Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction

Background: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). Methods: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 mL·min –1 ·1.73 m – 2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33–0.77]; P =0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min –1 ·1.73 m –2 ( P -interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (–2.0 [95% CI, –2.2 to –1.9] versus –2.7 [95% CI, –2.8 to –2.5] mL·min –1 ·1.73 m –2 per year). Conclusions: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

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Prevalence and Prognostic Significance of Chronic Kidney Disease in Patients with Heart Failure and Preserved Ejection Fraction in Australia

Heart Lung and Circulation ◽

10.1016/j.hlc.2019.06.123 ◽

2019 ◽

Vol 28 ◽

pp. S187

Author(s):

L. Kearney ◽

S. Kim ◽

K. Lu ◽

J. McGillion ◽

M. Duong ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Ejection Fraction ◽

Prognostic Significance ◽

Preserved Ejection Fraction ◽

Patients With Heart Failure

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Association between use of beta-blockers and mortality/morbidity in patients with heart failure with reduced, midrange or preserved ejection fraction and advanced chronic kidney disease

European Heart Journal ◽

10.1093/ehjci/ehaa946.1045 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Fu ◽

A Uijl ◽

F.W Dekker ◽

L.H Lund ◽

G Savarese ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Ejection Fraction ◽

Beta Blocker ◽

Beta Blockers ◽

Preserved Ejection Fraction ◽

Advanced Chronic Kidney Disease ◽

Patients With Heart Failure ◽

All Cause Mortality

Abstract Background Beta-blockers reduce mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, patients with advanced chronic kidney disease (CKD) were underrepresented in landmark trials. Purpose We evaluated if beta-blockers are associated with improved survival and cardiovascular outcomes in patients with HFrEF and advanced CKD, and if potential benefits of beta-blockers would extend also to HFpEF and HFmrEF with advanced CKD. Methods We identified 3906 persons with an ejection fraction <40% and advanced CKD (eGFR <30 mL/min/1.73m2) enrolled in the Swedish Heart Failure Registry during 2001–2016. We did not exclude patients with atrial fibrillation. The associations between beta-blocker use, 5-year all-cause mortality, and the composite of time to cardiovascular (CV) mortality/first HF hospitalization were assessed by multivariable Cox regression. Analyses were adjusted for 36 variables, including demographics, laboratory measures, comorbidities, medication use, medical procedures, and socioeconomic status. To assess consistency, the same analyses were performed in a positive control cohort of 12,673 patients with moderate CKD (eGFR <60–30 mL/min/1.73m2). Analyses were repeated in individuals with HF with preserved ejection fraction (HFpEF; EF ≥50%) or midrange ejection fraction (HFmrEF; EF 40–49%). Results In HFrEF and advanced CKD, 89% received beta-blockers. Overall, median (IQR) age was 81 (74–86) years, 36% were women and median eGFR was 26 (20–28) ml/min/1.73m2. During a median of 1.3 years follow-up, 2086 (53.4%) individuals had a subsequent HF hospitalization, and 2954 (75.6%) individuals died, of which 2089 (70.1%) due to cardiovascular causes. Beta-blocker use was associated with a significant reduction in 5-year all-cause mortality [adjusted hazard ratio (HR) 0.86; 95% confidence interval (CI) 0.76–0.96)] and CV mortality/HF hospitalization (HR 0.87; 95% CI 0.77–0.98). The magnitude of the associations between beta-blocker use and outcomes was similar to that observed for HFrEF patients with mild/moderate CKD [all-cause mortality: 0.85 (95% CI 0.78–0.91); CV mortality/HF hospitalization: 0.88 (95% CI 0.82–0.96)]. Adjusted HRs were 0.88 (95% CI 0.77–1.02) and 1.07 (95% CI 0.92–1.24) for individuals with HFpEF and advanced CKD and 0.95 (95% CI 0.80–1.13) and 1.13 (95% CI 0.94–1.36) for individuals with HFmrEF and advanced CKD, for all-cause mortality and CV mortality/HF hospitalization, respectively. Conclusion Despite lack of trial evidence, the use of beta-blockers in patients with HFrEF and advanced CKD was high in routine Swedish care, and was independently associated with reduced mortality to the same degree as HFrEF with moderate CKD. However, these benefits were not observed in patients with HFpEF or HFmrEF with severe CKD. Funding Acknowledgement Type of funding source: None

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Chronic Kidney Disease and Heart Failure With Preserved Ejection Fraction: The Role of Mitochondrial Dysfunction

