Search

Aims Patients with tetralogy of Fallot (TOF) are often affected by right ventricular fibrosis, which has been associated with arrhythmias. This study aimed to assess fibrosis distribution in right ventricular outflow tract (RVOT) myocardium of TOF patients to evaluate the utility of single histology-section analyses, and to explore the possibility of fibrosis quantification in unlabelled tissue by second harmonic generation imaging (SHGI) as an alternative to conventional histology-based assays. Methods and results We quantified fibrosis in 11 TOF RVOT samples, using a tailor-made automated image analysis method on Picrosirius red-stained sections. In a subset of samples, histology- and SHGI-based fibrosis quantification approaches were compared. Fibrosis distribution was highly heterogeneous, with significant and comparable variability between and within samples. We found that, on average, 67.8 mm2 of 10 µm thick, histologically processed tissue per patient had to be analysed for accurate fibrosis quantification. SHGI provided data faster and on live tissue, additionally enabling quantification of collagen anisotropy. Conclusion Given the high intra-individual heterogeneity, fibrosis quantification should not be conducted on single sections of TOF RVOT myectomies. We provide an analysis algorithm for fibrosis quantification in histological images, which enables the required extended volume analyses in these patients.

Rationale: Right ventricular (RV) fibrosis in pulmonary arterial hypertension contributes to RV failure. While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied. Objective: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental pulmonary arterial hypertension. Methods and Results: Male Sprague-Dawley rats received monocrotaline (MCT; 60 mg/kg) or saline. Drinking water containing no supplement or the PDK (pyruvate dehydrogenase kinase) inhibitor dichloroacetate was started 7 days post-MCT. At week 4, treadmill testing, echocardiography, and right heart catheterization were performed. The effects of PDK activation on mitochondrial dynamics and metabolism, RVfib proliferation, and collagen production were studied in RVfib in cell culture. Epigenetic mechanisms for persistence of the profibrotic RVfib phenotype in culture were evaluated. PDK expression was also studied in the RVfib of patients with decompensated RV failure (n=11) versus control (n=7). MCT rats developed pulmonary arterial hypertension, RV fibrosis, and RV failure. MCT-RVfib (but not left ventricular fibroblasts) displayed excess mitochondrial fission and had increased expression of PDK isoforms 1 and 3 that persisted for >5 passages in culture. PDK-mediated decreases in pyruvate dehydrogenase activity and oxygen consumption rate were reversed by dichloroacetate (in RVfib and in vivo) or siRNA targeting PDK 1 and 3 (in RVfib). These interventions restored mitochondrial superoxide and hydrogen peroxide production and inactivated HIF (hypoxia-inducible factor)-1α, which was pathologically activated in normoxic MCT-RVfib. Redox-mediated HIF-1α inactivation also decreased the expression of TGF-β1 (transforming growth factor-beta-1) and CTGF (connective tissue growth factor), reduced fibroblast proliferation, and decreased collagen production. HIF-1α activation in MCT-RVfib reflected increased DNMT (DNA methyltransferase) 1 expression, which was associated with a decrease in its regulatory microRNA, miR-148b-3p. In MCT rats, dichloroacetate, at therapeutic levels in the RV, reduced phospho-pyruvate dehydrogenase expression, RV fibrosis, and hypertrophy and improved RV function. In patients with pulmonary arterial hypertension and RV failure, RVfib had increased PDK1 expression. Conclusions: MCT-RVfib manifest a DNMT1-HIF-1α-PDK–mediated, chamber-specific, metabolic memory that promotes collagen production and RV fibrosis. This epigenetic mitochondrial-metabolic pathway is a potential antifibrotic therapeutic target.

