Volume Overload Heart Failure Research Articles

P164 SOLUBLE GUANYLATE CYCLASE STIMULATORS: AN EMERGING OPTION IN THE TREATMENT OF PRESSURE AND VOLUME OVERLOAD INDUCED CHRONIC HEART FAILURE

Pressure and volume overload-induced chronic heart failure (HF) is associated with characteristic cardiac remodeling and ventricular myocardial proteomic alterations, that can lead to the formation of a substrate for arrhythmias. Antiarrhythmic drug therapy is still suboptimal and current therapies are not efficacious enough. The purpose of the current study was therefore to examine the efficiency of nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) stimulator. We used as an experimental model male hypertensive Ren-2 transgenic rats (TGR) (n = 16), normotensive Hannover Sprague–Dawley rats (HSD, n = 17), and a volume-overload HF rat model induced by creating the aortocaval fistula (ACF) in rats of both strains (n = 27). Rats were after the induction of ACF treated by sGC stimulator BAY41-8543 (3 mg/kg/day for 30 weeks) alone or combined with angiotensin-converting enzyme inhibitor (ACEi) Trandolapril (0.25 mg/kg/day for 30 weeks). The age of the animals at the end of the experiment was 40 weeks. Left ventricle tissue and plasma samples were used for further analyses. Blood pressure (BP) was measured by telemetry. Combined treatment with sGC stimulator and ACEi was the most potent in lowering BP. Moreover, supplementation by sGC stimulator alone significantly decreased mortality and increased levels of the antioxidant enzyme superoxide dismutase 1, matrix metalloproteinase 2, total and phosphorylated connexin 43 as well as protein kinase C epsilon, implicated in remodeling of extracellular matrix and intercellular communication, in the left ventricle of TGR rats. Application of the sGC stimulator also slightly normalized elevated collagen deposition and hydroxyproline content in the left ventricular tissue of TGR rats. Unfortunately, we did not observe any effect of the sGC stimulator in the TGR ACF group. These results support the hypothesis that sGC stimulators might represent a class of drugs suitable for the prevention and treatment of related disorders in HF. This work was supported by APVV-21-0410, VEGA 2/0006/23, and EXCELES LX22NPO5104. Supported by APVV-21-0410, VEGA 2/0006/23, and EXCELES LX22NPO5104.

#2920 Peritoneal dialysis for volume overload in heart failure: a single-center experience

Abstract Background and Aims While diuretics are considered the first-line therapy to control volume overload in heart failure (HF), diuretic resistance can develop, limiting the effectiveness of pharmacological therapy. Peritoneal dialysis (PD) is a kidney replacement therapy usually implemented in advanced or acute kidney failure. However, it can be used to allow ultrafiltration and volume control in refractory cases, either due to kidney or refractory congestive HF. The aim of this study was to describe a single-center experience and study the clinical outcomes of a population of patients with HF that initiated PD for volume control. Method Retrospective single-center study with patients who started PD for volume control between January 1st 2011 and December 31st 2023, with a follow-up of 12 months after start of dialysis or until technique dropout. Demographic and clinical information regarding comorbidities, characteristics of HF, therapeutic management and markers of volume overload (NT-proBNP and CA-125) was collected. The impact on both therapy management and overload markers after six months of PD was also studied. Results Nineteen patients were included in this study, 78.9% of male gender and with a mean age of 63.4 ± 17.2 years. Comorbidities included diabetes in 63.2%, hypertension in 73.7%, coronary arterial disease in 57.8% and peripheral arterial disease in 26.3%. The NYHA (New York Heart Association) class was III or IV in 12 patients (63.1%), with an average left ventricle ejection fraction of 40% ± 14.1, due to ischemic and/or valvular causes in 73.7%. PD vintage was 12 months (IQR 0), with a median glomerular filtration rate (GFR) at the start of peritoneal dialysis of 15 ml/min (IQR 11) while nine patients (47.3%) started with a GFR above 15 mL/min. There was an increase in the number of patients being treated with renin-angiotensin-aldosterone system inhibitors, sodium-glucose co-transporter-2 inhibitors and mineralocorticoids receptor antagonists at six months. Outcomes reported low numbers of major adverse cardiac events, episodes of peritonitis and infection of the peritoneal catheter outer orifice. The number of hospitalizations due to HF was also significantly lower after start of PD (p-value = 0.044). There was a decrease in serum NT-proBNP levels after six months of therapy (p-value = 0.571), with a statistically significant decrease in CA-125 (p-value < 0.001). There was only one reported death during follow-up. Conclusion While PD has classically been viewed only as a kidney replacement therapy, it can also be considered a viable option for refractory volume overload associated with HF. Results suggest an optimization of HF guideline-directed therapy and a decreased number of hospitalizations, with consequent better management of the disease and improved quality of life. There was no negative impact associated with the implementation of PD in this population, with the decrease in CA-125 serum levels also suggesting an overall decrease of volume overload with this technique.

