Chronic Kidney Disease Heart Failure Research Articles

Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification.

Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed. In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events); secondary outcomes included 4-year HF (183 events), HF with reduced ejection fraction (137 events), and HF with preserved ejection fraction (165 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multi-protein risk models was compared to the PCP-HF risk score. Over 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10-5. After adjustment for covariates including N-terminal pro-B-type natriuretic peptide, 17 proteins remained associated at P < 1 × 10-5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C-statistic (95% confidence interval [CI]) for the 48-protein model in CRIC was 0.790 (0.735, 0.844) vs. 0.703 (0.644, 0.762) for the PCP-HF model (P = .001). C-statistic (95% CI) for the protein model in ARIC was 0.747 (0.707, 0.787). Large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population.

Cost-effectiveness analysis of sodium zirconium cyclosilicate for hyperkalemia among patients with chronic kidney disease or heart failure in Kuwait

Introduction Our model was conducted from Kuwaiti payer’s perspective to provide evidence on the cost-effectiveness of Sodium zirconium cyclosilicate (SZC) versus patiromer to correct and maintain serum potassium (K+) in combination with renin‐angiotensin‐aldosterone system inhibitors (RAASis) with different dose titration in patients with chronic kidney disease/heart failure (CKD/HF) with/without renal replacement therapy (RRT). Methodology The model was developed as a patient-level, fixed-time increment stochastic simulation to simulate the complexity of disease, including multiple coexisting and competing conditional risks. This model was established to compare SZC versus patiromer as a treatment for hyperkalemia (HK) among adult populations with underlying conditions of advanced CKD stages 3a–5 or HF to correct and maintain serum K + over a lifetime horizon. The clinical outcomes of SZC and patiromer were demonstrated through arm-specific K + trajectories extracted from the HARMONIZE trial and OPAL-HK trial, respectively. The utility data was captured from different studies. Direct medical cost was captured from local data from Kuwaiti hospitals. Sensitivity analyses were conducted to assess the uncertainty in the model. Results Within different scenarios of CKD/HF, SZC was a cost-saving option, with/without RRT, whether one-off administration or repeated administration, except for one-off treatment administration among the HF cohort, which generated an incremental cost effectiveness ratio of KWD 331/quality adjusted life year (QALY). The incremental QALY of SZC ranged from 0.007 to 0.202. In addition, the savings observed with SZC fall within a range of KWD −60 to KWD −1,235 at serum K+ ≥ 5.1 mmol/L. Conclusion The evidence generated by our model recommends the inclusion of SZC as a treatment option to correct HK and maintain normal serum K + level for CKD/HF patients within the Kuwaiti healthcare system. The costs saved from reducing frequent HK episodes, RAASis discontinuation/down titration, major cardiovascular events, and hospitalization offset the drug acquisition cost of SZC.

Heart Failure in Patients with Chronic Kidney Disease.

The function of the kidney is tightly linked to the function of the heart. Dysfunction/disease of the kidney may initiate, accentuate, or precipitate of the cardiac dysfunction/disease and vice versa, contributing to a negative spiral. Further, the reciprocal association between the heart and the kidney may occur on top of other entities, usually diabetes, hypertension, and atherosclerosis, simultaneously affecting the two organs. Chronic kidney disease (CKD) can influence cardiac function through altered hemodynamics and salt and water retention, leading to venous congestion and therefore, not surprisingly, to heart failure (HF). Management of HF in CKD is challenging due to several factors, including complex interplays between these two conditions, the effect of kidney dysfunction on the metabolism of HF medications, the effect of HF medications on kidney function, and the high risk for anemia and hyperkalemia. As a result, in most HF trials, patients with severe renal impairment (i.e., eGFR 30 mL/min/1.73 m2 or less) are excluded. The present review discusses the epidemiology, pathophysiology, and current medical management in patients with HF developing in the context of CKD.