Background The clinical utility of comprehensive cardiac magnetic resonance (CMR) for the assessment of myocardial structure and function remains unknown in patients with low gradient (LG) aortic stenosis (AS). Purpose This study sought to compare CMR characteristics of myocardial structure and function according to different flow / gradient patterns of AS: classical low flow LG (LFLG); paradoxical LFLG; normal flow LG; and high gradient, and to evaluate their impact on the outcomes of these patients. Methods International multicentric prospective study included 147 patients with LG moderate to severe AS and 18 patients with high gradient severe AS who underwent comprehensive CMR evaluation of left ventricular global longitudinal strain (LVGLS), extracellular volume fraction (ECV), and late gadolinium enhancement (LGE). Results Patients with classical LFLG (n=90) had more LV adverse remodeling and impaired longitudinal function including higher ECV, and higher LGE and volume, and worst LVGLS, compared to other patterns of AS. Over a median follow-up of 2-years, 43 deaths and 48 composite outcomes of death or heart failure hospitalization occurred in LG AS patients. As LVGLS or ECV worsened, risks of adverse events also increased (per tertile of LVGLS: HR [95% CI] for mortality, 1.50 [1.02–2.20]; p=0.04; HR [95% CI] for composite outcome, 1.45 [1.01–2.09]; p Conclusions In this international multicentric study of LG AS, comprehensive CMR assessment of myocardial structure and function provides independent prognostic value that is cumulative and incremental to clinical and echocardiographic characteristics. Funding Acknowledgement Type of funding sources: None.

In patients with atrial fibrillation (AF), diffuse left ventricular (LV) fibrosis may occur as a result of AF-induced or -mediated cardiomyopathy (AF-CM). It is believed that AF-CM is triggered in part due to tachycardia, irregular rhythm, dyssynchrony, lack of atrial contraction, and functional

Atrial fibrillation (AF) is one of the most common tachyarrhythmias observed in the clinic and is characterized by structural and electrical remodelling. Atrial fibrosis, an emblem of atrial structural remodelling, is a complex multifactorial and patient‑specific process involved in the occurrence and maintenance of AF. Whilst there is already considerable knowledge regarding the association between AF and fibrosis, this process is extremely complex, involving intricate neurohumoral and cellular and molecular interactions, and it is not limited to the atrium. Current technological advances have made the non‑invasive evaluation of fibrosis in the atria and ventricles possible, facilitating the selection of patient‑specific ablation strategies and upstream treatment regimens. An improved understanding of the mechanisms and roles of fibrosis in the context of AF is of great clinical significance for the development of treatment strategies targeting the fibrous region. In the present review, a focus was placed on the atrial fibrosis underlying AF, outlining its role in the occurrence and perpetuation of AF, by reviewing recent evaluations and potential treatment strategies targeting areas of fibrosis, with the aim of providing a novel perspective on the management and prevention of AF.

Introduction: On cardiac CT of pulmonary hypertension (PH), two right ventricular (RV) hypertrophic (RVH) morphological types are seen, namely RV outflow tract-dominant and RV-diffuse. However, clinical significance of this difference is unclear. Hypothesis: These two morphological RVH types have different effects on myocardial characteristics, clinical severity and prognosis in PH patients. Methods: We retrospectively analyzed 43 PH patients (33 females, 55±15yrs, 31 chronic thromboembolic PH (CTEPH), 7 idiopathic pulmonary arterial (PA) hypertension). On CT, RV fibrosis was defined as contrast defects in early phase and abnormal enhancement in late phase. Cases were divided into 3 groups: RV outflow tract-dominant RVH (gp 1), RVH-diffuse (gp 2), and no RVH (gp 3). Mean follow up was 39.3±20.1, 58.3±17.7, 68.2±11.9 months, respectively. Results: There were 6, 26, 11 patients in gps 1, 2, 3, respectively. There were no significant differences in these percentages between CTEPH and idiopathic PA hypertension or between ages ≥60 and Conclusions: In PH patients, RV outflow tract-dominant RVH was relatively easy to diagnose and manifested with greater occurrence of RV fibrosis than diffuse-type. RV outflow tract-dominant RVH showed significant positive correlations of maximum RV wall thickness in end-diastole with plasma BNP and estimated PASP.

