Fibrosis is a common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor4,5, but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

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Background Whether mitral valve repair (MVRep) during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown. Methods and Results Patients with ejection fraction ≤ 35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy (MED) with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary endpoint was mortality. Of 1212 randomized patients, 435 (36%) had none/trace, 554 (46%) mild, 181 (15%) moderate, and 39 (3%) severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace, 114 (44%) with mild and 58 (50%) in moderate-severe MR. In patients with moderate-severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (HR vs. MED 1.20, 95% CI 0.77–1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (HR vs. MED 0.62, 95% CI 0.35–1.08). After adjustment for baseline prognostic variables, the HR for CABG with mitral surgery vs. CABG alone was 0.41 (95%CI 0.22–0.77; p=0.006). Conclusions While these observational data suggest that adding MVRep to CABG in patients with LV dysfunction and moderate-severe MR may improve survival compared with CABG alone or MED alone, a prospective randomized trial would be necessary to confirm the validity of these observations.

Native smooth muscle L-type Ca v 1.2 calcium channels have been shown to support a fraction of Ca 2؉ currents with a window current that is close to resting potential. The smooth muscle L-type Ca 2؉ channels are also more susceptible to inhibition by dihydropyridines (DHPs) than the cardiac channels. It was hypothesized that smooth muscle Ca v 1.2 channels exhibiting hyperpolarized shift in steady-state inactivation would contribute to larger inhibition by DHP, in addition to structural differences of the channels generated by alternative splicing that modulate DHP sensitivities. In addition, it has also been shown that alternative splicing modulates DHP sensitivities by generating structural differences in the Ca v 1.2 channels. Here, we report a smooth muscle L-type Ca v 1.2 calcium channel splice variant, Ca v 1.2SM (1/8/9*/32/⌬33), that when expressed in HEK 293 cells display hyperpolarized shifts for steady-state inactivation and activation potentials when compared with the established Ca v 1.2b clone (1/8/9*/32/33). This variant activates from more negative potentials and generates a window current closer to resting membrane potential. We also identified the predominant cardiac isoform Ca v 1.2CM clone (1a/8a/⌬9*/32/33) that is different from the established Ca v 1.2a (1a/8a/⌬9*/31/33). Importantly, Ca v 1.2SM channels were shown to be more sensitive to nifedipine blockade than Ca v 1.2b and cardiac Ca v 1.2CM channels when currents were recorded in either 5 mM Ba 2؉ or 1.8 mM Ca 2؉ external solutions. This is the first time that a smooth muscle Ca v 1.2 splice variant has been identified functionally to possess biophysical property that can be linked to enhanced state-dependent block by DHP.

BackgroundTo review the experience of surgical repair of post-infarction ventricular septal rupture (VSR) and analyze the associated outcomes and prognostic factors.MethodsFollowing approval from the Singhealth Centralised Institutional Review Board (reference: 2011/881/C), a retrospective review was performed on 38 consecutive patients who had undergone surgical repair of post-infarction VSR between 1999 and 2011. Continuous variables were expressed as either mean ± standard deviation or median with 25th and 75th percentiles. These were compared using two-tailed t-test or Mann–Whitney U test respectively. Categorical variables were compared using chi-square or Fisher’s exact test. To identify predictors of operative mortality, univariate analysis of perioperative variables followed by multivariate analysis of significant univariate risk factors was performed. A two-tailed p-value < 0.05 was used to indicate statistical significance.ResultsMean age was 65.7 ± 9.4 years with 52.6% males. The VSR was anterior in 28 (73.7%) and posterior in 10 patients. Median interval from myocardial infarction to VSR was 1 day (1, 4). Pre-operative intra-aortic balloon pump was inserted in 37 patients (97.8%). Thirty-six patients (94.7%) underwent coronary angiography.Thirty-five patients (92.1%) underwent patch repair. Mean aortic cross clamp time was 82 ± 40 minutes and mean cardiopulmonary bypass time was 152 ± 52 minutes. Coronary artery bypass grafting (CABG) was performed in 19 patients (50%), with a mean of 1.5 ± 0.7 distal anastomoses. Operative mortality within 30 days was 39.5%.Univariate analysis identified emergency surgery, New York Heart Association (NYHA) class, inotropic support, right ventricular dysfunction, EuroSCORE II, intra-operative red cell transfusion, post-operative renal failure and renal replacement therapy (RRT) as predictors of operative mortality. Multivariate analysis identified NYHA class and post-operative RRT as predictors of operative mortality.Ten year overall survival was 44.4 ± 8.4%. Right ventricular dysfunction, LVEF and NYHA class at presentation were independent factors affecting long-term survival. Concomitant CABG did not influence early or late survival.ConclusionsSurgical repair of post-infarction VSR carries a high operative mortality. NYHA class at presentation and post-operative RRT are predictors of early mortality. Right ventricular dysfunction, LVEF and NYHA class at presentation affect long-term survival. Concomitant CABG does not improve survival.

