaling in NRCMs. Furthermore, treatment with the calcineurin inhibitor cyclosporine blocked hypertrophy in NRCMs and ARCMs overexpressing RAF1. Thus, we have identified calcineurin as a novel interaction partner for RAF1 and established a mechanistic link and possible therapeutic target for pathological cardiomyocyte hypertrophy induced by mutant RAF1. This article is part of a Special Issue entitled 'Possible Editorial'.

Defibrillation thresholds in hypertrophic cardiomyopathy.

BACKGROUND: Defibrillation threshold (DFT) testing is performed in part to ensure an adequate safety margin for the termination of spontaneous ventricular arrhythmias. Left ventricular mass is a predictor of high DFTs, so patients with hypertrophic cardiomyopathy (HCM) are often considered to be at risk for increased defibrillation energy requirements. However, there are little prospective data addressing this issue. OBJECTIVE: To assess DFTs in patients with HCM and evaluate the clinical predictors of elevated DFTs. METHODS: Eighty-nine consecutive patients with HCM and 600 control patients with ischemic or nonischemic cardiomyopathy underwent a uniform modified step-down DFT testing protocol. DFT was compared between the control and HCM populations. Predictors of elevated DFT were evaluated in the HCM group. RESULTS: There was no difference in DFT between HCM and control groups (10.4 ± 5.8 J vs 11.2 ± 5.6 J, respectively). Among patients with HCM, clinical parameters such as left ventricular ejection fraction, interventricular septal thickness, left ventricular mass, and QRS duration were not predictive of an elevated DFT. Only 3 patients (3.4%) with HCM had a DFT >20 J. CONCLUSION: Patients with HCM do not have elevated DFTs as compared to more typical populations undergoing implantable cardioverter-defibrillator implant; high-energy devices or complex lead systems are not needed routinely in this population.

Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes.

Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors and various downstream signaling pathways involving, for example, ras, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families. Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Galphaq and Galpha11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.

Effect of cardiac resynchronization on gradient reduction in patients with obstructive hypertrophic cardiomyopathy: preliminary study.

BACKGROUND: The purpose of this study was to assess the effectiveness of cardiac resynchronization therapy (CRT) in terms of outflow tract gradient reduction and functional improvement in symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM) requiring implantable cardioverter-defibrillator (ICD) implantation. METHODS: Eleven consecutive symptomatic HOCM patients with a significant (≥40 mmHg) gradient and indications for ICD, but without indications for resynchronization, underwent CRT-D implantation. Nine of them (four female, median age of 50 years) in whom the procedure succeeded were screened for New York Heart Association (NYHA) class, outflow gradient, mechanical dyssynchrony, QRS-width change, and 6-minute walking distance (6MWD) and peak oxygen consumption (VO(2)peak) improvement after 6 months and remotely. RESULTS: After 6 months of pacing, NYHA class decreased (median 1 vs 2, respectively); peak (33 vs 84 mmHg) and mean (13 vs 38 mmHg) outflow tract gradients were reduced; and QRS width (143 vs 105 ms), intraventricular dyssynchrony (35 vs 55 ms), and VO(2)peak (19.5 vs 14.2 mL/kg/min) increased significantly (all P < 0.05) compared to baseline. In six of nine patients (67%), the peak gradient was reduced >50% and reached <40 mmHg. After a median of 36 months, the outflow gradient decreased even more (8 mmHg) and was significantly (P < 0.05) lower than after 6 months of CRT. CONCLUSIONS: These preliminary data suggest that CRT seems to be an effective method of reducing the outflow tract gradient and improving the functional status of symptomatic HOCM patients requiring ICD implantation. Our findings need to be confirmed by more extensive studies.

Cost-Effectiveness Analysis of Evolocumab Therapy in Patients at High Risk of Cardiovascular Events in the Context of the Brazilian Unified Health System. / Análise de Custo-Efetividade da Terapia com Evolocumabe em Pacientes com Alto Risco de Eventos Cardiovasculares no Contexto do SUS ­ Brasil.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH) secondary to systemic hypertension (HTN) may be associated with left atrial (LA) functional abnormalities. OBJECTIVES: We aimed to characterize LA mechanics in HCM and HTN and determine any correlation with the extent of left ventricular (LV) fibrosis measured by cardiac magnetic resonance (CMR) in HCM patients. METHODS: Two-dimensional speckle tracking-derived longitudinal LA function was acquired from apical views in 60 HCM patients, 60 HTN patients, and 34 age-matched controls. HCM patients also underwent CMR, with measurement of late gadolinium enhancement (LGE) extension. Association with LA strain parameters was analyzed. Statistical significance was set at p<0.05. RESULTS: Mean LV ejection fraction was not different between the groups. The E/e' ratio was impaired in the HCM group and preserved in the control group. LA mechanics was significantly reduced in HCM, compared to the HTN group. LA strain rate in reservoir (LASRr) and in contractile (LASRct) phases were the best discriminators of HCM, with an area under the curve (AUC) of 0.8, followed by LA strain in reservoir phase (LASr) (AUC 0.76). LASRr and LASR-ct had high specificity (89% and 91%, respectively) and LASr had sensitivity of 80%. A decrease in 2.79% of LA strain rate in conduit phase (LASRcd) predicted an increase of 1cm in LGE extension (r2=0.42, ß 2.79, p=0.027). CONCLUSIONS: LASRr and LASRct were the best discriminators for LVH secondary to HCM. LASRcd predicted the degree of LV fibrosis assessed by CMR. These findings suggest that LA mechanics is a potential predictor of disease severity in HCM.