Introduction: Previous cardiac MRI studies reported that the baseline diffuse LV fibrosis status should be evaluated before performing catheter ablation (CA) to identify the responders early and triage them with appropriate treatment. However, no study has been conducted to evaluate diffuse LV fibrosis in conjunction with pre-ablation planning cardiac CT. Objectives: The purpose of this study was to quantify diffuse left ventricular (LV) fibrosis by the CT-derived extracellular volume fraction (CT-ECV%) in conjunction with cardiac CT performed for CA planning and evaluate its determinants in patients with atrial fibrillation (AF). Methods: Prior to AF ablation, 98 patients (50 patients with paroxysmal AF and 48 patients with persistent AF) underwent pre-ablation planning cardiac CT. Additionally, delayed cardiac CT was performed to measure CT-ECV% as an index of diffuse myocardial fibrosis. Results: Persistent AF patients more frequently had a history of heart failure. Left atrial (LA) volume index was greater in persistent AF patients compared with paroxysmal AF patients. CT-ECV% of persistent AF patients was significantly higher than that of paroxysmal AF patients (30 ± 5 % vs. 26 ± 5 %, p < 0.001). Univariate and multivariate analysis revealed that only persistent AF was independent associated with CT-ECV%. Furthermore, CT-ECV% in recurrence group after CA for AF was higher than that in non-recurrence group (29 ± 4 % vs. 26 ± 5 %, p = 0.013). Multivariate logistic regression analysis revealed that CT-ECV% was significantly correlated with AF recurrence after CA for AF. Receiver operating characteristic analysis showed that more than 28 % in the CT-ECV% was a significant predictor of AF recurrence (area under the curve 0.692, log-rank test: p < 0.001). Conclusions: The quantification of diffuse LV fibrosis by CT-ECV% in conjunction with pre-ablation planning cardiac CT is feasible in AF patients, and persistent AF is independently associated with increasing diffuse LV fibrosis. Furthermore, CT-ECV% was significantly associated with AF recurrence after CA for AF. These findings suggested that it was more important to evaluate cardiac remodeling using CT and intervene early in AF.

Background Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. Methods Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n = 4) or 9 (n = 4) weeks after Sugen5416 and hypoxia and 12 weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. Results In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. Conclusions Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

BACKGROUND: Left ventricular (LV) extracellular volume fraction (ECV) provides prognostic information in patients with variety of cardiomyopathies. However, data on the clinical significance of LV ECV in patients with atrial fibrillation (AF), especially in patients without replacement fibrosis are sparse. This study sought to investigate whether the presence of LV fibrosis identified by cardiac magnetic resonance (CMR) ECV quantification would independently predict the recurrence of AF after first catheter ablation (CA) in patients with AF. METHODS: A total of 130 consecutive patients who were referred for CA of AF underwent CMR examination prior to ablation. LV function, T1 mapping derived LV ECV, LV late gadolinium enhancement (LGE) were assessed. Patients were followed for arrhythmia recurrence after the CA procedure. RESULTS: Of 130 AF patients, 65 patients had paroxysmal AF, and 65 patients had persistent AF. There were 50 AF recurrences over a median follow-up period of 13 months. LV ECV were significantly higher in patients with recurrent AF compared to those with no recurrence (30.4%±3.3% vs. 27.4%±2.9%, P

Graphical abstract, Highlights • CMR may identify AFD among cardiomyopathies that present as LVH. • AFD is a progressive lysosomal storage disease that is treatable with ERT. • Screening tools to detect early-stage AFD are crucial.

Despite successful repair in early life, patients with coarctation of the aorta (CoA) are predisposed to several cardiovascular complications in later life related to systemic hypertension or left ventricular (LV) dysfunction, or both, the pathogenesis of which is unclear.Three-week-old Sprague-Dawley rats underwent transverse aortic constriction (TAC) or a sham operation, with release of the constriction 3 weeks later. Twenty-five weeks after the repair operation, animals underwent hemodynamic assessment, LV gene profiling, and histologic analysis.Animals with repaired aortic constriction exhibited a significantly elevated central systolic pressure (116 ± 5 mm Hg vs 103 ± 4 mm Hg; p0.05) despite the absence of any significant pressure gradient across the former constriction site compared with shams (5 ± 4 mm Hg vs 0 ± 2 mm Hg; p = 0.2). They also had more than a 2-fold increase in LV collagen deposition (4.86% ± 0.24% vs 2.40% ± 0.18%; p0.001). However, no significant differences were noted between the groups in maximum LV pressure (116 ± 3 mm Hg vs 107 ± 3 mm Hg; p = 0.1), LV mass indexed to tibial length (p = 0.07), or myocyte size. There was no significant differential expression of hypertrophy or fibrosis-related genes in the left ventricles of the repaired animals compared with shams.Despite successful early relief of simulated CoA in early life, relative hypertension and LV fibrosis were demonstrable late consequences in this animal model. This abnormal fibrosis persists in the absence of altered LV hemodynamics and gene expression.

