Accelerated idioventricular rhythm as a manifestation of chronic renocardiac syndrome: A case report.

In this case report, we describe a patient who presented with chronic symptoms and signs of uremia and persistent accelerated idioventricular rhythm (AIVR) on electrocardiogram. Findings from blood tests, echocardiography, renal ultrasound, and renal scan were suggestive of heart failure with reduced ejection fraction and chronic kidney disease, and attendance of daily hemodialysis sessions led to the restoration of sinus rhythm. Typically, AIVR has a favorable prognosis and, if necessary, medical intervention focuses on addressing the underlying responsible causes. Accumulation of uremic toxins has the potential to trigger the formation of AIVR and clearance of small solutes through conventional hemodialysis may contribute to sinus rhythm restoration.

Publication Trends and Research Hotspots of the Cardiorenal Syndrome: A Bibliometrics and Visual Analysis from 2003 to 2023.

INTRODUCTION: Cardiorenal syndrome encompasses a range of disorders involving both the heart and kidneys, wherein dysfunction in one organ may induce dysfunction in the other, either acutely or chronically. METHODS: This study conducted a literature search on cardiorenal syndrome from January 1, 2003, to September 8, 2023. Meanwhile, a quantitative analysis of the developmental trajectory, research hotspots and evolutionary trends in the field of cardiorenal syndrome through bibliometric analysis and knowledge mapping was carried out. RESULTS: The annual publication trend analysis revealed a consistent annual increase in cardiorenal syndrome literature over the last 20 years. The IL6, REN, and INS genes were identified as the current research hotspots. CONCLUSION: The field of cardiorenal syndrome exhibits promising potential to grow and is emerging as a prominent research area. Future endeavours should prioritise a comprehensive understanding of the field and foster multi-centre co-operation among different countries and regions.

Cardiorenal Syndromes and Their Role in Water and Sodium Homeostasis.

Sodium is the main osmotically active ion in the extracellular fluid and its concentration goes hand in hand with fluid volume. Under physiological conditions, homeostasis of sodium and thus amount of fluid is regulated by neural and humoral interconnection of body tissues and organs. Both heart and kidneys are crucial in maintaining volume status. Proper kidney function is necessary to excrete regulated amount of water and solutes and adequate heart function is inevitable to sustain renal perfusion pressure, oxygen supply etc. As these organs are bidirectionally interconnected, injury of one leads to dysfunction of another. This condition is known as cardiorenal syndrome. It is divided into five subtypes regarding timeframe and pathophysiology of the onset. Hemodynamic effects include congestion, decreased cardiac output, but also production of natriuretic peptides. Renal congestion and hypoperfusion leads to kidney injury and maladaptive activation of renin-angiotensin-aldosterone system and sympathetic nervous system. In cardiorenal syndromes sodium and water excretion is impaired leading to volume overload and far-reaching negative consequences, including higher morbidity and mortality of these patients. Keywords: Cardiorenal syndrome, Renocardiac syndrome, Volume overload, Sodium retention.

Cardiorenal Syndrome: An Evolutionary Appraisal.

A recent American Heart Association Scientific Statement and Presidential Advisory recognized a new syndrome, the cardiovascular-kidney-metabolic syndrome. This expands our understanding of what has been called cardiorenal syndrome by incorporating the pathophysiological interrelatedness of metabolic risk factors into the previous concept of cardiorenal syndrome. Importantly, perturbation of cardiac or renal physiology combines to produce significant detrimental outcomes. The cardiorenal syndrome is a significant part of the cardiovascular-kidney-metabolic syndrome and contributes to health care cost, disability, and mortality. It is a vexing malady that has generated considerable interest. To understand the syndrome evaluation of its teleological origins is important. In life's beginning, eukaryotes acquired exocytosis for excretion, formed tubular secretory systems for clearance, and a mesenchymal nucleic acid vasoform for nutritional distribution. Those structures progressed to cardiovascular and renal systems of evolving organisms, whose migration to rivers and land imposed complex, coordinated, homeostatic roles to maintain intravascular stability. Tissue mineralization of vertebrate endoskeleton added renal calcium balance regulation, which in kidney failure results in cardiovascular calcification. Insight into cardiorenal disease can be traced to ancient Egyptian and Chinese medicine, through the Scientific Revolution, and into current insights regarding human physiology and pathophysiology. The post-World War II epidemic of cardiovascular mortality generated considerable information on cardiovascular disease, which being higher in patients with kidney disease, drew increasing health concerns. The cardiorenal syndrome was formally introduced in this setting with a focus on ultrafiltration to manage volume overload. An evolutionary review of insight into cardiorenal syndrome will help us better understand the new cardiovascular-kidney-metabolic syndrome.