FUNDAMENTO: Em associação às estatinas, os inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9) demonstraram ser eficazes na redução de eventos cardiovasculares em pacientes de alto risco. OBJETIVO: Analisar a custo-efetividade da implementação de evolocumabe para pacientes com alto risco de eventos cardiovasculares no contexto do Sistema Único de Saúde (SUS) no Brasil. MÉTODOS: Um modelo de Markov foi utilizado, baseando-se em uma amostra ambulatorial de pacientes com doença arterial coronariana. Os desfechos primários analisados foram infarto agudo do miocárdio, acidente vascular cerebral isquêmico (AVCi), revascularização do miocárdio e morte cardiovascular. O resultado foi expresso por meio da razão de custo-efetividade incremental (RCEI), considerando-se uma taxa de desconto de 5% ao ano, e uma análise de sensibilidade foi realizada, tendo em vista a imprecisão de valores. RESULTADOS: Selecionaram-se 61 pacientes com risco cardiovascular estimado em 35% em 10 anos, se em uso de atorvastatina 80mg/dia, e em 22,75%, se adicionado o evolocumabe. O custo global por paciente no período de 10 anos foi de R$ 46.522,44 no grupo em monoterapia com atorvastatina versus R$ 236.141,85 na terapia combinada, com uma efetividade global de 0,54 e 0,73, respectivamente. Isso resultou em uma RCEI R$ 1.011.188,07 (R$ 864.498,95 a R$ 1.296.748,43) por desfecho cardiovascular evitado. CONCLUSÕES: Apesar de não existirem padrões nacionais para custo-efetividade, os dados encontrados sugerem que a estratégia de associação do evolocumabe à terapia com estatina não é, no momento, custo-efetiva.

Novel use of a vascular plug to anchor an azygous vein ICD lead.

We describe the case of a young patient with severe hypertrophic cardiomyopathy and marginal defibrillation thresholds (DFTs) at implant of a standard transvenous implantable cardioverter-defibrillator (ICD) system. The patient subsequently experienced multiple failed ICD shocks during a prolonged episode of spontaneous ventricular tachycardia/fibrillation. Placement of a second single-coil shocking lead in the azygous vein resulted in acceptable DFTs, but the new lead migrated superiorly within hours of the procedure. To stabilize the lead position, a vascular plug was placed in the distal azygous vein, and the shocking lead screw was actively fixated to the meshwork of the device. Subsequent testing confirmed both adequate defibrillation and stable lead position.

Fropofol prevents disease progression in mice with hypertrophic cardiomyopathy.

AIMS: Increased myofilament contractility is recognized as a crucial factor in the pathogenesis of hypertrophic cardiomyopathy (HCM). Direct myofilament desensitization might be beneficial in preventing HCM disease progression. Here, we tested whether the small molecule fropofol prevents HCM phenotype expression and disease progression by directly depressing myofilament force development. METHODS AND RESULTS: Force, intracellular Ca2+, and steady-state activation were determined in isolated trabecular muscles from wild-type (WT) and transgenic HCM mice with heterozygous human α-myosin heavy chain R403Q mutation (αMHC 403/+). αMHC 403/+ HCM mice were treated continuously with fropofol by intraperitoneal infusion for 12 weeks. Heart tissue was analysed with histology and real-time PCR of prohypertrophic and profibrotic genes. Fropofol decreased force in a concentration-dependent manner without significantly altering [Ca2+]i in isolated muscles from both WT and αMHC 403/+ HCM mouse hearts. Fropofol also depressed maximal Ca2+-activated force and increased the [Ca2+]i required for 50% activation during steady-state activation. In whole-animal studies, chronic intra-abdominal administration of fropofol prevented hypertrophy development and diastolic dysfunction. Chronic fropofol treatment also led to attenuation of prohypertrophic and profibrotic gene expression, reductions in cell size, and decreases in tissue fibrosis. CONCLUSIONS: Direct inhibition of myofilament contraction by fropofol prevents HCM disease phenotypic expression and progression, suggesting that increased myofilament contractile force is the primary trigger for hypertrophy development and HCM disease progression.

Prevention of cardiac hypertrophy in mice by calcineurin inhibition.

Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.