Safety of low-dose spironolactone administration in chronic haemodialysis patients

Background. Prevention of cardiovascular diseases is essential in chronic haemodialysis patients. Recently, low-dose spironolactone has been shown to decrease cardiovascular mortality in patients with severe heart failure. However, since haemodialysis patients are prone to hyperkalaemia, a known side effect of spironolactone, this treatment is not used in this population. We performed a study to assess whether low-dose spironolactone (3 × 25 mg/week) could be administered without inducing hyperkalaemia in haemodialysis patients. Methods. The study design included a 2-week baseline period, followed by a 4-week treatment period in which doses of spironolactone were started at 12.5 mg three times/week for 2 weeks, then increased to 25 mg three times/week, and followed by a 2-week wash-out period. Fourteen patients receiving low-dose spironolactone after each dialysis were compared with 21 haemodialysis patients (control group). Results. Low-dose spironolactone did not change mean serum potassium (4.9 ± 0.7 vs 4.9 ± 0.3 mmol/l: control). The mean plasma canrenone level induced by administration of spironolactone 25 mg three times/week in the 14 treated patients was 13 ± 5.3 ng/ml. Serum aldosterone was not significantly modified by the administration of spironolactone in these patients [before, median 0.35; interquartile range (IQR) 0.11-2.83 nmol/l vs after, median 0.22; IQR 0.12-0.60 nmol/l, NS]. Dietary potassium intake and the use of ion-exchange resin, angiotensin-converting enzyme inhibitors and β-blockers were similar for the two groups throughout the study. Conclusion. This non-randomized and non-blinded study shows that administration of 25 mg spironolactone thrice weekly is not associated with an increased frequency of hyperkalaemia in haemodialysis patients when they are carefully monitored. More studies are required, however, before concluding that spironolactone administration is safe in the chronic haemodialysis populatio

Diagnostic value of PET-measured heterogeneity in myocardial blood flows during cold pressor testing for the identification of coronary vasomotor dysfunction

Background: We aimed to evaluate the diagnostic value of a positron emission tomography (PET)-measured heterogeneity in longitudinal myocardial blood flow (MBF) during cold pressor testing (CPT) and global MBF response to CPT from rest (ΔMBF) for identification of coronary vasomotor dysfunction. Methods and Results: In 35 patients CPT-induced alterations in epicardial luminal area were determined with quantitative angiography as the reference. MBF was assessed over the whole left ventricle as global MBF and regionally in the mid and mid-distal myocardium as MBF difference or MBF heterogeneity with nitrogen-13 ammonia and PET. The sensitivity and specificity of a longitudinal MBF difference during CPT in the identification of epicardial vasomotor dysfunction were significantly higher, than the global ΔMBF to CPT (88% vs 79% and 82% vs 64%, respectively; P<.05). Combining both parameters resulted in an optimal sensitivity of 100% at the expense of an intermediate specificity of 73%. The diagnostic accuracy was higher for the combined analysis than that for the MBF difference alone and global ΔMBF alone (91% vs 86% and 74%, respectively; P<.05). Conclusions: The combined evaluation of a CPT-induced heterogeneity in longitudinal MBF and the change in global MBF from rest may emerge as a new promising analytic approach to further optimize the identification and characterization of coronary vasomotor dysfunctio

Structural epicardial disease and microvascular function are determinants of an abnormal longitudinal myocardial blood flow difference in cardiovascular risk individuals as determined with PET/CT