Treatment of high-output cardiac failure secondary to anemia in three cats

Case series summary Three cats presented for clinical signs of respiratory distress and varying etiologies of anemia. Echocardiograms revealed evidence of cardiac dilation without other significant structural or functional heart disease. Thoracic imaging via point-of-care ultrasound and/or radiographs confirmed evidence of volume overload by pleural effusion. Each cat was diagnosed with presumed high-output cardiac failure secondary to anemia. Mainstays of treatment included controlling congestion and correcting the anemia with transfusions in the short-term while addressing the underlying etiology of the anemia in the long-term. Relevance and novel information Reports, treatment and management of high-output failure in the veterinary literature are limited. Extrapolating from human medicine, cats presenting with anemia and findings consistent with volume overload will benefit from treatment of their anemia to reduce neuroendocrine activation and the associated sodium and water retention. Therefore, blood transfusion should neither be avoided nor delayed in anemic cats with changes consistent with volume overload and congestive heart failure.

Pre-emptive intraoperative administration of PCC4 in cardiac surgery patients at high risk of bleeding: Apilot study.

Four-factor prothrombin complex (PCC4), a concentrate of factors II, VII, IX, and X and proteins C and S, has been used selectively for reversal of oral anticoagulation before surgery. There is data to support PCC4 as opposed to supplemental fresh frozen plasma (FFP) to manage postoperative bleeding following cardiac surgery. The preemptive, intraoperative use of PCC4 in cardiothoracic surgery has not been studied though it may prevent postoperative bleeding, the need for blood transfusion and the risk of transfusion-related acute lung injury, volume overload, and right ventricular (RV) heart failure. The purpose of this study is to evaluate the intraoperative administration of PCC4 to decrease bleeding and lower the rate of blood transfusion. A single institution retrospective chart review was conducted from May 2020 to November 2021 of patients who received PCC4 intraoperatively during cardiothoracic surgery of high-risk variety. Patients were evaluated for the type of surgery, demographics, baseline anticoagulation, PCC4 dose, type and quantity of blood transfusion within 72 hours (h) postoperatively, chest tube output, the incidence of RV failure, hypersensitivity reactions, acute kidney injury (AKI), thrombosis, acute lung injury, and mortality within 45 days of the operative dose of PCC4. Thirty-five patients received PCC4 at a mean dose of 2920 units (U). Sixty-fivepercent of cases were left ventricular assist devices(LVADs) or heart transplants. The protocol is to use PCC4 30 units (U)/kg immediately after the completion of protamine administration. Inclusion criteria are cardiothoracic surgery with increased risk of postoperative right heart failure commonly secondary to blood product transfusion, or cardiothoracic surgery associated with increased risk of bleeding, including heart transplant, LVAD implant, aortic dissection, and redo sternotomy (e.g., coronary artery bypass). Total chest tube output was recorded as a mean of 757 ml for 24 h after surgery (32 ml/h). Overall median event rates of FFPand red blood cell (RBC) transfusions were 0 (interquartile range [IQR]: 0-3 U) and 4 (IQR: 2-5 U). Overall, 43%and 89%of cases received FFP and RBC, respectively. There was one occurrence of RV failure, one occurrence of AKI requiring renal replacement therapy, one occurrence of venoarterial extracorporeal membrane oxygenation, one occurrence of venous thromboembolism related to a central venous access line, and one death unrelated to surgery or PCC4 that was attributed to advanced heart failure not amenable to advanced therapies. Overall patients received a low rate of blood transfusion, had minimal chest tube output, and there was a small incidence of right heart failure. Patients did not have an increased risk of adverse effects such as AKI or venous thromboembolism. A randomized controlled clinical trial comparing the observed dose and timing of PCC4 versus routine postoperative bleeding management with blood product transfusion is recommended.

