Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways.

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.

Roles of Mineralocorticoid Receptors in Cardiovascular and Cardiorenal Diseases.

Mineralocorticoid receptor (MR) activation in the heart and vessels leads to pathological effects, such as excessive extracellular matrix accumulation, oxidative stress, and sustained inflammation. In these organs, the MR is expressed in cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, and inflammatory cells. We review the accumulating experimental and clinical evidence that pharmacological MR antagonism has a positive impact on a battery of cardiac and vascular pathological states, including heart failure, myocardial infarction, arrhythmic diseases, atherosclerosis, vascular stiffness, and cardiac and vascular injury linked to metabolic comorbidities and chronic kidney disease. Moreover, we present perspectives on optimization of the use of MR antagonists in patients more likely to respond to such therapy and review the evidence suggesting that novel nonsteroidal MR antagonists offer an improved safety profile while retaining their cardiovascular protective effects. Finally, we highlight future therapeutic applications of MR antagonists in cardiovascular injury.

Renal Denervation to Treat Heart Failure.

Heart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these limitations, are necessary to attenuate the progression of HF pathophysiology while continuing to reduce morbidity and mortality. Renal denervation is an endovascular procedure, whereby the ablation of renal nerves results in reduced renal afferent and efferent sympathetic nerve activity in the kidney and globally. In this review, we discuss the current state of preclinical and clinical research related to renal sympathetic denervation to treat HF.

Chronic kidney disease in type 1 diabetes: translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes.

Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.

Interleukin-33 Mediates Cardiomyopathy After Acute Kidney Injury by Signaling to Cardiomyocytes.

BACKGROUND: Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy. METHODS: We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene Il1rl1 (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type-specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well. RESULTS: Mice deficient in Il33 were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, but not in mice lacking Il1rl1. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte-specific deletion of Il1rl1 but not in endothelial cell- or fibroblast-specific deletion of Il1rl1. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy. CONCLUSIONS: These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease.

In chronic kidney disease altered cardiac metabolism precedes cardiac hypertrophy.

Conduit arterial disease in chronic kidney disease (CKD) is an important cause of cardiac complications. Cardiac function in CKD has not been studied in the absence of arterial disease. In an Alport syndrome model bred not to have conduit arterial disease, mice at 225 days of life (dol) had CKD equivalent to humans with CKD stage 4-5. Parathyroid hormone (PTH) and FGF23 levels were one log order elevated, circulating sclerostin was elevated, and renal activin A was strongly induced. Aortic Ca levels were not increased, and vascular smooth muscle cell (VSMC) transdifferentiation was absent. The CKD mice were not hypertensive, and cardiac hypertrophy was absent. Freshly excised cardiac tissue respirometry (Oroboros) showed that ADP-stimulated O2 flux was diminished from 52 to 22 pmol/mg (P = 0.022). RNA-Seq of cardiac tissue from CKD mice revealed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. To examine the effect of activin A signaling, some Alport mice were treated with a monoclonal Ab to activin A or an isotype-matched IgG beginning at 75 days of life until euthanasia. Treatment with the activin A antibody (Ab) did not affect cardiac oxidative phosphorylation. However, the activin A antibody was active in the skeleton, disrupting the effect of CKD to stimulate osteoclast number, eroded surfaces, and the stimulation of osteoclast-driven remodeling. The data reported here show that cardiac mitochondrial respiration is impaired in CKD in the absence of conduit arterial disease. This is the first report of the direct effect of CKD on cardiac respiration.NEW & NOTEWORTHY Heart disease is an important morbidity of chronic kidney disease (CKD). Hypertension, vascular stiffness, and vascular calcification all contribute to cardiac pathophysiology. However, cardiac function in CKD devoid of vascular disease has not been studied. Here, in an animal model of human CKD without conduit arterial disease, we analyze cardiac respiration and discover that CKD directly impairs cardiac mitochondrial function by decreasing oxidative phosphorylation. Protection of cardiac oxidative phosphorylation may be a therapeutic target in CKD.

Enrollment strategies in the era of digital revolution: Experience from a remote health management program.