Background: The aim of this study was to determine whether epicardial structural disease may affect the manifestation of a longitudinal decrease in myocardial blood flow (MBF) or MBF difference during hyperemia in cardiovascular risk individuals, and its dependency on the flow increase. Methods and Results: In 54 cardiovascular risk individuals (at risk) and in 26 healthy controls, MBF was measured with 13N-ammonia and PET/CT in mL/g/min at rest and during dipyridamole stimulation. Computed tomography coronary angiography (CTA) was performed using a 64-slice CT of a PET/CT system. Absolute MBFs during dipyridamole stimulation were mildly lower in the mid-distal than in the mid-LV myocardium in controls (2.20±.51 vs 2.29±.51, P<.0001), while it was more pronounced in at risk with normal and abnormal CTA (1.56±.42 vs 1.91±.46 and 1.18±.34 vs 1.51±.40mL/g/min, respectively, P<.0001), resulting in a longitudinal MBF difference that was highest in at risk with normal CTA, intermediate in at risk abnormal CTA, and lowest in controls (.35±.16 and .22±.09 vs .09±.04mL/g/min, respectively, P<.0001). On multivariate analysis, log-CCS and mid-LV hyperemic MBF increase, indicative of microvascular function, were independent predictors of the observed longitudinal MBF difference (P≤.004 by ANOVA). Conclusions: Epicardial structural disease and microvascular function are important determinants of an abnormal longitudinal MBF difference as determined with PET/C

Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines

Aims To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. Methods and results Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with 13N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m2 at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m2 (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (−0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = −0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = −0.31, P = 0.250). Conclusions Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesit

Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways

Genetic deletion of p66Shc, as shown in the present study, leads to increased myocardial infarction in response to short-term ischaemia and reperfusion. Therefore, heart-specific activation of p66Shc protein may represent a promising novel strategy to prevent ischaemic and reperfusion myocardial injury. In particular, pharmacological modulation of apoptosis via myocardial salvage pathways involving p66Shc might be a promising approach to limit short-term ischaemic injury, for instance in patients with acute coronary syndrome (ACS) from the time of symptom onset to percutaneous coronary intervention. However, the present study also adds complexity to the use of this pathway as a therapeutic target. Indeed, given the different effects of activation and silencing of p66Shc in different cells, tissues and organs, tissue selective inhibition would be required. Indeed, while short-term activation might be protective in the context of an ACS, long-term inhibition may prevent endothelial dysfunction, atherosclerosis, and diabetic vascular disease. Obviously, this complexity also raises safety concerns for the potential use of p66Shc in acute myocardial infarction that need to be clarified by additional researc

Inferior vena cava parameters predict re-admission in ischaemic heart failure

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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

GPR55 agonist lysophosphatidylinositol and lysophosphatidylcholine inhibit endothelial cell hyperpolarization via GPR-independent suppression of Na+-Ca2 + exchanger and endoplasmic reticulum Ca2 + refilling

Lysophosphatidylinositol (LPI) and lysophosphatidylcholine (LPC) are lipid signaling molecules that induce endothelium-dependent vasodilation. In addition, LPC suppresses acetylcholine (Ach)- induced responses. We aimed to determine the influence of LPC and LPI on hyperpolarizing responses in vitro and in situ endothelial cells (EC) and identify the underlying mechanisms. Using patch-clamp method, we show that LPI and LPC inhibit EC hyperpolarization to histamine and suppress Na + /Ca 2+ exchanged (NCX) currents in a concentration-dependent manner. The inhibition is non-mode-specific and unaffected by intracellular GDPβS infusion and tempol, a superoxide dismutase mimetic. In excised mouse aorta, LPI strongly inhibits the sustained and the peak endothelial hyperpolarization induced by Ach, but not by SKA-31, an opener of Ca 2+ - dependent K + channels of intermediate and small conductance. The hyperpolarizing responses to consecutive histamine applications are strongly reduced by NCX inhibition. In a Ca 2+ -re-addition protocol, bepridil, a NCX inhibitor, and KB-R7943, a blocker of reversed NCX, inhibit the hyperpolarizing responses to Ca 2+ -re-addition following Ca 2+ stores depletion. These finding indicate that LPC and LPI inhibit endothelial hyperpolarization to Ach and histamine independently of G-protein coupled receptors and superoxide anions. Reversed NCX is critical for ER Ca 2+ refilling in EC. The inhibition of NCX by LPI and LPC underlies diminished endothelium-dependent responses and endothelial dysfunction accompanied by increased levels of these lipids in the blood