Publications by authors named "Dalane Kitzman"

388 Publications

Incidence and Outcomes of Acute Heart Failure With Preserved Versus Reduced Ejection Fraction in SPRINT.

Circ Heart Fail 2021 Nov 26:CIRCHEARTFAILURE121008322. Epub 2021 Nov 26.

Cardiovascular Medicine Section, Wake Forest School of Medicine, Winston-Salem, NC. (B.U., D.W.K.).

Background: In the SPRINT (Systolic Blood Pressure Intervention Trial), intensive BP treatment reduced acute decompensated heart failure (ADHF) events. Here, we report the effect on HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF) and their subsequent outcomes.

Methods: Incident ADHF was defined as hospitalization or emergency department visit, confirmed, and formally adjudicated by a blinded events committee using standardized protocols. HFpEF was defined as EF ≥45%, and HFrEF was EF <45%.

Results: Among the 133 participants with incident ADHF who had EF assessment, 69 (52%) had HFpEF and 64 (48%) had HFrEF ( value: 0.73). During average 3.3 years follow-up in those who developed incident ADHF, rates of subsequent all-cause and HF hospital readmission and mortality were high, but there were no significant differences between those who developed HFpEF versus HFrEF. Randomization to the intensive arm had no effect on subsequent mortality or readmissions after the initial ADHF event, irrespective of EF subtype. During follow-up among participants who developed HFpEF, although relatively modest number of events limited statistical power, age was an independent predictor of all-cause mortality, and Black race independently predicted all-cause and HF hospital readmission.

Conclusions: In SPRINT, intensive BP reduction decreased both acute decompensated HFpEF and HFrEF events. After initial incident ADHF, rates of subsequent hospital admission and mortality were high and were similar for those who developed HFpEF or HFrEF. Randomization to the intensive arm did not alter the risks for subsequent all-cause, or HF events in either HFpEF or HFrEF. Among those who developed HFpEF, age and Black race were independent predictors of clinical outcomes.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.121.008322DOI Listing
November 2021

Economic Outcomes of Rehabilitation Therapy in Older Patients With Acute Heart Failure in the REHAB-HF Trial: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2021 Nov 24. Epub 2021 Nov 24.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.

Importance: In the Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a novel 12-week rehabilitation intervention demonstrated significant improvements in validated measures of physical function, quality of life, and depression, but no significant reductions in rehospitalizations or mortality compared with a control condition during the 6-month follow up. The economic implications of these results are important given the increasing pressures for cost containment in health care.

Objective: To report the economic outcomes of the REHAB-HF trial and estimate the potential cost-effectiveness of the intervention.

Design, Setting, Participants: The multicenter REHAB-HF trial randomized 349 patients 60 years or older who were hospitalized for acute decompensated heart failure to rehabilitation intervention or a control group; patients were enrolled from September 17, 2014, through September 19, 2019. For this preplanned secondary analysis of the economic outcomes, data on medical resource use and quality of life (via the 5-level EuroQol 5-Dimension scores converted to health utilities) were collected. Medical resource use and medication costs were estimated using 2019 US Medicare payments and the Federal Supply Schedule, respectively. Cost-effectiveness was estimated using the validated Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model, which uses an individual-patient simulation model informed by the prospectively collected trial data. Data were analyzed from March 24, 2019, to December 1, 2020.

Interventions: Rehabilitation intervention or control.

Main Outcomes And Measures: Costs, quality-adjusted life-years (QALYs), and the lifetime estimated cost per QALY gained (incremental cost-effectiveness ratio).

Results: Among the 349 patients included in the analysis (183 women [52.4%]; mean [SD] age, 72.7 [8.1] years; 176 non-White [50.4%] and 173 White [49.6%]), mean (SD) cumulative costs per patient were $26 421 ($38 955) in the intervention group (excluding intervention costs) and $27 650 ($30 712) in the control group (difference, -$1229; 95% CI, -$8159 to $6394; P = .80). The mean (SD) cost of the intervention was $4204 ($2059). Quality of life gains were significantly greater in the intervention vs control group during 6 months (mean utility difference, 0.074; P = .001) and sustained beyond the 12-week intervention. Incremental cost-effectiveness ratios were estimated at $58 409 and $35 600 per QALY gained for the full cohort and in patients with preserved ejection fraction, respectively.

Conclusions And Relevance: These analyses suggest that longer-term benefits of this novel rehabilitation intervention, particularly in the subgroup of patients with preserved ejection fraction, may yield good value to the health care system. However, long-term cost-effectiveness is currently uncertain and dependent on the assumption that benefits are sustained beyond study follow-up, which needs to be corroborated in future trials in this patient population.
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http://dx.doi.org/10.1001/jamacardio.2021.4836DOI Listing
November 2021

Left Atrial Stiffness Index Independently Predicts Exercise Intolerance and Quality of Life in Older Patients with Obese HFpEF.

J Card Fail 2021 Nov 10. Epub 2021 Nov 10.

Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, Texas. Electronic address:

Background: Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. The primary chronic symptom in HFpEF is exercise intolerance, associated with reduced quality of life (QoL). Emerging evidence implicates left atrial (LA) dysfunction as an important pathophysiologic mechanism. Here we extend prior observations by relating LA dysfunction to peak oxygen uptake (peak VO), physical function (distance walked in six minutes, 6MWD) and QoL (Kansas City Cardiomyopathy Questionnaire, KCCQ).

Methods: We compared 75 older, obese, HFpEF patients to 53 healthy age-matched controls. LA strain was assessed by magnetic resonance cine imaging using feature tracking. LA function was defined according to its three distinct phases, with the LA serving as a reservoir during systole, as a conduit during early diastole, and as a booster pump at the end of diastole. LA stiffness index was calculated as the ratio of early mitral inflow velocity-to-early annular tissue velocity (E/e', by Doppler ultrasound) and LA reservoir strain.

Results: HFpEF had decreased reservoir strain (16.4±4.4% vs. 18.2±3.5%, p=0.018), lower conduit strain (7.7±3.3% vs. 9.1±3.4%, p=0.028), and increased stiffness index (0.86±0.39 vs. 0.53±0.18, p<0.001), as well as decreased peak VO, 6MWD, and lower QoL. Increased LA stiffness was independently associated with impaired peak VO (β=9.0±1.6, p<0.001), 6MWD (β=117±22, p=0.003), and KCCQ score (β=-23±5, p=0.001), even after adjusting for clinical covariates.

Conclusion: LA stiffness is independently associated with impaired exercise tolerance and QoL and may be an important therapeutic target in obese HFpEF.

Registration: NCT00959660.
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http://dx.doi.org/10.1016/j.cardfail.2021.10.010DOI Listing
November 2021

The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial.

Nat Med 2021 Nov 28;27(11):1954-1960. Epub 2021 Oct 28.

Saint Luke's Mid America Heart Institute, Kansas City, MO, USA.

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3-9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0-9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7-10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6-34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1-7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05-2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01-1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF.
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http://dx.doi.org/10.1038/s41591-021-01536-xDOI Listing
November 2021

Predictors of Clinically Meaningful Gait Speed Response to Caloric Restriction among Older Adults Participating in Weight Loss Interventions.

J Gerontol A Biol Sci Med Sci 2021 Oct 25. Epub 2021 Oct 25.

Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC.

Background: The purpose of this study was to examine whether select baseline characteristics influenced the likelihood of an overweight/obese, older adult experiencing a clinically meaningful gait speed response (±0.05 m/s) to caloric restriction (CR).

Methods: Individual level data from 1188 older adults participating in eight, five/six-month, weight loss interventions were pooled, with treatment arms collapsed into CR (n=667) or no CR (NoCR; n=521) categories. Exercise assignment was equally distributed across groups (CR: 65.3% versus NoCR: 65.4%) and did not interact with CR (p=0.88). Poisson risk ratios (95% CI) were used to examine whether CR assignment baseline characteristic subgroups: age (≥65 years), sex (female/male), race (black/white), body mass index (BMI; ≥35 kg/m 2), comorbidity (diabetes, hypertension, cardiovascular disease) status (yes/no), gait speed (<1.0 m/s), or inflammatory burden (C-reactive protein ≥3 mg/L, interleukin-6 ≥2.5 pg/mL) to influence achievement of ±0.05 m/s fast-paced gait speed change. Main effects were also examined.

Results: The study sample (69.5% female, 80.1% white) was 67.6±5.3 years old with a BMI of 33.8±4.4 kg/m 2. Average weight loss achieved in the CR versus NoCR group was -8.3±5.9% versus -1.1±3.8%; p<0.01. No main effect of CR was observed on the likelihood of achieving a clinically meaningful gait speed improvement [RR: 1.09 (95% CI: 0.93,1.27)] or gait speed decrement [RR: 0.77 (95% CI: 0.57,1.04)]. Interaction effects were non-significant across all subgroups.

Conclusion: The proportion of individuals experiencing a clinically meaningful gait speed change was similar for CR and NoCR conditions. This finding is consistent across several baseline subgroupings.
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http://dx.doi.org/10.1093/gerona/glab324DOI Listing
October 2021

Physical Rehabilitation in Patients with Heart Failure. Reply.

N Engl J Med 2021 09;385(14):1340-1341

Duke University School of Medicine, Durham, NC.

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http://dx.doi.org/10.1056/NEJMc2113494DOI Listing
September 2021

Early Response in Albuminuria and Long-Term Kidney Protection during Treatment with an Endothelin Receptor Antagonist: A Prespecified Analysis from the SONAR Trial.

J Am Soc Nephrol 2021 Nov 22;32(11):2900-2911. Epub 2021 Sep 22.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands.

Background: Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown.

Methods: To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2-4) and a urinary albumin creatinine ratio (UACR) of 300-5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD.

Results: UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata.

Conclusions: Our findings do not support UACR response as a causal predictor of atrasentan's treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.
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http://dx.doi.org/10.1681/ASN.2021030391DOI Listing
November 2021

A grandfather's legacy.

Authors:
Dalane W Kitzman

J Am Geriatr Soc 2021 Sep 21. Epub 2021 Sep 21.