Oxidative stress induced by superoxide (O 2¯⋅ ) and other reactive oxygen species (ROS) has critical roles in the pathogenesis of cardiovascular disease [1]. Potential enzymatic sources of ROS in vasculature include the mitochondrial respiration chain, lipoxygenase and cyclooxygenase, xanthine oxidase, NADPH oxidase, nitric oxide (NO) synthase and cytochrome P450 enzymes. Although our understanding of the mechanisms for superoxide production in vascular cells is incomplete, increasing evidence suggests that NADPH oxidase is a AbstractNADPH oxidases are important sources of vascular superoxide, which has been linked to the pathogenesis of atherosclerosis. Previously we demonstrated that the Nox4 subunit of NADPH oxidase is a critical catalytic component for superoxide production in quiescent vascular smooth muscle cells. In this study we sought to determine the role of Nox4 in superoxide production in human aortic smooth muscle cells (AoSMC) and embryonic kidney (HEK293) cells under proinflammatory conditions. Incubation with tumor necrosis factor-α (TNF-α, 10 ng/ml) for 12h increased superoxide production in both cell types, whereas angiotensin II, platelet-derived growth factor or interleukin-1β had little effects. Superoxide production was completely abolished by the NADPH oxidase inhibitors diphenyline iodonium and apocynin, but not by inhibitors of xanthine oxidase, nitric oxide synthase or mitochondrial electron transport. TNF-α upregulated the expression of Nox4 in AoSMC at both message and protein levels, while Nox1 and Nox2 were unchanged. In contrast, upregulation of Nox2 appeared to mediate the enhanced superoxide production by TNF-α in HEK293 cells. We suggest that Nox4 may be involved in increased superoxide generation in vascular smooth muscle cells under proinflammatory conditions.

Cardiac fibroblasts are crucial in pathophysiology of the myocardium whereby their aberrant proliferation has significant impact on cardiac function. Hydrogen sulphide (H2S) is a gaseous modulator of potassium channels on cardiomyocytes and has been reported to attenuate cardiac fibrosis. Yet, the mechanism of H2S in modulating proliferation of cardiac fibroblasts remains poorly understood. We hypothesized that H2S inhibits proliferative response of atrial fibroblasts through modulation of potassium channels. Biophysical property of potassium channels in human atrial fibroblasts was examined by whole-cell patch clamp technique and their cellular proliferation in response to H2S was assessed by BrdU assay. Large conductance Ca2+-activated K+ current (BKCa), transient outward K+ current (Ito) and inwardly rectifying K+ current (IKir) were found in human atrial fibroblasts. Current density of BKCa (IC50 = 69.4 μM; n = 6), Ito (IC50 = 55.1 μM; n = 6) and IKir (IC50 = 78.9 μM; n = 6) was significantly decreased (P < 0.05) by acute exposure to NaHS (a H2S donor) in atrial fibroblasts. Furthermore, NaHS (100–500 μM) inhibited fibroblast proliferation induced by transforming growth factor-β1 (TGF-β1; 1 ng/ml), Ang II (100 nM) or 20% FBS. Pre-conditioning of fibroblasts with NaHS decreased basal expression of Kv4.3 (encode Ito), but not KCa1.1 (encode BKCa) and Kir2.1 (encode IKir). Furthermore, H2S significantly attenuated TGF-β1–stimulated Kv4.3 and α-smooth muscle actin expression, which coincided with its inhibition of TGF-β–induced myofibroblast transformation. Our results show that H2S attenuates atrial fibroblast proliferation via suppression of K+ channel activity and moderates their differentiation towards myofibroblasts.

Recent developments in aortic valve replacement include the truly stentless pericardial bioprostheses with single point attached commissures (SPAC) implantation technique. The leaflet geometry available for the SPAC valves can either be a simple tubular or a complex three-dimensional structure molded using specially designed molds. Our main objective was to compare these two leaflet designs, the tubular vs. the molded, by dynamic finite element simulation. Time-varying physiological pressure loadings over a full cardiac cycle were simulated using ABAQUS. Dynamic leaflet behavior, leaflet coaptation parameters, and stress distribution were compared. The maximum effective valve orifice area during systole is 633.5 mm(2) in the molded valve vs. 400.6 mm(2) in the tubular valve, and the leaflet coaptation height during diastole is 4.5 mm in the former, in contrast to 1.6 mm in the latter. Computed compressive stress indicates high magnitudes at the commissures and inter-leaflet margins of the tubular valve, the highest being 3.83 MPa, more than twice greater than 1.80 MPa in the molded valve. The molded leaflet design which resembles the native valve exerts a positive influence on the mechanical performance of the SPAC pericardial valves compared with the simple tubular design. This may suggest enhanced valve efficacy and durability.