We share our experience on the strategies implemented for identifying and enrolling participants in a randomized remote implementation trial. We aimed to evaluate the effectiveness of various digital and traditional screening and outreach methods in participant enrollment. This study focuses on understanding the success and challenges associated with different approaches to patient engagement.

Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-ß, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1ß) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

Rationale and Design of the DECONGEST (Diuretic Treatment in Acute Heart Failure With Volume Overload Guided by Serial Spot Urine Sodium Assessment) Study.

AIMS: To evaluate whether early-combination diuretic therapy guided by serial post-diuretic urine sodium concentration (UNa+) assessments in acute heart failure (AHF) facilitates safe and effective decongestion. METHODS: The Diuretic Treatment in Acute Heart Failure with Volume Overload Guided by Serial Spot Urine Sodium Assessment (DECONGEST) study is a pragmatic, 2-center, randomized, parallel-arm, open-label study aiming to enroll 104 patients with AHF and clinically evident fluid overload requiring treatment with intravenous loop diuretics. Patients are randomized to receive standard of care or a bundled approach comprising: (1) systematic post-diuretic UNa+ assessments until successful decongestion, defined as no remaining clinical signs of fluid overload with a post-diuretic UNa+ ≤ 80 mmol/L; (2) thrice-daily intravenous loop diuretic bolus therapy, with dosing according to estimated glomerular filtration rate; (3) upfront use of intravenous acetazolamide (500 mg once daily [OD]); and (4) full nephron blockade with high-dose oral chlorthalidone (100 mg OD) and intravenous canreonate (200 mg OD) for diuretic resistance, defined as persisting signs of fluid overload with a post-diuretic UNa+ ≤ 80 mmol/L. The primary endpoint of the DECONGEST study is a hierarchical composite of (1) survival at 30 days; (2) days alive and out of hospital or care facility up to 30 days; and (3) greater relative decrease in natriuretic peptide levels from baseline to day 30. CONCLUSION: The DECONGEST study aims to determine whether an intensive diuretic regimen focused on early combination therapy, guided by serial post-diuretic UNa+ assessments, safely enhances decongestion, warranting further evaluation in a larger trial powered for clinical events.

Assessment and management of heart failure in patients with chronic kidney disease.

Heart failure (HF) and chronic kidney disease (CKD) are two pathological conditions with a high prevalence in the general population. When they coexist in the same patient, a strict interplay between them is observed, such that patients affected require a clinical multidisciplinary and personalized management. The diagnosis of HF and CKD relies on signs and symptoms of the patient but several additional tools, such as blood-based biomarkers and imaging techniques, are needed to clarify and discriminate the main characteristics of these diseases. Improved survival due to new recommended drugs in HF has increasingly challenged physicians to manage patients with multiple diseases, especially in case of CKD. However, the safe administration of these drugs in patients with HF and CKD is often challenging. Knowing up to which values ​​of creatinine or renal clearance each drug can be administered is fundamental. With this review we sought to give an insight on this sizable and complex topic, in order to get clearer ideas and a more precise reference about the diagnostic assessment and therapeutic management of HF and CKD.

The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes: an updated systematic review and meta-analysis.

BACKGROUND: The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality. METHODS: We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE. RESULTS: Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D. CONCLUSIONS: This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.

Cardiovascular and renal diseases in type 2 diabetes patients: 5-year cumulative incidence of the first occurred manifestation and hospitalization cost: a cohort within the French SNDS nationwide claims database.