International audience; BACKGROUND: The estimation of myocardial work by pressure strain loops (PSLs) is a totally new non-invasive approach to assess myocardial performance, and its role in patients with hypertrophic cardiomyopathy is unknown. The aims of the present study are therefore: (a) to compare myocardial work in patients with non-obstructive hypertrophic cardiomyopathy (HCM) and in a subset of age-matched healthy controls and (b) to assess the correlation between myocardial work and left ventricular (LV) fibrosis.DESIGN: Eighty-two patients with non-obstructive HCM (58 ± 14 years) and 20 age-matched healthy subjects (58 ± 7 years, P = 0.99) underwent standard and speckle-tracking echocardiography to assess myocardial dimensions and deformation parameters. PSLs analysis was used to estimate global myocardial constructive work (GCW) and wasted work (GWW). LV fibrosis was estimated at cardiac magnetic resonance (CMR) by qualitative assessment of late gadolinium enhancement (LGE), and significant fibrosis was defined as LGE in ≥2 LV segments.RESULTS: Global constructive work (1599 ± 423 vs 2248 ± 249 mm Hg%, P < 0.0001) was significantly reduced in HCM compared to the control group. No difference was observed in GWW (141 ± 125 vs 101 ± 88 mm Hg%, P = 0.18) and LV ejection fraction (LVEF) (63 ± 13 vs 66 ± 4% P = 0.17) between the two groups. In HCM, GCW was the only predictor of LV fibrosis at multivariable analysis (OR 1.01, 95% CI: 0.99-1.08, P = 0.04). A cutoff value of 1623 mm Hg% (AUC 0.80, 95% CI: 0.66-0.93, P < 0.0001) was able to predict myocardial fibrosis with a good sensitivity and fair specificity (82% and 67%, respectively).CONCLUSIONS: Global constructive work is significantly reduced in HCM despite normal LVEF and is associated with the LV fibrosis as assessed by LGE.

Cardiac magnetic resonance (CMR) allows noninvasive assessment of regional replacement fibrosis and diffuse interstitial fibrosis. Two CMR surrogate biomarkers for diffuse interstitial fibrosis have emerged: extracellular volume (ECV) fraction and indexed ECV. We evaluate CMR biomarkers of

The ability of the right ventricle to compensate pressure overload determines survival in pulmonary arterial hypertension (PAH). Nitric oxide (NO) reduces the right ventricular afterload through pulmonary vasodilation, but excessive NO amounts cause oxidative stress. Oxidative stress drives remodeling of pulmonary arteries and the right ventricle. In the present study, we hypothesized that nitric oxide synthase 2 (NOS2) induction leads to excessive NO amounts that contribute to oxidative stress and impair right ventricular adaptation to PAH. We used a surgical pulmonary artery banding (PAB) mouse model in which right ventricular dysfunction and remodeling occur independently of changes in the pulmonary vasculature. Three weeks after PAB, NOS2 expression was increased twofold in the hypertrophied right ventricle on transcript and protein levels together with increased NO production. Histomorphology localized NOS2 in interstitial and perivascular cardiac fibroblasts after PAB, which was confirmed by cell isolation experiments. In the hypertrophied right ventricle, NOS2 induction was accompanied by an increased formation of reactive oxidants blocked by ex vivo NOS inhibition. We show that reactive oxidant formation in the hypertrophied right ventricle is in part NOS2 dependent (in NOS2-deficient mice [NOS2