Serial direct sodium removal in patients with heart failure and diuretic resistance.

AIMS: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance. METHODS AND RESULTS: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved. CONCLUSIONS: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS. CLINICAL TRIAL REGISTRATION: RED DESERT (NCT04116034), SAHARA (NCT04882358).

Hepato-Cardio-Renal Syndrome.

Hepatorenal syndrome has conventionally been regarded as a multisystem syndrome in which pathophysiologic pathways that link cirrhosis with impairment in kidney function are followed by dysfunction of several organs such as the heart. The advances in cardiac studies have helped diagnose more subtle cardiac abnormalities that would have otherwise remained unnoticed in a significant subset of patients with advanced liver disease and cirrhosis. Accumulating data suggests that in many instances, the cardiac dysfunction precedes and predicts development of kidney disease in such patients. These observations point to the heart as a key player in hepatorenal syndrome and challenge the notion that the cardiac abnormalities are either the consequence of aberrancies in hepatorenal interactions or have only minor effects. As such, the disturbances traditionally bundled within hepatorenal syndrome may indeed represent a hepatic form of cardiorenal syndrome whereby the liver affects the kidney in part through cardiorenal pathways (that is, hepato-cardio-renal syndrome).

Renal Sodium Avidity in Heart Failure.

BACKGROUND: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. SUMMARY: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure. KEY MESSAGES: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.

Rat Models of Cardiorenal Syndrome and Methods for Functional Assessment.

Cardiorenal syndrome (CRS) is a clinical disorder involving combined heart and kidney dysfunction, which leads to poor clinical outcomes. To understand the complex pathophysiology and mechanisms that lie behind this disease setting, and design/evaluate appropriate treatment strategies, suitable animal models are required. Described here are the protocols for establishing surgically induced animal models of CRS including important methods to determine clinically relevant measures of cardiac and renal function, commonly used to assess the degree of organ dysfunction in the model and treatment efficacy when evaluating novel therapeutic strategies.

Practical Approaches to the Management of Cardiorenal Disease beyond Congestion.

BACKGROUND: The coexistence of heart and kidney diseases, also called cardiorenal syndrome, is very common, leads to increased morbidity and mortality, and poses diagnostic and therapeutic difficulties. There is a risk-treatment paradox, such that patients with the highest risk are treated with lesser disease-modifying medical therapies. SUMMARY: In this document, different scientific societies propose a practical approach to address and optimize cardiorenal therapies and related comorbidities systematically in chronic cardiorenal disease beyond congestion. Cardiorenal programs have emerged as novel models that may assist in delivering coordinated and holistic management for these patients. KEY MESSAGES: (1) Cardiorenal disease is a ubiquitous entity in clinical practice and is associated with numerous barriers that limit medical treatment. (2) The present article focuses on the practical approaches to managing chronic cardiorenal disease beyond congestion to overcome some of these barriers and improve the treatment of this high-risk population.

Practical Requirements for the Development of an Advanced Cardiorenal Unit.

BACKGROUND: Heart failure is frequently associated with kidney disease, and patients with kidney disease are at increased risk of heart failure. The co-occurrence of both entities not only significantly increases morbidity and mortality but also complicates therapy. SUMMARY: Cardiorenal syndrome often requires a broad, comprehensive, and multidisciplinary approach. As a result, a need has arisen to create specialized cardiorenal units that allow for rigorous and personalized management of this condition. Moreover, in some cases, cardiorenal syndrome is more complex, owing to an acute and critical situation that requires the concept of the cardiorenal unit to be extended toward advanced diagnostic and therapeutic positions, thus confirming the need for an advanced cardiorenal unit. The creation of these units constitutes a real challenge, necessitating a specific multilevel action plan, covering governance and management, type of patient, personnel requirements, service portfolio, care process, information systems, and other resources. Specific lines of action must be proposed for each of the relevant points in order to facilitate development of these units, together with continuous evaluation of unit activity through specific indicators, and to detect areas for improvement. KEY MESSAGES: This study addresses the conditions and organizational characteristics that enable the creation, development, and continuous improvement of advanced cardiorenal units.

