Avirup Guha

HV1 Acts as a Sodium Sensor and Promotes Superoxide Production in Medullary Thick Ascending Limb of Dahl Salt-Sensitive Rats

We previously characterized a H+ transport pathway in medullary thick ascending limb nephron segments that when activated stimulated the production of superoxide by nicotinamide adenine dinucleotide phosphate oxidase. Importantly, the activity of this pathway was greater in Dahl salt-sensitive rats than salt-resistant (SS.13BN) rats, and superoxide production was enhanced in low Na+ media. The goal of this study was to determine the molecular identity of this pathway and its relationship to Na+. We hypothesized that the voltage-gated proton channel, HV1, was the source of superoxide-stimulating H+ currents. To test this hypothesis, we developed HV1−/− null mutant rats on the Dahl salt-sensitive rat genetic background using zinc-finger nuclease gene targeting. HV1 could be detected in medullary thick limb from wild-type rats. Intracellular acidification using an NH4Cl prepulse in 0 sodium/BaCl2 containing media resulted in superoxide production in thick limb from wild-type but not HV1−/− rats (P<0.05) and more rapid recovery of intracellular pH in wild-type rats (&Dgr;pHI 0.005 versus 0.002 U/s, P=0.046, respectively). Superoxide production was enhanced by low intracellular sodium (<10 mmol/L) in both thick limb and peritoneal macrophages only when HV1 was present. When fed a high-salt diet, blood pressure, outer medullary renal injury (tubular casts), and oxidative stress (4-hydroxynonenal staining) were significantly reduced in HV1−/− rats compared with wild-type Dahl salt-sensitive rats. We conclude that HV1 is expressed in medullary thick ascending limb and promotes superoxide production in this segment when intracellular Na+ is low. HV1 contributes to the development of hypertension and renal disease in Dahl salt-sensitive rats.

Cardiac implantable electronic device infection in patients with end-stage renal disease

INTRODUCTION Cardiac implantable electronic devices (CIED) are increasingly being used in end-stage renal disease (ESRD) patients. These patients have a high risk of device infection. OBJECTIVES To study the optimal management of device infections in patients with ESRD. METHOD We used the United States Renal Data System (USRDS) to assess the presence of a CIED and associated comorbidities, risk factors for infection, and mortality following device extraction or medical management in ESRD patients with CIED infection. Univariable, multivariable, and survival analyses were performed using USRDS data from 2005 to 2009. RESULTS Of 546,769 patients, 6.4% had CIED and 8.0% of those developed CIED infection. The major risk factors for device infection were black race, temporary dialysis catheter, and body mass index >25. Patients with artificial valves were excluded from the analysis. Only 28.4% of infected CIED were removed. CIED removal was more common in those with congestive heart failure. The median time to death following diagnosis of a CIED infection was 15.7 months versus 9.2 months for those treated via device extraction versus medical-only therapy (hazard ratio: 0.75; 95% confidence interval: 0.68-0.82). CONCLUSION Patients with ESRD and infected CIEDs have a poor prognosis. Rates of device extraction are low, but this strategy appears to be associated with modest improvement in survival.

Unusual Cause of Acute Mitral Regurgitation: Idiopathic Hypereosinophilic Syndrome

Idiopathic hypereosinophilic syndrome (HES) is a rare multisystem condition characterized by dysregulated overproduction of eosinophils. Cardiac involvement in HES is characterized by necrosis from infiltration of eosinophils and thrombus formation and, in the late stage, by fibrosis and chronic valvular regurgitation. We report a very unusual presentation of idiopathic HES with acute mitral regurgitation due to papillary muscle rupture. The transesophageal echocardiogram was suggestive of a flail posterior leaflet and suspicious for endocarditis. Intraoperatively, papillary muscle rupture was seen and the patient underwent mitral valve replacement. The pathologic examination of the valve revealed eosinophilic infiltration of the papillary muscle. The patient was treated with steroids and responded well clinically.

Prognostic Value of Normal Stress Echocardiography in Obese Patients

Background. Chest pain is a common problem in obese patients. Because of the body habitus, the results of noninvasive evaluation for CAD may be limited in this group. Methods. We reviewed the records of 1446 consecutive patients who had undergone clinically indicated stress echocardiography (SE). We compared major adverse cardiac events (MACE; myocardial infarction, cardiac intervention, cardiac death, subsequent hospitalization for cardiac events, and emergency department visits) at 1 year in normal weight, overweight, and obese subjects with normal SE. Results. Excluding patients with an abnormal and indeterminate SE and those who were lost to follow-up, a retrospective analysis of 704 patients was performed. There were 366 obese patients (BMI ≥ 30), 196 overweight patients (BMI 25–29.9), and 142 patients with normal BMI (18.5–24.9). There was no MACE in the groups at 1-year follow-up after a normal SE. Conclusions. In obese patients including those with multiple risk factors and symptoms concerning for cardiac ischemia, stress echocardiography is an effective and reliable noninvasive tool for identifying those with a low 1-year risk of cardiac events.

Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle?

Hv1 is a voltage-gated proton channel highly expressed in phagocytic cells, where it participates in the NADPH oxidase-dependent respiratory burst. We have recently identified Hv1 as a novel renal channel, expressed in the renal medullary thick ascending limb that appears to importantly contribute to the pathogenesis of renal hypertensive injury in the Dahl salt-sensitive rat model. The purpose of this review is to describe the experimental approaches that we have undertaken to identify the source of excess reactive oxygen species production in the renal outer medulla of Dahl salt-sensitive rats and the resulting evidence that the voltage-gated proton channel Hv1 mediates augmented superoxide production and contributes to renal medullary oxidative stress and renal injury. In addition, we will attempt to point out areas of current controversy, as well as propose areas in which further experimental studies are likely to move the field forward. The content of the following review was presented as part of the Water and Electrolyte Homeostasis Section New Investigator Award talk at Experimental Biology 2014.

Adenosine-Induced Atrial FibrillationClinical Perspective

Background: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado). Methods: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). Results: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10–100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P<0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P<0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10–100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P<0.01) and GIRK4 (1.7±0.8-fold; P<0.05) protein expression than lateral/posterior LA. Conclusions: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.Background: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels ( I K,Ado). Methods: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). Results: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10–100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P <0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P <0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10–100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P <0.01) and GIRK4 (1.7±0.8-fold; P <0.05) protein expression than lateral/posterior LA. Conclusions: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine. # Clinical Perspective {#article-title-40}

RISK STRATIFICATION SCORING PREDICTS MORTALITY IN DIALYSIS PATIENTS WITH ATRIAL FIBRILLATION

The CHA2DS2VASc score predicts stroke occurrence and mortality in atrial fibrillation (AF) patients. AF and End Stage Renal Disease (ESRD) share many risk factors including heart failure, hypertension, and diabetes. Patients with ESRD and AF may exhibit some or all of these risk factors, suggesting