Endothelin type A receptor blockade attenuates aorto-caval fistula-induced heart failure in rats with angiotensin II-dependent hypertension.

Evaluation of the effect of endothelin type A (ET A ) receptor blockade on the course of volume-overload heart failure in rats with angiotensin II-dependent hypertension. Ren-2 renin transgenic rats (TGR) were used as a model of hypertension. Heart failure was induced by creating an aorto-caval fistula (ACF). Selective ET A receptor blockade was achieved by atrasentan. For comparison, other rat groups received trandolapril, an angiotensin-converting enzyme inhibitor (ACEi). Animals first underwent ACF creation and 2 weeks later the treatment with atrasentan or trandolapril, alone or combined, was applied; the follow-up period was 20 weeks. Eighteen days after creating ACF, untreated TGR began to die, and none was alive by day 79. Both atrasentan and trandolapril treatment improved the survival rate, ultimately to 56% (18 of 31 animals) and 69% (22 of 32 animals), respectively. Combined ACEi and ET A receptor blockade improved the final survival rate to 52% (17 of 33 animals). The effects of the three treatment regimens on the survival rate did not significantly differ. All three treatment regimens suppressed the development of cardiac hypertrophy and lung congestion, decreased left ventricle (LV) end-diastolic volume and LV end-diastolic pressure, and improved LV systolic contractility in ACF TGR as compared with their untreated counterparts. The treatment with ET A receptor antagonist delays the onset of decompensation of volume-overload heart failure and improves the survival rate in hypertensive TGR with ACF-induced heart failure. However, the addition of ET A receptor blockade did not enhance the beneficial effects beyond those obtained with standard treatment with ACEi alone.

Risk of volume depletion events with concomitant use of sodium glucose co-transporter 2 inhibitors and loop diuretics: A self-controlled case series study.

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are used to prevent cardiovascular complications in type 2 diabetes mellitus (T2DM) and newly indicated to treat heart failure (HF). Loop diuretics are commonly prescribed to manage volume overload in HF and may increase the risk of volume depletion in real-world practice. This study evaluated the risk of volume depletion following concomitant use of SGLT2is and loop diuretics in veterans. Veterans with T2DM were included if they received concomitant loop diuretics and SGLT2is and experienced at least one volume depletion event between December 2012 and December 2019, utilizing a self-controlled case series design. Concomitant prescribing periods were divided into focal windows of 1 to 14 days, 14 to 28 days, and greater than 28 days. Incidence rate ratios (IRR) were estimated using multivariable Poisson regressions adjusted for age and renal function. 3352 patients experienced at least one volume depletion event and were concomitantly prescribed SGLT2is and loop diuretics at least once. The risk of volume depletion increased in the treatment versus control windows during the 1 to 14-day window (IRR=1.82, 95% CI 1.63-2.02) the 15-to-28-day window (IRR=1.46, 95% CI 1.28-1.67), and the greater than 28-day window (IRR=1.22, 95% CI 1.21-1.34). Concomitant prescribing of SGLT2is and loop diuretics is associated with an increased risk of volume depletion, an effect that attenuates with longer therapy durations. Prescribers need to closely monitor fluid status in patients receiving concomitant therapy, especially those with advancing age or with eGFR below 60.

