Nifedipine in Scleroderma Ulcerations

Cutaneous ulcerations may be due to a variety of causes, including vasculitis. infections, arterial insufficiency, and microvascular damage. The net effect is diminished blood flow to the skin. Nifedipine, a calcium antagonist, has been shown to improve cutaneous blood How and to alleviate reactive vasospastic ischemia (Raynaud's phenomenon). The authors report an ischemic ulcer of scleroderma showing visible improvement with nifedipine therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65515/1/j.1365-4362.1984.tb01233.x.pd

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Deguelin Attenuates Reperfusion Injury and Improves Outcome after Orthotopic Lung Transplantation in the Rat

The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling

Left ventricular diastolic dysfunction, including an impaired myocardial relaxation pattern, predicts long-term cardiovascular and non-cardiovascular mortality in the community

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Prior studies have demonstrated abnormalities of diastolic function are independent predictors of heart failure and all-cause mortality. The optimal way to classify diastolic function has continued to evolve over time, particularly in those with preserved left ventricular ejection fraction. A notable change in the 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) guidelines is that individuals with impaired myocardial relaxation and normal filling pressure can be classified as normal diastolic function. Purpose To determine whether the association of diastolic dysfunction with increased risk of all-cause mortality is driven by cardiovascular or non-cardiovascular death. Second, to evaluate if the presence of an impaired myocardial relaxation inflow pattern without other diastolic abnormalities conveys a marker of increased risk. Methods This study utilized the Olmsted County Heart Function Study (OCHFS), a well characterized prospective adult community cohort with comprehensive echocardiography between 2001 and 2004 and long-term follow-up. Only individuals with measurable diastolic function were included (n = 1,104). Those with reduced left ventricular ejection fraction, more than moderate valve disease, or a clinical diagnosis of heart failure (n = 52); or indeterminate diastolic function (n = 47) were excluded. Diastolic function was assessed by the current Mayo Clinic diagnostic algorithm (Figure). Results A total of 695 individuals were classified as normal, 265 with impaired myocardial relaxation or grade 1 diastolic dysfunction, and 45 with grade 2-3 diastolic dysfunction. Those with diastolic dysfunction were older and had more comorbidities including diabetes, hypertension and coronary disease (Table). There were 264 deaths in the median follow up period of 15.2 years (IQR 14.4 – 18.0), including 173 non-cardiovascular and 81 cardiovascular deaths. Both cardiovascular and non-cardiovascular mortality were associated with the presence and grade of diastolic dysfunction (Table 1). Individuals classified as normal by 2016 ASE/EACVI criteria, but grade 1 by the Mayo algorithm had an increased risk of all-cause mortality after univariate analysis (HR 4.35, 95% CI (3.35, 5.65), p &amp;lt; 0.0001) compared to normal subjects and remained associated after adjustment for age (HR 1.55, 95% CI (1.15, 2.09), p &amp;lt; 0.0001. Subjects with a grade 1 pattern had a higher rate of cardiovascular mortality (ꭕ2 70.1, p &amp;lt; 0.0001). Conclusions Individuals with diastolic dysfunction, including those with an impaired relaxation mitral inflow, were at increased risk of mortality, particularly cardiovascular mortality. This study highlights the importance of separating grade 1 diastolic dysfunction from normal in the assessment of diastolic function as it represents a clinically significant risk marker of myocardial disease. Abstract Figure.  Abstract Figure. </jats:sec