BACKGROUND: Myocardial infarction (MI), stroke, peripheral arterial disease (PAD), heart failure (HF) and chronic kidney disease (CKD) are common cardiovascular renal diseases (CVRD) manifestations for type 2 diabetes. The objective was to estimate the incidence of the first occurring CVRD manifestation and cumulative hospitalization costs of each CVRD manifestation for type 2 diabetes without CVRD history. METHODS: A cohort study of all type 2 diabetes free of CVRD as of January 1st 2014, was identified and followed-up for 5 years within the French SNDS nationwide claims database. The cumulative incidence of the first occurring CVRD manifestation was estimated using the cumulative incidence function, with death as a competing risk. Cumulative hospitalization costs of each CVRD manifestations were estimated from the perspective of all payers. RESULTS: From 2,079,089 type 2 diabetes without cancer or transplantation, 76.5% were free of CVRD at baseline with a mean age of 65 years, 52% of women and 7% with microvascular complications history. The cumulative incidence of a first CVRD manifestation was 15.3% after 5 years of follow-up with a constant linear increase over time for all CVRD manifestations: The most frequent was CKD representing 40.6% of first occurred CVRD manifestation, followed by HF (23.0%), then PAD (13.5%), stroke (13.2%) and MI (9.7%). HF and CKD together reached about one patient out of ten after 5 years and represented 63.6% of first CVRD manifestations. The 5-year global cost of all CVRD hospitalizations was 3.9 billion euros (B€), i.e. 2,450€ per patient of the whole cohort, with an exponential increase over time for each specific CVRD manifestation. The costliest was CKD (2.0 B€), followed by HF (1.2 B€), then PAD (0.7 B€), stroke (0.6 B€) and MI (0.3 B€). CONCLUSIONS/INTERPRETATION: While MI, stroke and PAD remain classic major risks of complications for CVRD-free type 2 diabetes, HF and CKD nowadays represent individually a higher risk and cost than each of these classic manifestations, and jointly represents a risk and a cost twice as high as these three classic manifestations all together. This should encourage the development of specific HF and CKD preventive strategies.

Inflammation Links Cardiac Injury and Renal Dysfunction: A Cardiovascular Magnetic Resonance Study.

Background: Inflammation is essential in cardiorenal syndrome, however there is still a lack of evidence proving the interaction between cardiac injury, renal dysfunction and the inflammatory response. This study aimed to illustrate the association between renal dysfunction and cardiac injury with a specific focus on the role of inflammation. Methods: A single-center, retrospective study included patients with heart failure admitted to the cardiovascular department from September 2019 to April 2022. Patients received cardiovascular magnetic resonance (CMR) imaging (T1 mapping and late gadolinium enhancement (LGE)). Demographic, creatinine and native T1 were analyzed using pearson correlation, linear regression and adjusted for confounders. Interaction and subgroup analysis were performed. Results: Finally, 50 validated heart failure (HF) patients (age 58.5 ± 14.8 years; 78.0% men) were included. Cardiac global native T1 for the high estimated glomeruar filtration rate (eGFR) group was 1117.0 ± 56.6 ms, and for the low eGFR group was 1096.5 ± 61.8 ms. Univariate analysis identified global native T1 ( ß = 0.16, 95% confidence interval (CI): 0.04-0.28, p = 0.014) and C-reactive protein (CRP) ( ß = 0.30, 95% CI: 0.15-0.45, p < 0.001) as determinants of creatinine. Multivariable linear regression analysis identified global native T1 ( ß = 0.12, 95% CI: 0.01-0.123, p = 0.040) as a determinant of creatinine while age and diabetes were adjusted. Significant interactions between CRP and global native T1 in relation to creatinine level (p for interaction = 0.005) were identified. Conclusions: Kidney dysfunction was associated with cardiac injury and inflammation, respectively. The interaction between myocardial injury and kidney dysfunction is contingent on the severity of the inflammatory response. Further studies were needed to identify the mechanisms of the inflammatory response in cardiorenal syndrome.

Non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease and type 2 diabetes.

Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is a major health challenge associated with a disproportionately high burden of end-stage renal disease, cardiovascular disease and death. This review summarizes the rationale, clinical evidence and practical implementation for non-steroidal mineralocorticoid receptor antagonists (nsMRAs), a drug class now approved and recommended for patients with T2D and CKD at risk of cardiorenal disease progression. Three nsMRAs (finerenone, esaxerenone and apararenone) have been evaluated but finerenone is currently the only approved nsMRA for this indication. Two large-scale, placebo-controlled, Phase 3 studies evaluated finerenone added to a maximally tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Over >2 years of treatment, finerenone was associated with a significant reduction in composite endpoints of renal and cardiovascular outcomes versus placebo. Esaxerenone or apararenone have both shown significant improvements in albuminuria versus placebo. In general, nsMRAs were well tolerated. Hyperkalaemia was the most notable treatment-related adverse event and could generally be managed through serum potassium monitoring and dose adjustments. The nsMRAs are now an important component of recommended treatment for CKD associated with T2D, providing a significant reduction in the risk of cardiorenal progression beyond what can be achieved with glucose and blood pressure control.