Association of Urine Galectin-3 With Cardiorenal Outcomes in Patients With Heart Failure

Approaches to distinguishing pathological cardiorenal dysfunction in heart failure (HF) from functional/hemodynamically mediated changes in serum creatinine are needed. We investigated urine galectin-3 as a candidate biomarker of renal fibrosis and a prognostic indicator of cardiorenal dysfunction phenotypes. We measured urine galectin-3 in 2 contemporary HF cohorts: the Yale Transitional Care Clinic (YTCC) cohort (n = 132) and the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial (n = 434). We assessed the association of urine galectin-3 with all-cause mortality in both cohorts and the association with an established marker of renal tissue fibrosis, urinary amino-terminal propeptide of type III procollagen (PIIINP) in TOPCAT. In the YTCC cohort, there was significant effect modification between higher urine galectin-3 and lower estimated glomerular filtration rates (eGFRs) (Pinteraction = 0.046), such that low eGFR levels had minimal prognostic importance if urine galectin-3 levels were low, but they were important and indicated high risk if urine galectin-3 levels were high. Similar observations were noted in the TOPCAT study (Pinteraction = 0.002). In TOPCAT, urine galectin-3 also positively correlated with urine PIIINP at both baseline (r = 0.43; P < 0.001) and at 12 months (r = 0.42; P < 0.001). Urine galectin-3 levels correlated with an established biomarker of renal fibrosis in 2 cohorts and was able to differentiate high- vs low-risk phenotypes of chronic kidney disease in HF. These proof-of-concept results indicate that additional biomarker research to differentiate cardiorenal phenotypes is warranted.

Association Between Diabetes, Chronic Kidney Disease, and Outcomes in People With Heart Failure From Asia

BackgroundDiabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF) are pathophysiologically linked and increasing in prevalence in Asian populations, but little is known about the interplay of DM and CKD on outcomes in HF. ObjectivesThis study sought to investigate outcomes in patients with heart failure with preserved ejection fraction (HFpEF) vs heart failure with reduced ejection fraction (HFrEF) in relation to the presence of DM and CKD. MethodsUsing the multinational ASIAN-HF registry, we investigated associations between DM only, CKD only, and DM+CKD with: 1) composite of 1-year mortality or HF hospitalization; and 2) Kansas City Cardiomyopathy Questionnaire scores, according to HF subtype. ResultsIn 5,239 patients with HF (74.6% HFrEF, 25.4% HFpEF; mean age 63 years; 29.1% female), 1,107 (21.1%) had DM only, 1,087 (20.7%) had CKD only, and 1,400 (26.7%) had DM+CKD. Compared with patients without DM nor CKD, DM+CKD was associated with 1-year all-cause mortality or HF hospitalization in HFrEF (adjusted HR: 2.07; 95% CI: 1.68-2.55) and HFpEF (HR: 2.37; 95% CI: 1.40-4.02). In HFrEF, DM only and CKD only were associated with 1-year all-cause mortality or HF hospitalization (both HRs: 1.43; 95% CI: 1.14-1.80), while in HFpEF, CKD only (HR: 2.54; 95% CI: 1.46-4.41) but not DM only (HR: 1.01; 95% CI: 0.52-1.95) was associated with increased risk (interaction P < 0.01). Adjusted Kansas City Cardiomyopathy Questionnaire scores were lower in patients with DM+CKD (HFrEF: mean 60.50, SEM 0.77, HFpEF: mean 70.10, SEM 1.06; P < 0.001) than with no DM or CKD (HFrEF: mean 66.00, SEM 0.65; and HFpEF: mean 75.80, SEM 0.99). ConclusionsCombined DM and CKD adversely effected outcomes independently of HF subtype, with CKD a consistent predictor of worse outcomes. Strategies to prevent and treat DM and CKD in HF are urgently required.

Chronic kidney disease and risk of atrial fibrillation and heart failure in general population-based cohorts: the BiomarCaRE project.

AimsChronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. The aim of this study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. We also included an assessment of baseline biomarkers of inflammation, myocardial injury, and left ventricular dysfunction with risk of AF and HF, respectively, to shed light on the potential underlying pathophysiology.Methods and resultsThis study was conducted within the BiomarCaRE project using harmonized data from 12 European population‐based cohorts (n = 48 518 participants). Renal function was assessed by glomerular filtration rate estimated using the combined Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation with standardized serum creatinine (Cr) and non‐standardized serum cystatin C (CysC). Incidence of AF and HF respectively, during a median follow‐up of 8 years was recorded. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and the competing risk of mortality after adjustment for covariates. The mean age at baseline was 51.4 (standard deviation 12.1) years, 49% were men. Overall, 4.3% of subjects had CKD at baseline. The rate for AF was 3.8 per 1000 person‐years during follow‐up. The HR for AF in patients with CKD compared with patients without CKD was 1.28 (95% confidence interval 1.07–1.54) after adjustment for covariates. The rate for incident HF was 4.1 per 1000 person‐years and the HR of CKD for HF was 1.71 (95% confidence interval 1.45–2.01. In subjects with CKD, N‐terminal‐pro‐brain natriuretic peptide (NT‐proBNP) showed an association with AF, whereas NT‐proBNP and C‐reactive protein were associated with HF.ConclusionsChronic kidney disease is an independent risk factor for subsequent AF and is even more closely associated with HF. In these relatively young participants with CKD, NT‐proBNP was strongly associated with subsequent risk of AF. For HF, in addition, elevated levels of hs‐C‐reactive protein at baseline were related to incident events.

FC 064A RENAL-CARDIO INFLAMMATORY AXIS MEDIATES CARDIAC DYSFUNCTION IN CKD VIA IL-33-ST2: A NOVEL MECHANISM

Abstract Background and Aims We developed a swine model of chronic kidney disease (CKD) that also display cardiac abnormalities associated with heart failure (HF). Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with CKD. Interleukin (IL)-33 is a tissue-derived nuclear cytokine from the IL family. IL-33 constitutively expressed but upregulated and released after cellular damage or necrotic cell death, acting as a pro-inflammatory cytokine. We hypothesize that IL-33 plays a prominent mechanistic role in renal-cardio pathophysiology in CKD. Method We induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. We developed a renally-targeted biopolymer-fused peptide inhibitor of nuclear-factor kappa (NF-k)B (ELP-p50i) and show it blocks NFkB activity in vitro and in vivo. NF-kB is a key pro-inflammatory transcription factor upregulated in CKD and closely interacts with IL-33. Pigs were observed for 6 weeks, renal (multi-detector CT) and cardiac structure and function (echo) were quantified, then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later. Blood was collected to measure circulating TNF-α, IL-33 and its specific decoy receptor soluble (s) ST2 (ELISA). Heart weights were measured after euthanasia, and renal and cardiac expression of ST2 and morphometric analyses were performed. Results Loss of renal function in CKD was accompanied by increased heart weight, left ventricular (LV) hypertrophy, diastolic dysfunction, abnormal LV strain, renal/cardiac fibrosis, circulating TNF-α, IL-33 but unchanged sST2, and increased renal/cardiac ST2 expression. Most of these changes were improved after intra-renal ELP-p50i and accompanied by augmented sST2, suggesting that inhibition of renal inflammation can attenuate cardiac abnormalities via augmented clearance of IL-33 (Figure). Conclusion Our study supports a prominent role for renal inflammation as a driving force for precursors of HF in CKD, proposing a renal-cardio inflammatory axis possibly mediated by NF-kB-TNF-α-IL-33/ST2 interactions. TNF-α can stimulate IL-33 as IL33 can activate NF-kB and TNF-α, extending this inflammatory loop in both the kidney and heart. We show that a translational renal anti-inflammatory strategy via targeted inhibition of renal NFkB inhibits this axis and improves renal and cardiac function, which may guide to new treatments targeting renal inflammation in CKD.

Personalizing heart failure management in chronic kidney disease patients.