Derangements and Reversibility of Energy Metabolism in Failing Hearts Resulting from Volume Overload: Transcriptomics and Metabolomics Analyses.

Derangements in cardiac energy metabolism have been shown to contribute to the development of heart failure (HF). This study combined transcriptomics and metabolomics analyses to characterize the changes and reversibility of cardiac energetics in a rat model of cardiac volume overload (VO) with the creation and subsequent closure of aortocaval fistula. Male Sprague–Dawley rats subjected to an aortocaval fistula surgery for 8 and 16 weeks exhibited characteristics of compensated hypertrophy (CH) and HF, respectively, in echocardiographic and hemodynamic studies. Glycolysis was downregulated and directed to the hexosamine biosynthetic pathway (HBP) and O-linked-N-acetylglucosaminylation in the CH phase and was further suppressed during progression to HF. Derangements in fatty acid oxidation were not prominent until the development of HF, as indicated by the accumulation of acylcarnitines. The gene expression and intermediates of the tricarboxylic acid cycle were not significantly altered in this model. Correction of VO largely reversed the differential expression of genes involved in glycolysis, HBP, and fatty acid oxidation in CH but not in HF. Delayed correction of VO in HF resulted in incomplete recovery of defective glycolysis and fatty acid oxidation. These findings may provide insight into the development of innovative strategies to prevent or reverse metabolic derangements in VO-induced HF.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

Glucose homeostasis is impaired in Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene‐Knockout and Gene‐Duplication Mutant Mice

Atrial and brain natriuretic peptides (ANP and BNP) are produced in the heart, regulate blood pressure (BP) and fluid homeostasis through vasodilatory and diuretic actions. Both ANP and BNP act by binding to guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPR‐A). Systemic disruption of Npr1(encoding GC‐A/NPRA) leads to volume overload, high BP, and congestive heart failure. However, the underlying mechanisms are not yet precisely determined. The aim of this study was to investigate whether Npr1plays a critical role in regulating glucose homeostasis in Npr1 gene‐disrupted mice. The adult male and female (16‐18 wk) Npr1 gene‐knockout haplotype (Npr1+/‐, 1‐copy), wild‐type (Npr1+/+, 2‐copy), and gene‐duplicated (Npr1+ +/+ +, 4‐copy) mice were fasted for 16 h and given free access to water. The glucose administration was done both orally and intraperitoneally (IP: 2 g/kg body weight) in mice to determine oral glucose tolerance test (OGTT) and IP glucose tolerance test (IPGTT). The glucose levels in blood were determined by performing tail bleeds at 0, 15, 30, 60, 90, and 120 min using the AlphaTRAK blood glucose monitoring system (Zoetis Inc, Kalamazoo, MI). Systolic BP (SBP) was determined by non‐invasive computerized tail‐cuff method (Visitech 2000). The results showed that the blood glucose level was elevated to the maximum value at 15 min after glucose administration. Glucose levels were declined to near base line at 120 min in 2 copy mice (OGTT: 102 ± 3 mg/dL in male and 97 ± 4 mg/dL in female, IPGT: 101 ± 4 mg/dL in male and 96 ± 3 mg/dL in female). However, in 1‐copy mice, the blood glucose levels remained elevated even after 120 min (OGTT: 248 ± 5 mg/dL in male and 226 ± 3 mg/dL in female, IPGT: 254 ± 4 mg/dL in male and 229 ± 5 mg/dL in female) compared with 2‐copy mice. The blood glucose levels were also significantly lower at 120 min in 4‐copy mice (OGTT: 77 ± 4 mg/dL in male and 74 ± 3 mg/dL in female, IPGT: 75 ± 3 mg/dL in male and 71 ± 2 mg/dL in female) compared with 2‐copy mice. SBP was significantly greater in 1‐copy mice (137 + 4 mmHg in male and 126 + 3 mmHg in female) than 2‐copy mice (100 + 2 mmHg in male and 91 + 2 mmHg in female). SBP was significantly lower in 4‐copy mice (83 + 2 mmHg in male and 77 + 2 mmHg in female) than 2‐copy mice. OGTT showed a significantly lower level of maximal blood glucose compared with IPGTT. The findings of the present study suggest that Npr1 plays a critical role in the regulation of glucose homeostasis and the loss of Npr1 significantly increases the glucose levels in mutant animals.