Key results from observational studies and real-world evidence of sodium-glucose cotransporter-2 inhibitor effectiveness and safety in reducing cardio-renal risk.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio-renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio-renal diseases and SGLT2 inhibitors has been explored through landmark trials and real-world evidence (RWE) studies, demonstrating significant reductions in cardio-renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real-world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio-renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower-limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio-renal protective effects in real-world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long-term effects and safety profiles.

Salty Subjects: Unpacking Racial Differences in Salt-Sensitive Hypertension.

PURPOSE OF REVIEW: To review underlying mechanisms and environmental factors that may influence racial disparities in the development of salt-sensitive blood pressure. RECENT FINDINGS: Our group and others have observed racial differences in diet and hydration, which may influence salt sensitivity. Dietary salt elicits negative alterations to the gut microbiota and immune system, which may increase hypertension risk, but little is known regarding potential racial differences in these physiological responses. Antioxidant supplementation and exercise offset vascular dysfunction following dietary salt, including in Black adults. Furthermore, recent work proposes the role of racial differences in exposure to social determinants of health, and differences in health behaviors that may influence risk of salt sensitivity. Physiological and environmental factors contribute to the mechanisms that manifest in racial differences in salt-sensitive blood pressure. Using this information, additional work is needed to develop strategies that can attenuate racial disparities in salt-sensitive blood pressure.

Targeting the TWEAK-Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury.

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+ ) handling alterations. Next, we investigated the role of the TWEAK-Fn14 axis in cardiomyocyte function following renal ischaemia-reperfusion (I/R) injury in mice. We observed that TWEAK-Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+ -adenosine triphosphatase 2a pump (SERCA2a ) and ryanodine receptor (RyR2 ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK-Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Improvement in Echocardiographic Indexes of Systolic Heart Failure Post-Kidney Transplantation: A Retrospective Analysis.

INTRODUCTION: End-stage renal disease is a major risk factor for cardiovascular morbidity and mortality, which can be partially eliminated by kidney transplantation. Systolic heart failure might be considered contraindication for kidney transplant, although some patients demonstrate myocardial recovery post-transplant. We aimed to identify and characterize the phenomenon of reverse myocardial remodeling in kidney transplanted patients. METHODS: The study is a retrospective cohort of patients undergoing kidney transplants between 2016 and 2019 (n = 604) at Rabin Medical Center. Patients were assessed according to availability of two echocardiographic examinations: pre- and post-kidney transplant. The change in estimated ejection fraction (EF) and possible predictors of myocardial recovery were examined. RESULTS: Data of 293 patients was available for the final analysis. Eighty-one (28%) patients had a LVEF improvement equal to or above 5%, whereas 36 (12%) patients had a LVEF improvement of 10% or more post-transplantation. Twenty-five patients (8.5%) had moderate or severe systolic heart failure with LVEF reduced to 40% or less at baseline. 13 of them (52%) had a LVEF improvement of ≥5%, and 10 patients (40%) had an improvement of ≥10% in their EF. Cox regression analyses identified female gender as the only independent variable associated with LVEF improvement of at least 10%. CONCLUSION: Renal transplantation might lead to improved LV systolic function in some patients.

Cardiorenal Syndrome in Right Heart Failure Due to Pulmonary Arterial Hypertension-The Right Ventricle as a Therapeutic Target to Improve Renal Function.

Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function.

Prognostic effect of a vasopressin V2 receptor antagonist in acute congestive heart failure patients with hypoperfusion, the wet-cold pattern.

PURPOSE: This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet-cold pattern), from the viewpoint of cardiorenal syndrome. METHODS: Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria-Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups. RESULTS: Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet-cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417). CONCLUSION: There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF.