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Background Previously we found that cardiac chambers' volumes correlate with estimated glomerular filtration rate (eGFR) of hospitalized patients. Currently we aimed to demonstrate this relation among apparently healthy individuals. Methods Ambulatory participants who underwent electrocardiography-gated cardiac computed tomography angiography (CCTA) were included. Subjects with an eGFR Results The cohort consisted of 89 apparently healthy individuals, mostly of male gender (70%), with a mean age of 51 years and a mean eGFR of 79.5 ml/min/1.73m2. A low calcium score (≤10HU) was found in 67.4%(n = 60) of the cohort. After adjustment for baseline characteristics, renal function was associated exclusively with the volume of the left atrium (LA; b-coefficient-0.15, 95%CI -0.3- -0.01, p = .041). A 15.9% (95%CI 0.3–33.9%, p = .045) increase in LA volume index (LAVI) was found among participants with eGFR of 80–90 when compared to those with eGFR>90 ml/min/1.73m2. Participants with a low calcium score showed an increase in LAVI only when eGFR was reduced from normal (>90 ml/min/1.73m2) to 70-80 ml/min/1.73m2 (and not to 80-90 ml/min/1.73m2), revealing a percentage increase of 24.7% (95%CI 5.5–47.4%, p = .011). Conclusions Renal function is closely related to LA volume even in the absence of overt renal failure, demonstrating that minor changes in eGFR instigate an increase in volumes. Risk factors for this interaction should be identified and treated prior to the development of cardio-renal syndrome.

Background Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS. Methods Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis. Results G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation. Conclusion Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.

AIMS Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. METHODS AND RESULTS A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CONCLUSIONS CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial.

Heart failure and cardiovascular death are common in patients with chronic kidney disease (CKD) and extremely prevalent in patients undergoing dialysis. It has been shown that the excess of cardiovascular mortality in this patient population is not fully accounted for by the traditional cardiovascular risk factors. Substantial evidence exists for the presence of sympathetic over-activity in patients with dialytic and non-dialytic CKD. Several studies have also been reported on reversible segmental left ventricular wall motion abnormality consistent with myocardial stunning in association with dialysis especially hemodialysis. In the literature, the most acceptable underpinning hypothesis for the myocardial stunning in CKD is "demand myocardial ischemia". However, the occurrence of cardiac sympathetic over-activation-disruption and repeated reversible myocardial stunning in patients with CKD can be compared to that occurring in acute Takotsubo syndrome where local cardiac sympathetic disruption may cause acute regional circumferential pattern of myocardial stunning. In this manuscript, converging evidences suggestive for the fact that acute, repetitive, and chronic TS may be one of the important causes of cardiac morbidity including myocardial stunning and heart failure and mortality in patients with CKD are provided.

We investigated the effects of human amniotic fluid stem cells (hAFS) and rat adipose tissue stromal vascular fraction GFP-positive cells (rSVC-GFP) in a model of cardio-renal syndrome type II (CRSII).RHF was induced by monocrotaline (MCT) in 28 Sprague-Dawley rats. Three weeks later, four million hAFS or rSVC-GFP cells were injected via tail vein. BNP, sCreatinine, kidney and heart NGAL and MMP9, sCytokines, kidney and heart apoptosis and cells (Cs) engraftment were evaluated. Cell-treated rats showed a significant reduction of serum NGAL and Creatinine compared to CRSII. In both hAFS and rSVC-GFP group, kidney protein expression of NGAL was significantly lower than in CRSII (hAFS p = 0.036 and rSVC-GFP p 0.0001) and similar to that of controls. In both hAFS and rSVC-GFP treated rats, we observed cell engraftment in the medulla and differentiation into tubular, endothelial and SMCs cells. Apoptosis was significantly decreased in cell-treated rats (hAFS 14.07 ± 1.38 and rSVC-GFP 12.67 ± 2.96 cells/mmCell therapy produced improvement in kidney function in rats with CRSII. This was the result of interstitial, vessel and tubular cell engraftment leading to tubular and vessel regeneration, decreased tubular cells apoptosis and mitigated pro-inflammatory milieu. Reduction of NGLA-MMP9 complexes mainly due to decrease MMPs activity prevented further negative heart remodeling.

Female gender, post-menopause, chronic kidney disease (CKD) and (CKD linked) microvascular disease are important risk factors for developing heart failure with preserved ejection fraction (HFpEF). Enhancing our understanding of the interrelation between these risk factors could greatly benefit the identification of new drug targets for future therapy. This review discusses the evidence for the protective role of estradiol (E2) in CKD-associated microvascular disease and related HFpEF. Elevated circulating levels of uremic toxins (UTs) during CKD may act in synergy with hormonal changes during post-menopause and could lead to coronary microvascular endothelial dysfunction in HFpEF. To elucidate the molecular mechanism involved, published transcriptome datasets of indoxyl sulfate (IS), high inorganic phosphate (HP) or E2 treated human derived endothelial cells from the NCBI Gene Expression Omnibus database were analyzed. In total, 36 genes overlapped in both IS- and HP-activated gene sets, 188 genes were increased by UTs (HP and/or IS) and decreased by E2, and 572 genes were decreased by UTs and increased by E2. Based on a comprehensive in silico analysis and literature studies of collected gene sets, we conclude that CKD-accumulated UTs could negatively impact renal and cardiac endothelial homeostasis by triggering extensive inflammatory responses and initiating dysregulation of angiogenesis. E2 may protect (myo)endothelium by inhibiting UTs-induced inflammation and ameliorating UTs-related uremic bleeding and thrombotic diathesis via restored coagulation capacity and hemostasis in injured vessels.

Background Cardio-renal anemia syndrome (CRAS) has begun to gather attention as a vicious circle since chronic heart failure (CHF), chronic kidney disease (CKD), and anemia are all able to be caused and exacerbated by each other. However, it remains unclear whether renal tubular damage (RTD), another type of kidney dysfunction, is associated with this vicious circle. The aim of the present study was to assess the association of RTD with CRAS in patients with CHF. Methods and results We included 300 consecutive patients with CHF. RTD was defined as a urinary β 2 -microglobulin to creatinine ratio ≥300μg/g. Patients with RTD had lower serum iron and higher levels of high sensitivity C-reactive protein than those without it. Multivariate logistic analysis showed that RTD was closely associated with anemia in patients with CHF, after adjustment for confounding factors. During a median period of 1098days, there were 86 cardiac events, including 14 cardiac deaths and 72 re-hospitalizations for worsening heart failure. Net reclassification improvement was significantly improved by addition of RTD to the model including age, New York Heart Association functional class, brain natriuretic peptide, anemia, and CKD. All patients were divided into 3 groups: CRAS+RTD group, CRAS group, and control group. Kaplan–Meier analysis demonstrated that CRAS+RTD had the greatest risk in patients with CHF. Conclusions RTD was associated with normocytic anemia, accompanying iron deficiency and inflammation. RTD added prognostic information to conventional CRAS, suggesting the importance of RTD in cardio-renal anemia interaction.

International audience; BACKGROUND: We sought to assess whether cardiorenal anemia syndrome (CRAS) in chronic heart failure (CHF) patients contributes to sympathetic overactivity through modulation of sympathetic reflexes. METHODS AND RESULTS: We prospectively studied 15 patients with CRAS and CHF and 15 control CHF patients, matched for age, gender distribution, type of cardiomyopathy, left ventricular ejection fraction (LVEF) and BMI. We compared muscle sympathetic nerve activity (MSNA) and the effect of peripheral chemoreflex deactivation on MSNA in both groups. We also compared sympathetic baroreflex function, assessed by the slope of the relationship between MSNA and diastolic blood pressure in both groups and while peripheral chemoreflexes were (by breathing 100% oxygen for 15min) or not deactivated. Baseline MSNA was significantly elevated in CHF patients with CRAS compared with control CHF patients (83.1±4.6 versus 64.9±2.9bursts/100 heart beats; P

The interactions between the heart and kidneys are known as cardiorenal syndrome (CRS) [1], which can easily occur in heart failure patients. The occurrence of CRS is an independent risk factor for poor prognosis in either acute or chronic heart failure. Moreover, patients with hypertrophic cardiomyopathy (HCM) are at high risk of heart failure, most of whom progress to heart failure with preserved left ventricular ejection fraction. However, no study has examined the characteristics and related factors of renal function changes in patients with HCM. This study presents a retrospective analysis of patients whowere diagnosed with HCM by echocardiography in the Zhongshan Hospital of Fudan University, Shanghai, China [2]. The patients underwent at least two renal function examinations at least 12months apart. The exclusion criteria consisted of a baseline epidermal glomerular filtration rate b60 ml/kg/min (according to theMDRD formula); patients N70 or b35 years old; surgical treatment (cardiac or non-cardiac surgery) after a baseline echocardiogram examination and renal function test; and chronic nephritis detected by renal biopsy. CRS was defined as an elevation of at least 44.2 mg/dl or 25% of the serum creatinine (SCr) value from baseline [3]. Basic clinical data were obtained from electronic medical records of the patients, including age, sex, smoking history, hypertension, history of diabetes, and dyslipidemia. The indices for the liver and renal