Chronic kidney disease (CKD) in heart failure (HF) patients is common, present in 49%, and is associated with a higher mortality hazard ratio [2.34 (95% confidence interval 2.20-2.50); P &lt; 0.001] and multiple hospital admissions. The management of HF in CKD can be challenging due to drug-induced electrolyte and creatinine changes, resistance to diuretics and infections related to device therapy. Evidence for improvement in mortality and HF hospitalizations exists in HF with reduced ejection fraction (HFrEF) in Stage 3 CKD patients from randomized controlled trials of angiotensin-converting enzyme inhibitor (ACEi) and mineralocorticoid receptor antagonist therapy but not in dialysis patients, where higher doses can cause hyperkalaemia. Evidence of improvement in cardiovascular death and HF hospitalizations has emerged with the angiotensin receptor neprilysin inhibitor ivabradine and more recently with sodium-glucose cotransporter inhibitors in HFrEF patients with CKD Stages 1-3. However, these studies have excluded CKD Stages 4 and 5 patients. Evidence for β-blocker therapy exists in CKD Stages 1-3 and separately in haemodialysis patients. Cardiac resynchronization therapy reduces HF hospitalizations and mortality in patients with CKD Stages 1-3 but has not been shown to do so in CKD Stages 4 and 5 or dialysis patients. Internal cardioverter and defibrillator therapy in HFrEF patients has been shown to be beneficial in CKD 3 patients but not in dialysis patients, where it is associated with high rates of infection. For HFpEF patients with CKD, therapy is symptomatic, as there is no proven therapy for improvement in survival or hospitalizations. HF patients with end-stage kidney disease with fluid overload may benefit from peritoneal dialysis. A multidisciplinary, personalized approach has been associated with better care and improved patient satisfaction.

Trends in the magnitude of chronic conditions in patients hospitalized with a first acute myocardial infarction.

Background:Among adults with heart disease, there is a high prevalence of concomitant chronic medical conditions. We studied patients with a first acute myocardial infarction to describe: sample population characteristics; trends of the most prevalent pairs of chronic conditions; and differences in hospital management according to burden of these morbidities.Methods and Results:Patients (n = 1,564) hospitalized with an incident AMI at the 3 major medical centers in central Massachusetts during 2005, 2011, and 2015 comprised the study population. Hospital medical records were reviewed to identify 11 more prevalent chronic conditions. The median age of this population was 68 years and 56% were men. The median number of previously diagnosed chronic conditions was 2. Patients hospitalized during 2015 were more likely to be younger than those hospitalized in the earliest study cohorts. The most common pairs of chronic conditions for those hospitalized in 2005 were: anemia-chronic kidney disease (31%), chronic kidney disease-heart failure (30%), and stroke-atrial fibrillation (27%). Among patients hospitalized during 2011, chronic kidney disease-heart failure (29%), hypertension-hyperlipidemia (27%), and hypertension-diabetes (27%) were the most common pairs whereas hypertension-hyperlipidemia (43%), diabetes-heart failure (30%), and chronic kidney disease-diabetes (23%) were the most frequent pairs recorded in 2015. There was a significant decrease in the odds of undergoing cardiac catheterization and a percutaneous coronary intervention in those with higher chronic disease burden in the most recent as compared to earliest study years.Conclusions:Our findings highlight the magnitude of chronic conditions in patients with AMI and the challenges of caring for this vulnerable population.

Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF, DAPA-CKD, and EMPA-KIDNEY.

In the past decade, many cardiovascular outcome trials (CVOT) on the efficacy and safety of glucose-lowering agents have been completed. Amongst newer agents available for treatment of type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter-2 (SGLT2) inhibitors have garnered much attention in contemporary clinical practice due to observed benefits on cardiovascular and kidney outcomes among patients with T2DM, as reported in large randomized controlled trials (RCT). These findings are reflected in the updated clinical guidelines of several major professional societies. Herein, we briefly review the mechanism of action of SGLT2 inhibitors and their pleiotropic effects, summarize key findings and limitations of initial CVOTs, then discuss three major kidney disease-focused outcome trials, including the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE) trial as well as two ongoing RCTs: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure-chronic kidney disease and EMPA-KIDNEY.

P3595Risk factors, comorbidities and early dynamic change in high-sensitive cardiac troponin T -The importance of initial troponin level at presentation

Abstract Background The one-hour troponin-algorithm is recommended together with a clinical evaluation for rule-in and rule-out of acute coronary syndrome (ACS) in the emergency department (ED). Since risk factors and many comorbidities are associated with small elevations of high-sensitive cardiac troponin T (hs-cTnT), their additive value for discrimination of ACS have been questioned. However, the importance of the initial troponin level for how risk factors and/or comorbidities associate with early dynamic change in hs-cTnT is poorly studied. Purpose To investigate the association between risk factors and early dynamic change of hs-cTnT among those with an elevated compared to non-elevated initial hs-cTnT. Methods This was a retrospective study among patients admitted to four urban emergency departments (ED) between 2014–2016 with the chief complaint of chest pain and with two clinical routine hs-cTnT measurements at presentation and at &gt;30–104 minutes later. Clinical data from the ED visit were cross-referenced to national registers retrieving information on diagnoses and treatments to identify: cardiovascular disease (CVD, defined as previous myocardial infarction, stroke or peripheral vascular disease), hypertension (HT), hyperlipidemia (HL), diabetes mellitus (DM), chronic kidney disease (CKD), Heart failure (CHF) and atrial fibrillation (AF). The association between risk factors and early dynamic change was studied separately for those with an elevated (&gt;14ng/L, dynamic change set as &gt;20%) and a non-elevated (≤14ng/L, dynamic change set as &gt;2ng/L) initial hs-cTnT. Results 9278 patients were identified. All risk factors and comorbidities were more common among those with an elevated hs-cTnT. Dynamic change was present in 236 (3.4%) of 7024 patients with an initial hs-cTnT ≤14ng/L and 307 (13.6%) of 2254 with an initial hs-cTnT &gt;14ng/L respectively. Among those with non-elevated initial hs-cTnT those with dynamic change were more likely to be older: age &gt;70 (odds ratio (OR); 95% CI: 1.5; 1.1–2.0), have CVD (1.7: 1.2–2.5), HT (1.4; 1.1–1.8), eGFR&lt;60 (1.8; 1.3–2.5) or AF (1.5; 1.0–2.4). Conversely, in patients with initial elevated hs-cTnT most conditions were negatively associated with early dynamic change: age &gt;70 (0.5; 0.4–0.6), CVD (0.5; 0.4–0.7), HT (0.6; 0.46–0.8), eGFR&lt;60 (0.4; 0.3–0.6), CHF (0.4; 0.3–0.5), AF (0.4; 0.3–0.6) and no risk factors were positively associated with dynamic change. Different cut-offs for dynamic change for instance &gt;4ng/L (at initial hs-cTnT &lt;14ng/L) and &gt;50% (initial &gt;14ng/L) were tested but did not affect the overall results. Fig 1. Forest plot dynamic hs-cTnT Conclusions Many risk factors and comorbidities show opposite associations with early dynamic change of hs-cTnT depending on the baseline concentration. The findings stress the importance of initial troponin level when assessing patients with risk factors presenting with ACS symptoms in the ED, however further investigations are needed to establish the definite dependency.

The Outcomes of Chronic Kidney Disease and Heart Failure with Reduced Ejection Fraction

IntroductionKidney disease and heart failure (HF) make a challenging duo. By sharing a neurohormonal interplay, these diseases are rarely seen in isolation. However, many of the pivotal HF trials excluded advanced kidney disease. This, combined with an apprehension to avoid some guideline-directed medical therapy (GDMT) for HF in chronic kidney disease (CKD), make cardiorenal management unclear and puzzling.MethodsA retrospective cohort study of 1,041 patients admitted from 2005-2014 with acute HF with reduced ejection fraction (HFrEF). Patients were divided into CKD and non-CKD groups. CKD included patients with stage III to ESRD. Non-CKD included normal function to stage II. We applied the primary outcomes of interest at 1 and 6 months, the length of hospital stay, readmission rates (RAR), and overall mortality.ResultsOut of the 1,041 HFrEF patients, 140 had CKD and 901 had non-CKD. Amongst the two groups, there was a difference in the medications. CKD patients were less likely to receive angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and digitalis, and more likely to receive torsemide than their counterparts. With readmissions, the CKD group had a higher 30-day RAR, with no difference in 6-month RAR or 1-yr RAR. Overall, there was no mortality difference between the two groups, in-hospital or mortality up to 180 days.ConclusionHFrEF patients with CKD are prescribed less GDMT for HF than non-CKD patients. There are consequences of this discrepancy and room for improvement to reduce HF RAR and improve quality of life. Kidney disease and heart failure (HF) make a challenging duo. By sharing a neurohormonal interplay, these diseases are rarely seen in isolation. However, many of the pivotal HF trials excluded advanced kidney disease. This, combined with an apprehension to avoid some guideline-directed medical therapy (GDMT) for HF in chronic kidney disease (CKD), make cardiorenal management unclear and puzzling. A retrospective cohort study of 1,041 patients admitted from 2005-2014 with acute HF with reduced ejection fraction (HFrEF). Patients were divided into CKD and non-CKD groups. CKD included patients with stage III to ESRD. Non-CKD included normal function to stage II. We applied the primary outcomes of interest at 1 and 6 months, the length of hospital stay, readmission rates (RAR), and overall mortality. Out of the 1,041 HFrEF patients, 140 had CKD and 901 had non-CKD. Amongst the two groups, there was a difference in the medications. CKD patients were less likely to receive angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and digitalis, and more likely to receive torsemide than their counterparts. With readmissions, the CKD group had a higher 30-day RAR, with no difference in 6-month RAR or 1-yr RAR. Overall, there was no mortality difference between the two groups, in-hospital or mortality up to 180 days. HFrEF patients with CKD are prescribed less GDMT for HF than non-CKD patients. There are consequences of this discrepancy and room for improvement to reduce HF RAR and improve quality of life.

The scope of a combined kidney failure-heart failure clinic

Chronic kidney disease in heart failure (CKD-HF) is common, with high mortality, poor quality of life (related to anaemia, fluid overload) and multiple clinical issues which require a multidisciplinary approach. The role of a combined nephrology-cardiology clinic to manage CKD-HF patients is not known, which this study investigates. This study examined the referral patterns, comorbidities, management issues and interventions in patients referred to a combined CKD-HF clinic in an inner-city tertiary care hospital. All data were collected as part of an audit for patients referred over …

Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction.

As the role of chronic kidney disease (CKD) in different types of heart failure (HF) is poorly understood, our aim was to compare CKD in HF with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF) with regard to prevalence, associations and prognostic role. Patients in the Swedish Heart Failure Registry were divided into three groups based on EF (≥50%, 40-49% and <40%). CKD was defined as an estimated glomerular filtration rate ≤60 mL/min.1.73 m2 . Associations between covariates and CKD and between CKD and mortality were assessed with multivariable regressions. Of 40 230 patients, 8875 (22%) had HFpEF, 8374 (21%) had HFmrEF, and 22 981 (57%) had HFrEF, with a CKD prevalence of 56%, 48%, and 45%, respectively. Associations between covariates and CKD were similar in all EF groups. One-year mortality with vs. without CKD was 23% vs. 13% in HFpEF, 22% vs. 8% in HFmrEF, and 23% vs. 8% in HFrEF (P < 0.001 for all). After adjustment, CKD was more strongly associated with death in HFrEF and HFmrEF than in HFpEF [hazard ratio (HR) and 95% confidence interval (CI); 1.49 (1.42-1.56) and 1.51 (1.40-1.63) vs. 1.32 (1.24-1.42); P for interaction <0.001]. In receiver operating characteristic (ROC) analyses, CKD was also a stronger predictor of death in HFrEF and HFmrEF than in HFpEF [area under the curve (AUC) 0.699 (0.689-0.709) and 0.700 (0.683-0.716) vs. 0.629 (0.613-0.645)]. CKD was associated with similar covariates regardless of EF. Although CKD was more common in HFpEF than in HFmrEF and HFrEF, it may have more of a 'bystander' role in HFpEF, being less associated with mortality and with lower prognostic discrimination.