Tolvaptan, a vasopressin V2 receptor antagonist, is the world's first approved drug for treatment of autosomal dominant polycystic kidney disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Fluid-filled cysts develop and enlarge in both kidneys, eventually leading to kidney failure. Tolvaptan is a selective vasopressin V2 receptor antagonist and the first and only drug approved for treatment of ADPKD. It blocks binding of arginine vasopressin (AVP) to V2 receptors in the collecting duct of kidney, thereby inducing water diuresis (aquaresis) without losing electrolytes. Therefore, tolvaptan was originally developed and approved as the first oral aquaretic agent for treatment of hyponatremia and fluid volume overload in heart failure and cirrhosis. During the development of tolvaptan as aquaretics, efficacy of V2 antagonist in polycystic kidney animal model was reported and then the development of tolvaptan for ADPKD was also initiated. Cyclic adenosine monophosphate (cAMP) plays an important role in cyst growth by promoting cell proliferation and fluid secretion. Tolvaptan showed suppression of cyst growth through inhibiting AVP-induced cAMP production and delayed the onset of end-stage renal disease in an animal model. In the phase 3 clinical trial in ADPKD patients (TEMPO 3:4 trial), 3-year treatment with tolvaptan slowed the disease progression including increase of kidney volume and decline in renal function. Efficacy of tolvaptan in patients with late-stage ADPKD was confirmed in another 1-year phase 3 REPRISE trial. Tolvaptan is approved for treatment of ADPKD in more than 40 countries and we expect it can contribute to more ADPKD patients worldwide. We also expect that drugs with new mechanisms will be available in the near future.

Measuring the Size and Expansion of the Common Femoral Vein as A New Method of Detection and Stratification of Heart Failure

Heart Failure (HF) is on the end stage of the disease spectrum with many confounders and thus no specific symptoms and signs. There is a need for a test that can effectively confirm the diagnosis of volume overload in HF at its earliest to guide the initial approach and subsequent management. This study aimed to evaluate the effectiveness of a new test noted as the Size and Expansion of Femoral Vein (SEFV) in the diagnosis and management of patients with HF. This test was used specifically on asymptomatic patients or those who presented with severe comorbidities. The patients who arrived at the emergency room with a diagnosis of HF or suspected HF were enrolled. Ten patients without HF formed the control group. All patients received a standard physical examination (PE). The patients with the obvious diagnosis of HF by PE formed the HF control group. All patients with tentative diagnoses formed the HF study group. All patients underwent the ultrasound test to measure the size of the common femoral vein (CFV) and artery (CFA). The study enlisted 167 patients with HF or suspected HF. The results showed that the SEFV test was more accurate (98%) than the PE (54%). The SEFV test accurately differentiated between severely sick patients with intravascular overload and moderately sick patients with extravascular overflow. The test was accurate in patients with severe comorbidities (93%) or hypotension (100%). The SEFV test was more accurate in confirming the presence of fluid overload in patients with severe comorbidities or hypotension.

Effects of Trandolapril on Structural, Contractile and Electrophysiological Remodeling in Experimental Volume Overload Heart Failure.

