AIMS:Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short-term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH).METHODS AND RESULTS:Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta-analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post-IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta-analysis Global Group in Chronic Heart Failure score-predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD-treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan-Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload-corrected exercise pulmonary capillary wedge pressure at the 6 months post-IASD study were associated with HFH.CONCLUSIONS:The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large-scale ongoing randomized studies are required to confirm the potential benefit of this therapy.

Overactivity of the sympathetic nervous system has been identified as an important contributor to resistant hypertension. Renal artery radiofrequency ablation is a new therapeutic approach for these patients. As shown in the Simplicity HTN-1 and -2 trials, there is evidence that catheter-based renal denervation has a substantial impact on central sympathetic outflow by reducing the renal norephedrine spillover and is associated with a sustained reduction in blood pressure. Importantly, these studies demonstrated peri- and postinterventional safety and may thus represent a promising option in management of patients with therapy-resistant hypertension as well as concomitant comorbidities.

Growth and injury represent recurrent and related themes in the study of progressive renal disease. We have previously demonstrated that a prooxidant diet, one deficient in antioxidants, selenium and vitamin E, induces renal enlargement, proteinuria, mild tubulointerstitial disease and diminished glomerular filtration rate (GFR). Our present study represents continued examination of these processes. We demonstrate that these diets increase thymidine incorporation into DNA and net DNA content in renal tissue, and induce expression of the mRNA for the proto-oncogene, c-myc, and the histone, H2b. We localize increased DNA synthesis as occurring mainly in the distal renal tubular epithelium. These deficient kidneys also exhibit interstitial expansion that parallels the pattern of DNA synthesis in that both processes are more prominent in the medulla than in the cortex. mRNAs for collagens I, III and IV in conjunction with transforming growth factor-beta1 (TGF-beta1) are up-regulated in the kidney in rats maintained on the deficient diet. In complementary in vitro studies, the exposure of rat kidney fibroblasts, NRK 49F cells, to noncytolytic doses of hydrogen peroxide, induces collagen III, collagen IV and TGF-beta1 mRNA. Induction of these genes is also observed in mesangial cells so exposed to noncytolytic doses of hydrogen peroxide. A final aspect of our study was the examination of renal generation of hydrogen peroxide and the profile of the hydrogen peroxide-degrading enzymes. Deficient kidneys exhibit increased mitochondrial generation of hydrogen peroxide independent of oxygen consumption but in conjunction with suppression of glutathione peroxidase mRNA and activity. Lipid peroxidation was increased twofold in the cortex and medulla of the deficient kidneys. Surprisingly, catalase activity, measured in the cortex and medulla, and whole kidney catalase mRNA were also reduced in rats maintained on the antioxidant deficient diet, effects that may further compromise the clearance of hydrogen peroxide. These changes in catalase represent an adverse response to this dietary deficiency, and may be relevant to decreased catalase activity described in chronic renal insufficiency. Thus, a chronic prooxidant state, with features that mimic those of clinical uremia, increases DNA synthesis of renal tubular epithelium, induces mRNA expression for collagens I, III and IV in conjunction with the mRNA for the fibrogenic cytokine, TGF-beta1. Oxidants also induce collagen III, collagen IV and TGF-beta1 mRNA in vitro.

577 Kidney transplantation in recipients of advanced age (≥60 years) is common. Graft survival is similar to that of younger recipients, with death being the major cause of graft loss in the elderly. Survival after graft loss is unknown in this population. We studied the course of 206 elderly (>60 years) first-time kidney transplant recipients at our institution. Graft loss has occurred in 78 patients. In 65% (n=51), the cause of graft loss was death. In the remaining 27 patients (mean±SEM age 63.4±0.6; 13 men, 14 women; 23 CAD, 4 LD; 19% diabetic), graft loss was due to chronic rejection(41%), acute rejection (26%), infection (15%), vascular events (11%), malignancy (4%), and HUS (4%). For the 27, the average time from transplant to graft loss was 1.8±0.4 years. Mean patient survival after graft loss was only 2.9±0.7 years. Early death was a frequent event; 41% (n=11) of patients died in the first year after graft loss. When compared with younger renal transplant recipients (age 18-59) at our institution, survival after graft loss was lower in elderly recipients (seeTable).The cause of death in the first year after graft loss was different in the older versus younger recipients. In the elderly, 72% of these deaths were due to cardiovascular events, compared with 19% in younger recipients(p<0.05). In conclusion, elderly kidney transplant recipients are at high risk of death following graft loss compared to younger recipients who lose their grafts. Since cardiovascular disease is the leading cause of death in these elderly patients, cardiac reevaluation is warranted at the time of graft loss.