Case Medical Research ◽

10.31525/ct1-nct03960073 ◽

2019 ◽

Author(s):

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Ejection Fraction ◽

Mitochondrial Dysfunction ◽

Preserved Ejection Fraction

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Abstract 14922: Prognostic Value of Baseline BNP and NT-ProBNP and its Interaction With Spironolactone in Patients With Heart Failure and Preserved Ejection Fraction in the TOPCAT Trial

Circulation ◽

10.1161/circ.132.suppl_3.14922 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Inder S Anand ◽

Scott D Solomon ◽

Brian Claggett ◽

Sanjiv J Shah ◽

Eileen O’Meara ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Primary Outcome ◽

Cox Regression ◽

Selection Criterion ◽

Adverse Outcomes ◽

Preserved Ejection Fraction ◽

Patient Selection Criterion ◽

Increased Risk ◽

Patients With Heart Failure

Background: Plasma natriuretic peptides (NP) are helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) and predict adverse outcomes. Levels of NP beyond a certain cut-off level are often used as inclusion criteria in clinical trials to ensure that the patients have HF, and to select patients at higher risk. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. In the I-Preserve trial a benefit of irbesartan on all outcomes was only seen in HFpEF patients with low but not high NP levels. We hypothesized that in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, spironolactone might have a greater benefit in patients with lower NP levels. Methods and Results: BNP (n=468) or NT-proBNP (n=400) levels were available at baseline in 868 patients with HFpEF enrolled in the natriuretic peptide stratum (BNP ≥100 pg/mL or an NT- proBNP ≥360 pg/mL) of the TOPCAT trial. In a multi-variable Cox regression model, that included age, gender, region (Americas vs. Russia/Georgia), atrial fibrillation, diabetes, eGFR, BMI and heart rate, higher BNP or NT-proBNP as a continuous, standardized log-transformed variable or grouped by terciles (see Figure for BNP & NT-proBNP tercile values) was independently associated with an increased risk of the primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for heart failure (Figure-1). There was a significant interaction between the effect of spironolactone and baseline BNP or NT-proBNP terciles for the primary outcome (P=0.02, Figure-2), with greater benefit of the drug in the lower compared to higher NP terciles. Conclusions: The benefit of spironolactone in lower risk HFpEF patients may indicate effects of the drug on early, but not late higher-risk stage of the disease. These findings question the strategy of using elevated NP as a patient selection criterion in HFpEF trials.

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Clinical Significance of Mean and Pulse Pressure in Patients With Heart Failure With Preserved Ejection Fraction

Hypertension ◽

10.1161/hypertensionaha.121.17782 ◽

2021 ◽

Author(s):

Fang-Fei Wei ◽

Yuzhong Wu ◽

Ruicong Xue ◽

Xiao Liu ◽

Xin He ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Pulse Pressure ◽

Total Mortality ◽

Posterior Wall ◽

Left Ventricular ◽

Adverse Outcomes ◽

Sensitivity Analyses ◽

Preserved Ejection Fraction ◽

Patients With Heart Failure

It remains debated whether pulse pressure is associated with left ventricular traits and adverse outcomes over and beyond mean arterial pressure (MAP) in patients with heart failure (HF) with preserved ejection fraction. We investigated these associations in 3428 patients with HF with preserved ejection fraction (51.5% women; mean age, 68.6 years) enrolled in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). We computed association sizes and hazards ratios with 1-SD increase in MAP and pulse pressure. In multivariable-adjusted analyses, association sizes ( P ≤0.039) for MAP were 0.016 cm and 0.014 cm for septal and posterior wall thickness, −0.15 for E/A ratio, −0.66 for E/e′, and −0.64% for ejection fraction, independent of pulse pressure. With adjustment additionally applied for MAP, E/A ratio and longitudinal strain increased with higher pulse pressure with association sizes amounting to 0.067 ( P =0.026) and 0.40% ( P =0.023). In multivariable-adjusted analyses of both placebo and spironolactone groups, lower MAP and higher pulse pressure predicted the primary composite end point ( P ≤0.028) and hospitalized HF ( P ≤0.002), whereas MAP was also significantly associated with total mortality ( P ≤0.007). Sensitivity analyses stratified by sex, median age, and region generated confirmatory results with exception for the association of adverse outcomes with pulse pressure in patients with age ≥69 years. In conclusion, the clinical application of MAP and pulse pressure may refine risk estimates in patients with HF with preserved ejection fraction. This finding may help further investigation for the development of HF with preserved ejection fraction preventive strategies targeting pulsatility and blood pressure control.