Chronic volume overload induces multiple cardiac remodeling processes that finally result in eccentric cardiac hypertrophy and heart failure. We have hypothesized that chronic angiotensin-converting enzyme (ACE) inhibition by trandolapril might affect various remodeling processes differentially, thus allowing their dissociation. Cardiac remodeling due to chronic volume overload and the effects of trandolapril were investigated in rats with an aortocaval fistula (ACF rats). The aortocaval shunt was created using a needle technique and progression of cardiac remodeling to heart failure was followed for 24 weeks. In ACF rats, pronounced eccentric cardiac hypertrophy and contractile and proarrhythmic electrical remodeling were associated with increased mortality. Trandolapril substantially reduced the electrical proarrhythmic remodeling and mortality, whereas the effect on cardiac hypertrophy was less pronounced and significant eccentric hypertrophy was preserved. Effective suppression of electrical proarrhythmic remodeling and mortality but not hypertrophy indicates that the beneficial therapeutic effects of ACE inhibitor trandolapril in volume overload heart failure might be dissociated from pure antihypertrophic effects.

Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive

Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF + EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF + EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF + EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (~ 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF + EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.

Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts.

A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses.

Not all fluid overloads are the same: some practical considerations for better decongestion

Not all fluid overloads are the same: some practical considerations for better decongestion

Temporal trends of a vasopressin V2 receptor antagonist in heart failure using a nationwide database in Japan.

AimsReal‐world data on the use of tolvaptan, an oral selective vasopressin 2 receptor antagonist, for patients with heart failure (HF) are not available in Western countries because tolvaptan is not indicated in the Western countries for volume overload in HF. This study aimed to investigate the current status and recent trends of tolvaptan use for HF in Japan by analysing a nationwide Japanese Diagnosis Procedure Combination database.Methods and resultsWe retrospectively identified 257 812 patients hospitalized because of HF between 1 April 2008 and 30 November 2018. The diagnosis of HF at admission was based on the International Classification of Diseases, Tenth Revision, and in‐hospital treatment. We investigated patient characteristics, in‐hospital diuretic treatment, and tolvaptan treatment after discharge. The proportion of patients who were prescribed with tolvaptan for HF increased from 3.2% in 2011 to 39% in 2018. Since 2015, tolvaptan was prescribed within 2 days of hospitalization in >50% of HF cases. At discharge of a patient who was prescribed with tolvaptan, the rate of oral loop diuretic prescription at a dose ≥80 mg decreased, while the rate of diuretic prescription at a dose <40 mg increased. After discharge, the rate of tolvaptan prescription gradually increased from 34.0% in 2011 to 69.7% in 2018; however, tolvaptan prescriptions lasting >14 days decreased after 2012.ConclusionsThis large‐scale survey indicated an increased rate of tolvaptan prescription and an early shift to tolvaptan treatment in patients with HF in Japan. The prognostic effects of this change in HF treatment remain unclear.

Protective effect of tolvaptan against cyclophosphamide-induced nephrotoxicity in rat models.

Cyclophosphamide (CP) is a chemotherapeutic agent which is extensively used in the treatment of multiple neoplastic and nonneoplastic diseases like breast cancer, lymphomas, systemic lupus erythematosus, and multiple sclerosis. Dose‐limiting side effects, mainly nephrotoxicity is a major problem hindering its use in the clinical practice. CP induces nephrogenic syndrome of inappropriate antidiuresis mostly via the activation of arginine vasopressin V2 receptors. Moreover, CP produces reactive metabolites which is responsible for augmentation of lipid peroxidation and oxidative stress. Tolvaptan (TOL) is a selective vasopressin V2 receptor antagonist used in the treatment of clinically significant hyponatremia, volume overload in heart failure, and liver cirrhosis with edema. The present study aimed to investigate the potential protective effect of TOL in CP‐induced nephrotoxicity. Twenty‐four adult male albino rats were randomly divided into four groups: the control group, TOL group that treated daily with tolvaptan (10 mg/kg/d, orally), CP group where CP was administered intraperitoneally 75 mg/kg on days 3, 4, 5, 19, 20, and 21 of study, and the CP + TOL group where animals were treated with TOL daily with (10 mg/kg/d, orally) for 22 days with concomitant administration of CP as described before. Coadministration of TOL with CP induces significant improvement in the level of urine volume, serum Na+, serum osmolarity, urinary creatinine, and free water clearance in addition to significant reduction of body weight, serum creatinine, urea, serum K+, blood pressure, urine osmolarity, and the fractional excretion of sodium as compared to CP‐treated group. In addition, coadministration of TOL significantly reduced MDA, the marker of lipid peroxidation, and different pro‐inflammatory cytokines. Histopathological changes showed improvement in the signs of nephrotoxicity with the coadministration of TOL. Also, co‐treatment with TOL significantly decreased the level of markers of apoptosis as caspase‐3 and Bax with increased expression of antiapoptotic Bcl‐2 in renal tissue as compared to CP‐treated group.