Cardiorenal syndrome (CRS) is defined as an interaction of cardiac disease with renal dysfunction that leads to diuretic resistance and renal function worsening, mainly with heart failure (HF) exacerbation. Hemodynamic variables linking heart and kidney are renal blood flow (cardiac output) and perfusion pressure, i.e., the aortic - renal venous pressure gradient. CRS has traditionally been interpreted as related to defective renal perfusion and arterial underfilling and, more recently, to elevation in central venous pressure transmitted back to renal veins. Our suggestion is that in a setting where aortic pressure is generally low, due to heart dysfunction and to vasodrepressive therapy, the elevated central venous pressure (CVP) contributes to lower the renal perfusion pressure below the threshold of kidney autoregulation (≤80mm Hg) and causes renal perfusion to become directly pressure dependent. This condition is associated with high neurohumoral activation and preglomerular vasoconstriction that may preserve pressure, but may decrease filtration fraction and glomerular filtration rate and enhance proximal tubular sodium absorption. Thus, congestion worsens and drives the vicious cycle of further sodium retention and HF exacerbation. Lowering CVP by targeting the lung-right heart interaction that sustains elevated CVP seems to be a more rational approach rather than reducing intravascular volume. This interaction is crucial and consists of a cascade with stepwise development of pulmonary post-capillary hypertension, precapillary arteriolar hypertone, right ventricular overload and enlargement with tricuspid incompetence and interference with left ventricular filling (interdependence). The resultant CVP rise is transmitted to the renal veins, eventually drives CRS and leads to a positive feedback loop evolving towards HF refractoriness.

To further understand the pathophysiology of concomitant cardiac and renal dysfunction, we investigated molecular, structural and functional changes in heart and kidney that occur when a kidney insult (5/6 nephrectomy-STNx) follows myocardial infarction (MI).Male Sprague Dawley rats (n=43) were randomized into four groups: Sham-operated MI+Sham-operated STNx (Sham+Sham), MI+Sham-operated STNx (MI+Sham), Sham-operated MI+STNx (Sham+STNx) and MI+STNx. MI/Sham surgery was followed by STNx/Sham surgery 4 weeks later. Cardiac and renal function was assessed prior to STNx/Sham surgery and again 10 weeks later. Hemodynamic parameters were measured prior to sacrifice.Compared to the MI+Sham group, STNx further accelerated the reduction in left ventricular (LV) ejection fraction by 21% (p0.01), and increased tau logistic by 38% (p0.01) in MI+STNx animals. Heart weight/body weight (BW) and lung weight/BW ratios were 39% (p0.001) and 16% (p0.01) greater in MI+STNx compared to MI+Sham animals. Similarly, myocyte cross-sectional area (p0.001), cardiac interstitial fibrosis (p0.01) and collagen I (p0.01) were increased in the LV non-infarct zone of the myocardium in the MI+STNx group. These changes were associated with significant increases in atrial natriuretic peptide (p0.001), transforming growth factor β1 (p0.05) and collagen I (p0.05) gene expression in MI+STNx animals. In comparison with the Sham+STNx group, renal tubulointerstitial fibrosis was increased by 64% in MI+STNx animals (p0.001), with no further deterioration in renal function.STNx accelerated cardiac changes post-MI whilst MI accelerated STNx-induced renal fibrosis, supporting bidirectional interactions in cardiorenal syndrome (CRS). This animal model may be of use in assessing the impact of therapies to treat CRS.

Anemia is common in cardio-renal syndrome and may contribute to increase mortality.To examine the prevalence of anemia and its relationship with cardio-renal syndrome, and to evaluate the risk factors for death.Retrospective study with all patients admitted with congestive heart failure (CHF). The parameters as age, gender, hemoglobin (Hb), estimated glomerular filtration rate (eGFR), New York Heart Association (NYHA) functional class, ejection fraction (EF%), hospital stay, hypertension, diabetes, smoking and CHF etiology were analyzed. Anemia was defined as Hb12 g/dL, systolic dysfunction EF55% and renal failure was stratified according to K-DOQI classification. Statistical analysis was done by the programs EpiInfo and SPSS for windows.A total of 174 patients were studied. The average age was 63+/-16 years, 65.5% were males, and 18 of them (11%) were non-survivors. Anemia was observed in 45% of patients, and 82% presented some degree of renal failure. The majority of patients (87%) were classified as NYHA functional class III or IV. The average ejection fraction was 43.9+/-16.6%, and there was no difference between survivors and non-survivors (p0.05). Mortality was not significantly higher among patients with anemia (12.4%) when comparing to those without anemia (8.3%, p=0.31). There was a progressive decrease in the level of hemoglobin as renal function decreased (p0.05). Increased serum creatinine was a significant risk factor for death (OR=1.59, 95% CI=1.074-2.363, p=0.021), and increased EF% was a protection factor against development of death (OR=0.904, 95% CI=0.845-0.973, p=0.007).The prevalence of anemia is high among patients with cardio-renal syndrome but was not associated with increased mortality. Increased serum creatinine and low EF% were variables associated with death.

Despite growing recognition of the frequent presentation of cardio-renal syndrome, its underlying pathophysiology is not well understood, and no consensus as to its appropriate management has been achieved. On the other hand, there is growing evidence that the presence of anemia can worsen cardiac function and symtomps in patients with congestive heart failure (CHF) and that correction of anemia may beneficial. We believe that the treatment modalities, especially eryhtropoietin, to correct anemia will be an important part of our therapeutic armemanterium in the battle against CHF.