Serum Bicarbonate and Structural and Functional Cardiac Abnormalities in Chronic Kidney Disease - A Report from the Chronic Renal Insufficiency Cohort Study

Background: Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. Methods: The association between serum bicarbonate and left ventricular (LV) hypertrophy (LVH), LV mass indexed to height^2.7, LV geometry, ejection fraction (EF) and diastolic dysfunction was assessed in 3,483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort study. Results: The mean estimated glomerular filtration rate was 42.5 ± 17 ml/min/1.73 m². The overall prevalence of LVH was 51.2%, with 57.8, 50.9 and 47.7% for bicarbonate categories <22, 22-26 and >26 mmol/l, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95% CI 1.07-1.64, and OR 1.57; 95% CI 1.14-2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR 1.07; 95% CI 0.66-1.72, and OR 1.27; 95% CI 0.64-2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up, no significant changes in LV mass or EF were observed in any bicarbonate strata. Conclusions: In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms.

Abstract 13240: Soluble Flt-1 Deficiency is One of the Mechanisms of Cardiac Hypertrophy and Heart Failure in CKD Through Up-regulation of MCP-1

Background: Uremic cardiomyopathy is responsible for high morbidity and mortality in patients with chronic kidney disease (CKD), which is characterized by cardiac hypertrophy and heart failure. But precise mechanisms are still unknown. In our previous data, soluble Flt-1 (sFlt-1), which is an endogenous inhibitor of PLGF (placental growth factor), is a key molecule of cardiovascular disease in CKD. Soluble Flt-1 production was decreased with the progression of renal diseases, and sFlt-1 deficiency resulted in progression of cardiac hypertrophy and heart failure, which was revealed by using sFlt-1 KO mice (sFlt-1 -/- ). In this study, we examined the novel mechanisms of heart failure and cardiac hypertrophy using sFlt-1 -/- mice which mimic the CKD condition. Methods and Results: We performed transverse aortic constriction (TAC) in sFlt-1 -/- and WT, and evaluated after 7 days. LV wall thickening was significantly increased and ejection fraction was decreased in sFlt-1 -/- compared to WT by echocardiography. Histological analysis showed that myocardial fibrosis and macrophage infiltration were significantly increased in sFlt-1 KO compared to WT. Anti-PLGF neutralizing antibody (αPLGF: ThromboGenics, Heverlee, Belgium) prevented pressure-overloaded cardiac hypertrophy and cardiac dysfunction after TAC in sFlt-1 -/- . In addition, MCP-1 expression was increased in the hearts of sFlt-1 -/- compared to WT after TAC. Echocardiographic analysis showed that inhibition of MCP-1 with neutralizing antibody prevented cardiac hypertrophy and systolic dysfunction in sFlt-1 -/- , which implied that MCP-1 was one of the key chemokines for the progression of heart failure in sFlt-1 deficiency. Human cardiac biopsy samples revealed that macrophage mobilization, fibrosis, and MCP-1 expression were increased in uremic cardiomyopathy, which was quite similar to sFlt-1 -/- . Conclusions: The present study demonstrated that PLGF activation in CKD by decrement of sFlt-1 induced macrophage activation and MCP-1 up-regulation which led to cardiac hypertrophy and heart failure. PLGF and MCP-1 are novel mechanisms and therapeutic target of cardiac hypertrophy and heart failure in CKD.

Soluble Flt-1 links microvascular disease with heart failure in CKD.