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Imaging and computational modeling of tricuspid regurgitation and repair

The tricuspid valve (TV) and right ventricle (RV) are a complex mechanical system. Tricuspid regurgitation impacts a growing and heterogeneous population, leading to right-sided volume overload and right heart failure if left untreated. In part because isolated surgical tricuspid valve repair (TVR) is performed infrequently and has a high mortality, several percutaneous TVR options are being developed. However, the mechanical effects of different types of percutaneous or surgical TVR are unclear. Both the quality of RV imaging and the power of cardiac computational modeling have increased, and accurate computational models of the TV + RV with simulated TVR are now possible. Computational models of TV + RV may aid in patient selection and procedural planning prior to surgical and percutaneous TVR.

Episodic stimulation of central chemoreceptor neurons elicits disordered breathing and autonomic dysfunction in volume overload heart failure.

Enhanced central chemoreflex (CC) gain is observed in volume overload heart failure (HF) and is correlated with autonomic dysfunction and breathing disorders. The aim of this study was to determine the role of the CC in the development of respiratory and autonomic dysfunction in HF. Volume overload was surgically created to induce HF in male Sprague-Dawley rats. Radiotelemetry transmitters were implanted for continuous monitoring of blood pressure and heart rate. After recovering from surgery, conscious unrestrained rats were exposed to episodic hypercapnic stimulation [EHS; 10 cycles/5 min, inspiratory fraction of carbon dioxide () 7%] in a whole body plethysmograph for recording of cardiorespiratory function. To determine the contribution of CC to cardiorespiratory variables, selective ablation of chemoreceptor neurons within the retrotrapezoid nucleus (RTN) was performed via injection of saporin toxin conjugated to substance P (SSP-SAP). Vehicle-treated rats (HF+Veh and Sham+Veh) were used as controls for SSP-SAP experiments. Sixty minutes post-EHS, minute ventilation was depressed in sham animals relative to HF animals (ΔV̇e: −5.55 ± 2.10 vs. 1.24 ± 1.35 mL/min 100 g, P < 0.05; Sham+Veh vs. HF+Veh). Furthermore, EHS resulted in autonomic imbalance, cardiorespiratory entrainment, and ventilatory disturbances in HF+Veh but not Sham+Veh rats, and these effects were significantly attenuated by SSP-SAP treatment. Also, the apnea-hypopnea index (AHI) was significantly lower in HF+SSP-SAP rats compared with HF+Veh rats (AHI: 5.5 ± 0.8 vs. 14.4 ± 1.3 events/h, HF+SSP-SAP vs. HF+Veh, respectively, P < 0.05). Finally, EHS-induced respiratory-cardiovascular coupling in HF rats depends on RTN chemoreceptor neurons because it was reduced by SSP-SAP treatment. Overall, EHS triggers ventilatory plasticity and elicits cardiorespiratory abnormalities in HF that are largely dependent on RTN chemoreceptor neurons.