Angiotensin II (Ang II) has growth promoting effects in a number of cells and tissues in vitro. The purpose of this study was to examine the in vivo effect of Ang II on the renal expression of the early growth response genes c-fos, Egr-1 and c-jun. Adult male rats underwent two basal 30 minute clearance periods during which the normal saline vehicle was infused into the left renal artery. Normal saline, Ang II (50 ng/kg/min), or Ang II plus the Ang II antagonist Sar1 Gly8-angiotensin II (10 micrograms/kg/min) were then selectively infused into the left renal artery for two additional 30 minute periods. MAP was similar during basal and Ang II infusion. Hemodynamic effects (decrease in GFR and RPF and increase in renal vascular resistance) were observed only in the Ang II-infused left kidney allowing the right kidney to serve as a paired control for the effects of anesthesia and surgery. Significant increases in the expression of the early growth response genes Egr-1 and c-fos, but not c-jun, were found in the Ang II-infused left kidney compared to the control right kidney. The simultaneous infusion of Ang II (50 ng/kg/min) and the Ang II antagonist Sar1 Gly8-angiotensin II (10 micrograms/kg/min) blocked the increase in Egr-1 and c-fos expression, demonstrating the specificity of the response to Ang II. To compare the effect of another renal vasoconstrictor on the expression of early growth response genes, norepinephrine (40 ng/kg/min) was infused into the left renal artery.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of cGMP in regulating renal cortical phosphate uptake was investigated in rats. Cyclic GMP (1 mM) produced a 27.7% +/- 1.4 (SE) increase in 32PO4 uptake by isolated renal cortical tubules (P less than 0.001) and cAMP (1 mM) a 28.7% +/- 1.4 increase (P less than 0.001), but their effects were not additive. Acetylcholine (Ach) (1 mM), in the presence of theophylline (T) (10 mM), increased cGMP in cortical slices from 24.1 pmol/g wet wt +/- 1.3 to 76.5 +/- 5.2 (P less than 0.001), but had no effect on cAMP, and Ach (1 mM) in the presence of T (1 mM) increased 32PO4 uptake 19.1% +/- 1.1 (P less than 0.001). Addition of Ca2+ to the incubation medium in the presence of T (10 mM) significantly increased cGMP in cortical slices from 7.4 pmol/g wet wt +/- 0.6 (0 Ca2+ plus EGTA, 0.5 mM) to 24.1 +/- 1.3 (1 mM Ca2+) and caused a 52.2% +/- 2.7 rise in 32PO4 uptake (P less than 0.001). Cyclic AMP was decreased by the addition of Ca2+. In summary, cGMP and cAMP stimulate 32PO4 uptake by renal cortex, and Ach and Ca2+ increase both cGMP and 32PO4 but do not increase cAMP. These data suggest that cGMP may play a role in regulating cellular uptake of phosphate.

ArticleA comparison of chloride- and citrate-filled microelectrodes for d-c recording.M E RosenbergM E RosenbergPublished Online:01 Jul 1973https://doi.org/10.1152/jappl.1973.35.1.166MoreSectionsPDF (716 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByMethods for Measuring Chloride Transport across Nerve, Muscle, and Glial CellspH-Dependent electrical properties and buffer permeability of theNecturus renal proximal tubule cellThe Journal of Membrane Biology, Vol. 100, No. 1Organic substrate effects on and heterogeneity of Necturus proximal tubule functionKidney International, Vol. 17, No. 4Risk and advantages of using strongly beveled microelectrodes for electrophysiological studies in cardiac Purkinje fibersPfl�gers Archiv European Journal of Physiology, Vol. 380, No. 1Biological and artificial ion exchangers: Electrical measurements with glass microelectrodesThe Journal of Membrane Biology, Vol. 40, No. 2Electrophysiological Measurements on the Renal TubuleThe effects of cholecystokinin-pancreozymin, acetylcholine and secretin on the membrane potentials of mouse pancreatic cellsin vitroPfl�gers Archiv European Journal of Physiology, Vol. 353, No. 2 More from this issue > Volume 35Issue 1July 1973Pages 166-8 https://doi.org/10.1152/jappl.1973.35.1.166PubMed4716153History Published online 1 July 1973 Published in print 1 July 1973 Metrics