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Abstract 471: Combination of Allogeneic Mesenchymal and Kidney Stem Cells Ameliorates Chronic Kidney Disease Induced Heart Failure With Preserved Ejection Fraction

Circulation Research ◽

10.1161/res.127.suppl_1.471 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Angela C Castellanos ◽

Bryon A Tompkins ◽

Makoto Natsumeda ◽

Victoria Florea ◽

Monisha Banerjee ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Stem Cells ◽

Stem Cell ◽

Kidney Disease ◽

Ejection Fraction ◽

Cell Therapy ◽

Renal Artery ◽

Preserved Ejection Fraction ◽

Kidney Stem Cells

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition involving multiple comorbidities. Phenotypic classification of HFpEF associated with chronic kidney disease (CKD) manifests worse outcomes, compared to other HFpEF phenotypes. Few treatments improve morbidity and mortality in HFpEF. Stem cell therapy promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that allogeneic stem cell treatment ameliorates HFpEF in a large animal model of CKD. Methods: Yorkshire pigs (n=26) underwent 5/6 embolization-mediated nephrectomy and 4-weeks later received either: allogeneic mesenchymal stem cells (MSCs) (10х10 6 ), Kidney stem cells (KSC; 10х10 6 ), combination (ACCT; MSC+KSC; 1:1 ratio [5х10 6 each]), or placebo (n=6-7/ group). Cell therapy was delivered via the patent renal artery of the remnant kidney. RNAsec analysis compared placebo and ACCT groups. Results: Mean arterial pressure increased significantly in the placebo- (21.89±6.05 mmHg, p<0.0001) compared to the ACCT-group (p=0.04) at 12 weeks. Glomerular filtration rate improved significantly in the ACCT group (p=0.002). RNAseq analysis revealed a significant decrease in genes normally increased during kidney transplant rejection (q<10 -6 , NES = -2.32) in ACCT. Consistent with these results, there was a downregulation of canonical drivers of tubular damage and regeneration, including SOX9 (-2.39 fold, p=0.0004) and apoptosis of kidney cell types (-24.89 fold, p=0.004), including podocytes (-2.065 fold, p=0.04) with ACCT. ACCT administration also downregulated genes related to oxidative stress (-4.6 fold, p<0.0001), fibrosis, inflammatory response (-4.760 fold, p=<0.05), and renin-angiotensin signaling (-3.162 fold, p=0.024), which are related to cardiac hypertrophy pathways (-7.23, fold, p<0.0001). EDPVR improved in with ACCT (p=0.003), indicating decreased ventricular stiffness. Ejection fraction, relative wall thickness, and left ventricular mass did not differ between groups at 12 weeks. Conclusion: Intra-renal artery allogeneic cell therapy was safe. Beneficial effects were observed in the ACCT and MSC groups in the kidney and heart. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

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SO057BETA-BLOCKERS ARE ASSOCIATED WITH REDUCED MORTALITY IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION AND ADVANCED CHRONIC KIDNEY DISEASE: COHORT STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa139.so057 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Edouard L Fu ◽

Alicia Uijl ◽

Friedo W Dekker ◽

Lars H Lund ◽

Gianluigi Savarese ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Ejection Fraction ◽

Beta Blocker ◽

Beta Blockers ◽

Advanced Chronic Kidney Disease ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure ◽