Chronic kidney disease (CKD) is associated with an increased risk of heart failure (HF). Elevated plasma concentrations of soluble Flt-1 (sFlt-1) have been linked to cardiovascular disease in CKD patients, but whether sFlt-1 contributes to HF in CKD is still unknown. To provide evidence that concludes a pathophysiological role of sFlt-1 in CKD-associated HF, we measured plasma sFlt-1 concentrations in 586 patients with angiographically documented coronary artery disease and renal function classified according to estimated glomerular filtration rate (eGFR). sFlt-1 concentrations correlated negatively with eGFR and were associated with signs of heart failure, based on New York Heart Association functional class and reduced left ventricular ejection fraction (LVEF), and early mortality. Additionally, rats treated with recombinant sFlt-1 showed a 15 % reduction in LVEF and a 29 % reduction in cardiac output compared with control rats. High sFlt-1 concentrations were associated with a 15 % reduction in heart capillary density (number of vessels/cardiomyocyte) and a 24 % reduction in myocardial blood volume. Electron microscopy and histological analysis revealed mitochondrial damage and interstitial fibrosis in the hearts of sFlt-1-treated, but not control rats. In 5/6-nephrectomised rats, an animal model of CKD, sFlt-1 antagonism with recombinant VEGF121 preserved heart microvasculature and significantly improved heart function. Overall, these findings suggest that a component of cardiovascular risk in CKD patients could be directly attributed to sFlt-1. Assessment of patients with CKD confirmed that sFlt-1 concentrations were inversely correlated with renal function, while studies in rats suggested that sFlt-1 may link microvascular disease with HF in CKD.

Arterial stiffness, central pressures, and incident hospitalized heart failure in the chronic renal insufficiency cohort study.

Chronic kidney disease is associated with an increased risk of heart failure (HF). We aimed to evaluate the role of large artery stiffness, brachial, and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multiethnic, multicenter prospective observational study of patients with chronic kidney disease. We studied 2602 participants who were free of HF at baseline. Carotid-femoral pulse wave velocity (CF-PWV; the gold standard index of large artery stiffness), brachial, and central pressures (estimated via radial tonometry and a generalized transfer function) were assessed at baseline. Participants were prospectively followed up to assess the development of new-onset hospitalized HF. During 3.5 years of follow-up, 154 participants had a first hospital admission for HF. CF-PWV was a significant independent predictor of incident hospitalized HF. When compared with the lowest tertile, the hazard ratios among subjects in the middle and top CF-PWV tertiles were 2.33 (95% confidence interval, 1.37-3.97; P=0.002) and 5.24 (95% confidence interval, 3.22-8.53; P<0.0001), respectively. After adjustment for multiple confounders, the hazard ratios for the middle and top CF-PWV tertiles were 1.95 (95% confidence interval, 0.92-4.13; P=0.079) and 3.01 (95% confidence interval, 1.45-6.26; P=0.003), respectively. Brachial systolic and pulse pressure were also independently associated with incident hospitalized HF, whereas central pressures were less consistently associated with this end point. The association between CF-PWV and incident HF persisted after adjustment for systolic blood pressure. Large artery stiffness is an independent predictor of incident HF in chronic kidney disease, an association with strong biological plausibility given the known effects of large artery stiffening of left ventricular pulsatile load.

Heart failure in patients with chronic kidney disease: a systematic integrative review.

Introduction. Heart failure (HF) is highly prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and is strongly associated with mortality in these patients. However, the treatment of HF in this population is largely unclear. Study Design. We conducted a systematic integrative review of the literature to assess the current evidence of HF treatment in CKD patients, searching electronic databases in April 2014. Synthesis used narrative methods. Setting and Population. We focused on adults with a primary diagnosis of CKD and HF. Selection Criteria for Studies. We included studies of any design, quantitative or qualitative. Interventions. HF treatment was defined as any formal means taken to improve the symptoms of HF and/or the heart structure and function abnormalities. Outcomes. Measures of all kinds were considered of interest. Results. Of 1,439 results returned by database searches, 79 articles met inclusion criteria. A further 23 relevant articles were identified by hand searching. Conclusions. Control of fluid overload, the use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and optimization of dialysis appear to be the most important methods to treat HF in CKD and ESRD patients. Aldosterone antagonists and digitalis glycosides may additionally be considered; however, their use is associated with significant risks. The role of anemia correction, control of CKD-mineral and bone disorder, and cardiac resynchronization therapy are also discussed.