ObjectiveThe relationship between right ventricular (RV) fibrosis and right heart reverse remodelling following pulmonary valve replacement (PVR) has not been well studied in adults with repaired tetralogy of Fallot (rTOF). Our aims were to histologically quantify RV fibrosis and to explore the relationship between fibrosis severity and cardiac remodelling post-PVR.MethodsAdults with rTOF and pre-PVR cardiovascular (CMR) imaging were consented to procurement of RV muscle during PVR. Samples were stained with picrosirius red to quantify collagen volume fraction. Clinical data at baseline and at last follow-up were reviewed. Adverse cardiovascular outcomes included death, sustained arrhythmia and heart failure.ResultsFifty-three patients (male 58%, 38±11 years) were studied. Those with severe fibrosis (collagen volume fraction >11.0%, n=13) had longer aortic cross-clamp times at initial repair compared with the remainder of the population (50 vs 33 min, p=0.018) and increased RV mass:volume ratio pre-PVR (0.20 vs 0.18 g/mL, p=0.028). Post-PVR, the severe fibrosis group had increased indexed RV end-systolic volume index (RVESVi) (74 vs 66 mL/m2, p=0.044), decreased RVESVi change (Δ29 vs Δ45 mL/m2, p=0.005), increased RV mass (34 vs 25 g/m2, p=0.023) and larger right atrial (RA) area (21 vs 17 cm2, p=0.021). A trend towards increased heart failure events was observed in the severe fibrosis group (15% vs 0%, p=0.057).ConclusionsSevere RV fibrosis was associated with increased RVESVi, RV mass and RA area post-PVR in rTOF. Further study is required to define the impact of fibrosis and persistent right heart enlargement on clinical outcomes.

Fibrosis and remodeling of the right ventricle (RV) are associated with RV dysfunction and mortality of patients with pulmonary hypertension (PH) but it is unknown how much RV fibrosis contributes to RV dysfunction and mortality. RV fibrosis manifests as fibroblast accumulation and collagen deposition which may be excessive. Although extracellular matrix deposition leads to elevated ventricular stiffness, it is not known to which extent it affects RV function. Various animal models of pulmonary hypertension have been established to investigate the role of fibrosis in RV dysfunction and failure. However, they do not perfectly resemble the human disease. In the current review we describe the major characteristics of RV fibrosis, molecular mechanisms regulating the fibrotic process, and discuss how therapeutic targeting of fibrosis might affect RV function.

A 79-year-old woman receiving haemodialysis was admitted because of heart failure. Twelve years previously she had been diagnosed with idiopathic pulmonary arterial hypertension (PAH) and treated w...

Although exercise mediates beneficial effects in patients after myocardial infarction (MI), the underlying mechanisms as well as the question of whether an early start of exercise after MI is safe or even beneficial are incompletely resolved. The present study analyzed the effects of exercise before and reinitiated early after MI on cardiac remodeling and function. Male C57BL/6N mice were housed sedentary or with the opportunity to voluntarily exercise for 6 wk before MI induction (ligation of the left anterior descending coronary artery) or sham operation. After a 5-day exercise-free phase after MI, mice were allowed to reexercise for another 4 wk. Exercise before MI induced adaptive hypertrophy with moderate increases in heart weight, cardiomyocyte diameter, and left ventricular (LV) end-diastolic volume, but without fibrosis. In sedentary mice, MI induced eccentric LV hypertrophy with massive fibrosis but maintained systolic LV function. While in exercised mice gross LV end-diastolic volumes and systolic function did not differ from sedentary mice after MI, LV collagen content and thinning of the infarcted area were reduced. This was associated with ameliorated activation of inflammation, mediated by TNF-α, IL-1β, and IL-6, as well as reduced activation of matrix metalloproteinase 9. In contrast, no differences in the activation patterns of various MAPKs or adenosine receptor expressions were observed 5 wk after MI in sedentary or exercised mice. In conclusion, continuous exercise training before and with an early reonset after MI ameliorates adverse LV remodeling by attenuating inflammation, fibrosis, and scar thinning. Therefore, an early reonset of exercise after MI can be encouraged.

This review discusses the complementary roles of echocardiography and cardiac magnetic resonance in the diagnosis and management of patients with hypertrophic cardiomyopathy (HCM). Imaging using novel echocardiographic techniques and cardiac magnetic resonance (CMR) imaging in HCM has demonstrated incremental utility in diagnosis and management guidance. Application of 3-D imaging has improved assessment of left ventricular (LV) mass and volume by echocardiography. Quantification of myocardial mechanics has shown promise for clarification of diagnosis, prognosis, and assessment of LV dysfunction. CMR permits 3-D tomographic characterization of cardiac structure and tissue characterization which has shown utility for assessing the diverse phenotypes in HCM and quantification of left ventricular fibrosis, an increasingly recognized poor prognostic marker. Non-invasive cardiac imaging remains central for the evaluation of HCM patients. An approach integrating echocardiography and CMR as complementary modalities allows for improved diagnostic and prognostic assessment.