All Cause Mortality

Abstract Background and Aims Beta-blockers reduce mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, patients with advanced chronic kidney disease (CKD) were underrepresented in landmark trials. We evaluated if beta-blockers are associated with improved survival in patients with HFrEF and advanced CKD. Method We identified 3906 persons with an ejection fraction <40% and advanced CKD (eGFR <30 mL/min/1.73m2) enrolled in the Swedish Heart Failure Registry during 2001-2016. The associations between beta-blocker use, 5-year all-cause mortality, and the composite of time to cardiovascular (CV) mortality/first HF hospitalization were assessed by multivariable Cox regression. Analyses were adjusted for 36 variables, including demographics, laboratory measures, comorbidities, medication use, medical procedures, and socioeconomic status. To assess consistency, the same analyses were performed in a positive control cohort of 12,673 patients with moderate CKD (eGFR <60-30 mL/min/1.73m2). Results The majority (89%) of individuals with HFrEF and advanced CKD received treatment with beta-blockers. Median (IQR) age was 81 (74-86) years, 36% were women and median eGFR was 26 (20-28) mL/min/173m2. During 5 years of follow-up, 2086 (53.4%) individuals had a subsequent HF hospitalization, and 2954 (75.6%) individuals died, of which 2089 (70.1%) due to cardiovascular causes. Beta-blocker use was associated with a significant reduction in 5-year all-cause mortality [adjusted hazard ratio (HR) 0.86; 95% confidence interval (CI) 0.76-0.96)] and CV mortality/HF hospitalization (HR 0.87; 95% CI 0.77-0.98). The magnitude of the associations between beta-blocker use and outcomes was similar to that observed for HFrEF patients with mild/moderate CKD, with adjusted HRs for all-cause mortality and CV mortality/HF hospitalization of 0.85 (95% CI 0.78-0.91) and 0.88 (95% CI 0.82-0.96), respectively. Conclusion Despite lack of trial evidence, the use of beta-blockers in patients with HFrEF and advanced CKD was high in routine Swedish care, and was independently associated with reduced mortality to the same degree as HFrEF with moderate CKD.

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The impact of frailty and aging on prognosis in patients with heart failure with preserved ejection fraction – insights from PURSUIT-HFpEF registry

European Heart Journal ◽

10.1093/ehjci/ehaa946.0961 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Okada ◽

K Inoue ◽

T Onishi ◽

K Iwakura ◽

T Yamada ◽

...

Keyword(s):

Heart Failure ◽

Confidence Interval ◽

Ejection Fraction ◽

Hazard Ratio ◽

Adverse Outcomes ◽

Funding Source ◽

Preserved Ejection Fraction ◽

Clinical Endpoint ◽

Patients With Heart Failure

Abstract Introduction Frailty and aging are two common conditions both associated with increased vulnerability to stressful events with high risk of adverse outcomes. Purpose To evaluate the association between frailty and aging and their impacts on clinical outcome in patients with heart failure with preserved ejection fraction (HFpEF). Methods Analysis was performed from a prospective multicenter observational registry for HFpEF (PURSUIT-HFpEF Registry) conducted in the Osaka region of Japan. A total of 757 patients hospitalized for acute heart failure (diagnosed by using Framingham criteria) met the inclusion criteria: a left ventricular ejection fraction ≥50% and brain natriuretic peptide ≥100pg/ml. We included 483 patients (age, 80±9 years; men, 45%; atrial fibrillation, 35%) whose follow-up data after survival discharge were available. Patients' frailty and aging were evaluated using the clinical frailty scale (CFS) and age quartiles (Q1: <76 years (n=122), Q2: 76–82 years (n=111), Q3: 82–87 years (n=127), Q4: >87 years (n=123)), respectively. The primary clinical endpoint was defined as the composite of death, re-hospitalization for heart failure, and cerebrovascular accident. Results The median (interquartile range) CFS rating was 3 (2–5), and there was a little correlation between CFS rating and age (r2=0.16, p<0.001). The prevalence of frailty, defined as a CFS rating >4 (n=132), was positively correlated with age quartiles (Q1: 9.0%, Q2: 21.4%, Q3: 29.9%, Q4: 48.0%, p<0.001). During the median follow-up period 396 days (interquartile range, 344–698) after discharge, the clinical endpoint was observed in 172 patients. The incidence was higher in patients with frailty than those without it (49.6% vs. 30.4%, log-rank p<0.001). It was also correlated with age quartiles (Q1: 23.0%, Q2: 34.2%, Q3: 36.2%, Q4: 48.8%, log-rank p=0.001). Multivariate Cox regression analysis revealed that frailty (hazard ratio, 1.52; 95% confidence interval, 1.09–2.10; p=0.013) and age (hazard ratio per quartile increase, 1.24; 95% confidence interval, 1.07–1.43; p=0.004) were both associated with the clinical endpoint. Subgroup analysis in 352 patients without frailty also revealed the significant impact of age on the endpoint (1.26; 1.06–1.51; p=0.008). However, in 131 patients with frailty, there was no significant impact of age on the endpoint (1.16; 0.90–1.51; p=0.25). Conclusions Frailty was common and was associated with aging in HFpEF patients. Although they were both associated with unfavorable events, aging was no longer a significant predictor of adverse outcomes under the frailty conditions. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostics K.K. and Fuji Film Toyama Chemical Co. Ltd.

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