Cell-Specific Targeting of the Endothelium in the Cardiorenal Syndrome.

BACKGROUND: The vascular endothelium serves as a semi-selective permeable barrier as a conduit for transport of fluid, solutes, and various cell populations between the vessel lumen and tissues. The endothelium thus has a dynamic role in the regulation of coagulation, immune system, lipid and electrolyte transport, as well as neurohumoral influences on vascular tone and end-organ injury to tissues such as the heart and kidney. SUMMARY: Within this framework, pharmacologic strategies for heart and kidney diseases including blood pressure, glycemic control, and lipid reduction provide significant risk reduction, yet certain populations are at risk for substantial residual risk for disease progression and treatment resistance and often have unwanted off-target effects leaving the need for adjunct, alternative targeted therapies. Recent advances in techniques in sequencing and spatial transcriptomics have paved the way for the development of new therapies for targeting heart and kidney disease that include various gene, cell, and nano-based therapies. Cell-specific endothelium-specific targeting of viral vectors will enable their use for the treatment of heart and kidney diseases with gene therapy that can avoid unwanted off-target effects, improve treatment resistance, and reduce residual risk for disease progression. KEY MESSAGES: The vascular endothelium is an important therapeutic target for chronic kidney and cardiovascular diseases. Developing endothelial-specific gene therapies can benefit patients who develop resistance to current treatments.

Cardiorenal Interactions in Acute Heart Failure: Renal Proximal Tubules in the Spotlight.

BACKGROUND: The maladaptive neurohormonal activation, an integral mechanism in the pathophysiology of heart failure (HF) and cardiorenal syndrome, has a profound impact on renal sodium handling. Congestion is the primary reason for hospitalization of patients with HF and the main target of therapy. As sodium is the main determinant of extracellular volume, the goal is to enhance urinary sodium excretion in order to address excess fluid. The interventions to increase natriuresis have conventionally focused on distal nephron as the primary segment that counterbalances the effects of loop diuretics. SUMMARY: Recent developments in the field of cardiorenal medicine have resulted in a shift of attention to renal proximal tubules (e.g., emerging evidence on proximal tubular dysfunction beyond handling of sodium). Herein, we discuss the three main mechanisms of sodium transport in the proximal tubules with emphasis on their intrinsic links to one another as well as to more distal transporters of sodium. Then, we provide an overview of the findings of the most recent clinical studies that have tried to enhance the conventional decongestive strategies through simultaneous blockade of these mechanisms. KEY MESSAGE: Interventions aiming at renal proximal tubules have the potential to significantly improve our ability to decongest patients with acute HF.

The Effect in Renal Function and Vascular Decongestion in Type 1 Cardiorenal Syndrome Treated with Two Strategies of Diuretics, a Pilot Randomized Trial.

AIM: The main treatment strategy in type 1 cardiorenal syndrome (CRS1) is vascular decongestion. It is probable that sequential blockage of the renal tubule with combined diuretics (CD) will obtain similar benefits compared with stepped-dose furosemide (SF). METHODS: In a pilot double-blind randomized controlled trial of CRS1 patients were allocated in a 1:1 fashion to SF or CD. The SF group received a continuous infusion of furosemide 100 mg during the first day, with daily incremental doses to 200 mg, 300 mg and 400 mg. The CD group received a combination of diuretics, including 4 consecutive days of oral chlorthalidone 50 mg, spironolactone 50 mg and infusion of furosemide 100 mg. The objectives were to assess renal function recovery and variables associated with vascular decongestion. RESULTS: From July 2017 to February 2020, 80 patients were randomized, 40 to the SF and 40 to the CD group. Groups were similar at baseline and had several very high-risk features. Their mean age was 59 ± 14.5 years, there were 37 men (46.2%). The primary endpoint occurred in 20% of the SF group and 15.2% of the DC group (p = 0.49). All secondary and exploratory endpoints were similar between groups. Adverse events occurred frequently (85%) with no differences between groups (p = 0.53). CONCLUSION: In patients with CRS1 and a high risk of resistance to diuretics, the use of CD compared to SF offers the same results in renal recovery, diuresis, vascular decongestion and adverse events, and it can be considered an alternative treatment. ClinicalTrials.gov with number NCT04393493 on 19/05/2020 retrospectively registered.