Aims: The ATP-binding cassette (ABC)G2 transporter protects the heart from pressure overload-induced ventricular dysfunction but also protects cancer cells from chemotherapeutic agents. It is upregulated in the myocardium of heart failure patients and clears hypoxia-induced intracellular metabolites. This study employs ABCG2 knockout (KO) mice to elucidate the relevance of ABCG2 for cardiac and pulmonary vascular structure and function in chronic hypoxia, and uses human primary cardiac fibroblasts to investigate the potential role of ABCG2 in cardiac fibrosis. Methods and results: ABCG2 KO and control mice (n = 10) were subjected to 4 weeks normoxia or hypoxia. This allowed for investigation of the interaction between genotype and hypoxia (GxH). In hypoxia, KO mice showed pronounced right (RV) and left (LV) ventricular diastolic dysfunction. Compared to normoxia, end-diastolic pressure (EDP) was increased in control vs. KO mice by +1.1 ± 0.3 mmHg vs. +4.8 ± 0.3 mmHg, p for GxH < 0.001 (RV) and +3.9 ± 0.5 mmHg vs. +11.5 ± 1.6 mmHg, p for GxH = 0.110 (LV). The same applied for myocardial fibrosis with +0.3 ± 0.1% vs. 1.3 ± 0.2%, p for GxH = 0.036 (RV) and +0.06 ± 0.03% vs. +0.36 ± 0.08%, p for GxH = 0.002 (LV), whereas systolic function and capillary density was unaffected. ABCG2 deficiency did not influence hypoxia-induced pulmonary hypertension or vascular remodeling. In line with these observations, human cardiac fibroblasts showed increased collagen production upon ABCG2 silencing in hypoxia (p for GxH = 0.04). Conclusion: Here we provide evidence for the first time that ABCG2 membrane transporter can play a crucial role in ventricular dysfunction and fibrosis in hypoxia-induced pulmonary hypertension.

Background: Ventricular fibrosis leads to progressive cardiac dysfunction and heart failure (HF). Statins are reported to reduce cardiac fibrosis through the cholesterol-independent pathway, but mechanisms remain elusive. We hypothesize simvastatin reduced TGF-β1-induced ventricular fibrosis through activation of SMAD protein phosphatase Mg 2+ /Mn 2+ -1A (PPM1A), -2A (PP2A). Methods: In the absence and presence of TGF-β1 (5ng) with or without simvastatin (1μM), the rate of fibroblast proliferation (doubling time), myofibroblast differentiation (ICC), α-SMA mRNA (RT-PCR) and protein expression (Western blot) and the release of collagen synthesis markers, pro-collagen type I C-terminal peptide (PICP) and pro-collagen type III N-terminal peptide (PIIINP), in the media (ELISA) were determined along with protein interaction between SMAD2/3 and PPM1A or PP2A (Co-IP) and SMAD2/3 phosphorylation (Western blot). Results: Simvastatin reduced the effect of TGF-β1 on hVF proliferation by 47% (50000 to 26500), p Conclusion: Involvement of PPM1A and PP2A in the anti-fibrotic effect of simvastatin reveals novel signaling mediators that may be selectively targeted for prevention of myocardial injury-induced ventricular fibrosis and HF.

Basso and colleagues1 elegantly describe a well-circumscribed entity combining mitral valve prolapse (MVP) with left ventricular fibrosis and ventricular arrhythmia causing 7% of all sudden cardiac deaths (SCDs) in young adults from the Veneto region. Malignant MVP affects a tiny minority of patients with MVP, and it is responsible for a very small absolute number of all SCDs in young adults. Assuming that the annual incidence of SCD in this age group ranges between 1.21 (in young athletes) and 3.76 (general population aged 12–35) per 100 000,2 malignant MVP may be causing …