Aims
Recent studies indicate that brain natriuretic peptide (BNP1–32) may be truncated into BNP3–32 by dipeptidyl peptidase IV (DPP4) and that BNP3–32 has reduced biological activities compared with BNP1–32. We investigated if DPP4 contributes to the cardiorenal alterations and to the attenuated response to BNP seen in heart failure.

Methods and results
Haemodynamic and renal assessment was performed in 12 pigs at baseline, 4 weeks after pacing‐induced heart failure, and during BNP infusion. They were randomized to either placebo or treatment with a DPP4 inhibitor, sitagliptin. After 4 weeks of pacing, heart rate was reduced compared with baseline in the sitagliptin group (60 ± 2 vs. 95 ± 16 b.p.m., P < 0.01), and an increase in stroke volume was observed in the sitagliptin group compared with placebo (+24 ± 6% vs. –17 ± 7%, P < 0.01). Glomerular filtration rate declined at week 4 compared with baseline in the placebo group (1.3 ± 0.4 vs. 2.3 ± 0.3 mL/kg/min, P < 0.01) but remained preserved in the sitagliptin group [1.8 ± 0.2 vs. 2.0 ± 0.3 mL/kg/min, P = NS (non‐significant)]. In the sitagliptin group, BNP infusion improved end‐systolic elastance (68 ± 5 vs. 31 ± 4 mmHg/kg/mL, P < 0.05), ventricular–arterial coupling, and mechanical efficiency. Compared with controls (n = 6), myocardial gene expression of BNP, interleukin‐6, Na+–Ca2+ exchanger, and calmodulin was up‐regulated in the placebo group, but not in the sitagliptin group.

Conclusion
In pacing‐induced heart failure, DPP4 inhibition preserves the glomerular filtration rate, modulates stroke volume and heart rate, and potentiates the positive inotropic effect of exogenous BNP at no energy expense.

 https://doi.org/10.1093/eurjhf/hfr146

Background
Small coronary vessels supply small myocardial territories. The clinical significance of small-vessel stenoses is therefore questionable. Moreover, percutaneous coronary intervention (PCI) of nonfunctionally significant lesions does not improve clinical outcome and might be associated with potential procedural or stent related risks. The aim of this study was to assess the clinical outcome of fractional flow reserve (FFR)-guided PCI in the treatment of small coronary vessel lesions as compared with an angio-guided PCI.

Methods and Results
From January 2004 to December 2008, all patients treated with PCI for stable or unstable angina in small native coronary vessels (reference vessel diameter and stent size <3 mm) were retrospectively analyzed. Patients were divided into angio-guided and an FFR-guided PCI groups. A total of 717 patients were enrolled (495 angio-guided, 222 FFR-guided). End points were death, nonfatal myocardial infarction (MI), combined death or nonfatal MI, target vessel revascularization (TVR), and procedure costs. Major adverse cardiac events (MACE) were defined as death, nonfatal MI, and TVR. Clinical follow-up was obtained in 97.5% (median follow-up: 3.3 [from 0.01–5] years) of the patients. Seventy-eight patients (35%) had a significant FFR (<0.80) and underwent PCI. Using a propensity score adjusted Cox analysis, patients treated with FFR-guided PCI had significantly lower combined death or nonfatal MI (hazard ratio [HR], 0.413; 95% confidence interval [CI], 0.227–0.750; P=0.004), nonfatal MI (HR, 0.063; 95% CI, 0.009–0.462; P=0.007), TVR (HR, 0.517; 95% CI, 0.323–0.826; P=0.006), and MACE (HR, 0.458; 95% CI, 0.310–0.679; P<0.001). No difference was observed in mortality alone (HR, 0.684; 95% CI, 0.355–1.316; P=0.255). Procedure costs were also reduced in the FFR guided strategy (3253±102 Euros versus 4714±37 Euros, P<0.0001).

Conclusions
FFR-guided PCI of small coronary arteries is safe and results in better clinical outcomes when compared with an angio-guided PCI.

https://doi.org/10.1161/CIRCINTERVENTIONS.111.966937

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.

https://doi.org/10.1083/jcb.201212110

Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3-13), P = 2 × 10-6; replication study OR = 8.59 (3.19-25.05), P = 3 × 10-8; combined OR = 6.99 (3.68-13.57), P = 4 × 10-11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (∼4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.

https://doi.org/10.1038/ng.309

Atherosclerosis is one of the principle pathologies of cardiovascular disease with blood cholesterol a significant risk factor. The World Health Organization estimates that approximately 2.5 million deaths occur annually because of the risk from elevated cholesterol, with 39% of adults worldwide at future risk. Atherosclerosis emerges from the combination of many dynamical factors, including haemodynamics, endothelial damage, innate immunity and sterol biochemistry. Despite its significance to public health, the dynamics that drive atherosclerosis remain poorly understood. As a disease that depends on multiple factors operating on different length scales, the natural framework to apply to atherosclerosis is mathematical and computational modelling. A computational model provides an integrated description of the disease and serves as an in silico experimental system from which we can learn about the disease and develop therapeutic hypotheses. Although the work completed in this area to date has been limited, there are clear signs that interest is growing and that a nascent field is establishing itself. This article discusses the current state of modelling in this area, bringing together many recent results for the first time. We review the work that has been done, discuss its scope and highlight the gaps in our understanding that could yield future opportunities.

https://doi.org/10.1093/bib/bbv081

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections’ map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.

https://doi.org/10.1073/pnas.1520289113