Diabetes modulation of the myocardial infarction-acute kidney injury axis.

As there is cross talk in functions of the heart and kidney, acute or chronic injury in one of the two organs provokes adaptive and/or maladaptive responses in both organs, leading to cardiorenal syndrome (CRS). Acute kidney injury (AKI) induced by acute heart failure is referred to as type 1 CRS, and a frequent cause of this type of CRS is acute myocardial infarction (AMI). Diabetes mellitus increases the risk of AMI and also the risk of AKI of various causes. However, there have been only a few studies in which animal models of diabetes were used to examine how diabetes modulates AMI-induced AKI. In this review, we summarize findings regarding the mechanisms of type 1 CRS and the impact of diabetes on both AMI and renal susceptibility to AKI and we discuss mechanisms by which diabetes modulates AMI-induced AKI. Hemodynamic alterations induced by AMI could be augmented by diabetes via its detrimental effect on infarct size and contractile function of the noninfarcted region in the heart. Diabetes increases susceptibility of renal cells to hypoxia and oxidative stress by modulation of signaling pathways that regulate cell survival and autophagy. Recent studies have shown that diabetes mellitus even at early stage of cardiomyopathy/nephropathy predisposes the kidney to AMI-induced AKI, in which activation of Toll-like receptors and reactive oxygen species derived from NADPH oxidases are involved. Further analysis of cross talk between diabetic cardiomyopathy and diabetic kidney disease is necessary for obtaining a more comprehensive understanding of modulation of the AMI-AKI axis by diabetes.

Nicorandil Decreases Renal Injury in Patients With Coronary Heart Disease Complicated With Type I Cardiorenal Syndrome.

ABSTRACT: Cardiorenal syndrome (CRS) is a group of disorders in which heart or kidney dysfunction worsens each other. This study aimed to explore the improvement effect of nicorandil on cardiorenal injury in patients with type I CRS. Patients with coronary heart disease complicated with type I CRS were enrolled. Based on the conventional treatment, the patients were prospectively randomized into a conventional treatment group and a nicorandil group, which was treated with 24 mg/d nicorandil intravenously for 1 week. Fasting peripheral venous blood serum and urine were collected before and at the end of treatment. An automatic biochemical analyzer and enzyme linked immunosorbent assay were used to detect B-type brain natriuretic peptide (BNP), serum creatinine (Scr) and cystatin C (Cys-C), renal injury index-kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) levels. The left ventricular ejection fraction was measured by echocardiography. All measurements were not significantly different between the nicorandil and conventional treatment groups before treatment (all P > 0.05), and BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were decreased in the 2 groups at the end of treatment (all P < 0.05). Compared with the conventional treatment group, BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were more significantly decreased in the nicorandil group (all P < 0.05) and left ventricular ejection fraction was more significantly increased (P < 0.05). Therefore, nicorandil could significantly improve the cardiac and renal function of patients with type I CRS. This may prove to be a new therapeutic tool for improving the prognosis and rehabilitation of type I CRS.

Entresto protected the cardiomyocytes and preserved heart function in cardiorenal syndrome rat fed with high-protein diet through regulating the oxidative stress and Mfn2-mediated mitochondrial functional integrity.

This study tested the hypothesis that Entresto (En) therapy protected the cardiomyocytes and heart function in cardiorenal syndrome (CRS) rats fed with high-protein diet (HPD) through regulating the oxidative-stress and Mfn2-mediated mitochondrial functional integrity. En (12.5 µM for the in-vitro study) protected the H9C2-cells against H2O2-induced cell apoptosis, whereas stepwise-increased H2O2 concentrations induced a significant increase in protein expressions of Mfn2/phosphorylated (p)-DRP1/mitochondrial-Bax in H9C2-cells. En downregulated H2O2-induced mitochondrial fission/upregulated mitochondrial fusion and deletion of Mfn2 gene (i.e., shMfn2) to significantly reduce H2O2-induced ROS production. En significantly suppressed and shMfn2 further significantly suppressed both H2O2-reduced mitochondrial-membrane potential and H2O2-induced ROS production/cell apoptosis/mitochondrial damage/mitochondrial-Bax released from mitochondria in H9C2 cells. En significantly reduced protein expressions of Mfn2 and p-DRP1. Additionally, En significantly suppressed and shMfn2 further significantly suppressed the protein expressions of mitochondrial-damaged (DRP1)/oxidative-stress (NOX-1/NOX-2)/apoptosis (mitochondrial-Bax/caspase-3/PARP)/autophagic (LC3B-II/LC3B-I) biomarkers (all p < 0.01). Rats were categorized into group 1 [sham-control + high-protein-diet (HPD)], group 2 (CRS + HPD) and group 3 (CRS+ HPD + En/100 mg/kg/day). By day 63 after CRS induction, the LVEF was significantly lower in group 3 and more significantly lower in group 2 than in group 1, whereas the protein expressions of oxidative-stress (NOX-1/NOX-2/p22phox/oxidized protein)/apoptotic (mitochondrial-Bax/caspase-3/PARP), fibrotic (Smad-3/TGF-ß), autophagic (Beclin-1/Atg5/ratio of LC3B-II/LC3B-I) and mitochondrial-damaged (DRP1/cyclophilin-D/cytosolic-cytochrome-C) biomarkers exhibited an opposite pattern of LVEF among the groups. Downregulation of Mfn2 by En or shMfn2 in cardiomyocytes avoided H2O2 damage and En improved the cardiac function in HPD-feeding CRS rat via adjusting Mfn2-mediated mitochondrial functional integrity.

Variación de la presión intraabdominal en los pacientes con insuficiencia cardíaca aguda según la fracción de eyección ventricular izquierda. Resultados del estudio PIA / Variation in intraabdominal pressure in patients with acute heart failure according to left ventricular ejection fraction. Results of an intraabdominal pressure study

Antecedentes El aumento de la presión intraabdominal (PIA) se ha correlacionado con elevación de la creatinina en pacientes con insuficiencia cardíaca con fracción de eyección ventricular izquierda gravemente deprimida (ICFEr). Sin embargo, dicha variable no se ha explorado en pacientes más estables o con insuficiencia cardíaca y fracción de eyección preservada (ICFEp). Pacientes y método Estudio observacional, prospectivo y descriptivo consistente en la medición de la PIA en pacientes ingresados por insuficiencia cardíaca (IC) descompensada. Se estratificó la muestra según la fracción de eyección ventricular izquierda (FEVI) con un punto de corte del 50%, con el objetivo de analizar la PIA, así como las características basales y el grado de congestión empleando la ecografía clínica y la impedanciometría. Resultados Se incluyeron un total de 56 pacientes, 22 con ICFEr y 34 con ICFEp. Los pacientes con ICFEr presentaron una mayor prevalencia de cardiopatía isquémica (11 vs. 6; p = 0,010) y EPOC/asma (6 vs. 2%; p = 0,025). La PIA fue más alta en pacientes con ICFEr (17,2 mmHg vs. 13,3 mmHg; p = 0,004), sin diferencias en la función renal al ingreso según la FEVI (CKD-EPI creatinina) (ICFEr 55,0 mL/min/1,73 m2 [32,6-83,6] vs. ICFEp 55,0 mL/min/1,73 m2 [44,0-74,9]; p = 0,485). Los pacientes con ICFEr presentaron un perfil más congestivo estimado por ecografía (colapso de la cava inferior [26% vs. 50%; p = 0,001]), impedanciometría (agua corporal total al ingreso: 46 L vs. 41 L; p = 0,052 y a las 72 horas 50,2 L vs. 39,1 L; p = 0,038) y concentración de CA125 (68 U/mL vs. 39 U/mL; p = 0,037). Conclusiones Durante los episodios de descompensación los pacientes con ICFEr tienen mayor elevación de la PIA y un mayor grado de congestión sistémica (AU)

Background The increase in intraabdominal pressure (IAP) has been correlated with increased creatinine levels in patients with heart failure with severely reduced left ventricular ejection fraction (HFrEF). However, IAP has not been examined in more stable patients or those with heart failure with preserved ejection fraction (HFpEF). Patients and method We conducted an observational, prospective descriptive study that measured the IAP of patients hospitalised for decompensated heart failure (HF). The sample was stratified according to left ventricular ejection fraction (LVEF), with a cut-off of 50%. The objective was to analyse the IAP, the baseline characteristics and degree of congestion using clinical ultrasonography and impedance audiometry. Results The study included 56 patients, 22 with HFrEF and 34 with HFpEF. The patients with HFrEF presented a higher prevalence of ischaemic heart disease (11% vs. 6%; p = 0.010) and chronic obstructive pulmonary disease/asthma (6% vs. 2%; p = 0.025). The IAP was higher in the patients with HFrEF (17.2 vs. 13.3 mmHg; p = 0.004), with no differences in renal function at admission according to the LVEF (CKD-EPI creatinine) (HFrEF 55.0 mL/min/1.73 m2 [32.6-83.6] vs. HFpEF 55.0 mL/min/1.73 m2 [44.0-74.9]; p = 0.485). The patients with HFrEF presented a more congestive profile determined through ultrasonography (inferior vena cava collapse [26% vs. 50%; p = 0.001]), impedance audiometry (total body water at admission, 46 L vs. 41 L; p = 0.052; and at 72 h, 50.2 L vs. 39.1 L; p = 0.038) and CA125 concentration (68 U/mL vs. 39 U/mL; p = 0.037). Conclusions During the decompensation episodes, the patients with HFrEF had a greater increase in IAP and a higher degree of systemic congestion (AU)

Endothelial-Mesenchymal Transition in Heart Failure With a Preserved Ejection Fraction: Insights Into the Cardiorenal Syndrome.

BACKGROUND: The management of clinical heart failure with a preserved ejection fraction (HFpEF) is often complicated by concurrent renal dysfunction, known as the cardiorenal syndrome. This, combined with the notable lack of evidence-based therapies for HFpEF, highlights the importance of examining mechanisms and targetable pathways in HFpEF with the cardiorenal syndrome. METHODS: HFpEF was induced in mice by uninephrectomy, infusion of d-aldosterone (HFpEF; N=10) or saline (Sham; N=8), and given 1% NaCl drinking water for 4 weeks. Renal fibrosis and endothelial-mesenchymal transition (endo-MT) were evident once HFpEF developed. Human aortic endothelial cells were treated for 4 days with 10% serum obtained from patients with chronically stable HFpEF with the cardiorenal syndrome (N=12) and compared with serum-treated human aortic endothelial cells from control subjects (no cardiac/renal disease; N=12) to recapitulate the in vivo findings. RESULTS: Kidneys from HFpEF mice demonstrated hypertrophy, interstitial fibrosis (1.9-fold increase; P<0.05) with increased expression of endo-MT transcripts, including pdgfrß (platelet-derived growth factor receptor ß), snail, fibronectin, fsp1 (fibroblast-specific protein 1), and vimentin by 1.7- (P=0.004), 1.7- (P=0.05), 1.8- (P=0.005), 2.6- (P=0.001), and 2.0-fold (P=0.001) versus Sham. Immunostaining demonstrated co-localization of CD31 and ACTA2 (actin α2) in kidney sections suggesting evidence of endo-MT. Similar to the findings in HFpEF mice, comparable endo-MT markers were also significantly elevated in human aortic endothelial cells treated with serum from patients with HFpEF compared with human aortic endothelial cells treated with serum from control subjects. CONCLUSIONS: These translational findings demonstrate a plausible role for endo-MT in HFpEF with cardiorenal syndrome and may have therapeutic implications in drug development for patients with HFpEF and concomitant renal dysfunction.