Department of Internal Medicine: Cardiology and Geriatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

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http://dx.doi.org/10.1111/jgs.17471DOI Listing
September 2021

Physical Rehabilitation in Older Patients Hospitalized with Acute Heart Failure and Diabetes: Insights from REHAB-HF.

Am J Med 2021 Sep 10. Epub 2021 Sep 10.

Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC. Electronic address:

Background: Prior studies showed an attenuated response to exercise training among patients with heart failure and type 2 diabetes mellitus. We explored the interaction between diabetes status and a novel, transitional, tailored, progressive rehabilitation intervention that improved physical function compared with usual care in the Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial.

Methods: The effect of the intervention on 3-month Short Physical Performance Battery (SPPB) (primary endpoint), 6-minute walk distance (6MWD), modified Fried frailty criteria, and quality-of-life scores (Kansas City Cardiomyopathy Questionnaire [KCCQ] and EuroQoL Visual Analogue Scale [VAS]) was compared between participants with and without diabetes. Differences in 6-month clinical outcomes were also explored.

Results: Of the 349 participants enrolled in REHAB-HF, 186 (53%) had diabetes. The prevalence of diabetes was higher in the intervention group (59% vs 48%). Participants with diabetes had worse baseline physical function by the SPPB and 6MWD, but similar frailty and quality-of-life scores. There was a consistent improvement with the intervention for 3-month SPPB, 6MWD, and VAS regardless of diabetes status (all interaction P value > .6), but participants with diabetes had significantly less improvement for frailty (P = .021) and a trend toward lower improvement in KCCQ (P = .11). There was no significant interaction by diabetes status for 6-month clinical event outcomes (all interaction P value > .3).

Conclusions: Participants with diabetes had worse baseline physical function but showed similar clinically meaningful improvements from the intervention. There was less benefit for frailty with the intervention in participants with diabetes.
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http://dx.doi.org/10.1016/j.amjmed.2021.08.001DOI Listing
September 2021

Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Sep;78(11):1166-1187

Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.
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http://dx.doi.org/10.1016/j.jacc.2021.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525886PMC
September 2021

Associations of High-Sensitivity Troponin and Natriuretic Peptide Levels With Outcomes After Intensive Blood Pressure Lowering: Findings From the SPRINT Randomized Clinical Trial.

JAMA Cardiol 2021 Sep 1. Epub 2021 Sep 1.

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas.

Importance: Elevated high-sensitivity cardiac troponin T (hscTnT) and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels are associated with risk of heart failure (HF) and mortality among individuals in the general population. However, it is unknown if this risk is modifiable.

Objective: To test the hypothesis that elevated hscTnT and NTproBNP levels would identify individuals with the greatest risk for mortality and HF and the largest benefit associated with intensive systolic blood pressure (SBP) lowering.

Design, Setting, And Participants: This is a nonprespecified post hoc analysis of the multicenter, prospective, randomized clinical Systolic Blood Pressure Intervention Trial (SPRINT), conducted from October 20, 2010, to August 20, 2015. A total of 9361 patients without diabetes with increased risk for cardiovascular disease were randomized to receive intensive vs standard SBP lowering. Statistical analysis was performed on an intention-to-treat basis from September 30, 2019, to July 29, 2021.

Interventions: Participants were randomized to undergo intensive (<120 mm Hg) or standard (<140 mm Hg) SBP lowering. High-sensitivity cardiac troponin T and NTproBNP levels were measured from stored specimens collected at enrollment, with elevated levels defined as 14 ng/L or more for hscTnT (to convert to micrograms per liter, multiply by 0.001) and 125 pg/mL or more for NTproBNP (to convert to nanograms per liter, multiply by 1.0).

Main Outcomes And Measures: The primary outcome of this ancillary study was HF and mortality.

Results: Of the 9361 participants enrolled in SPRINT, 8828 (5578 men [63.2%]; mean [SD] age, 68.0 [9.5] years) had measured hscTnT levels and 8836 (5585 men [63.2%]; mean [SD] age, 68.0 [9.5] years) had measured NTproBNP levels; 2262 of 8828 patients (25.6%) had elevated hscTnT levels, 3371 of 8836 patients (38.2%) had elevated NTproBNP, and 1411 of 8828 patients (16.0%) had both levels elevated. Randomization to the intensive SBP group led to a 4.9% (95% CI, 1.7%-7.5%) absolute risk reduction (ARR) over 4 years in death and HF (421 events) for those with elevated hscTnT and a 1.7% (95% CI, 0.7%-2.5%) ARR for those without elevated levels. Similarly, for those with elevated NTproBNP, the ARR for death and HF over 4 years was 4.6% (95% CI, 2.3%-6.5%) vs 1.8% (95% CI, 0.9%-2.5%) in those without elevated levels. For those with elevated levels of both biomarkers, the ARR for death and HF over 4 years was 7.8% (95% CI, 3.3%-11.3%) vs 1.7% (95% CI, 0.8%-2.3%) in those with neither biomarker elevated. No significant treatment group by biomarker category interactions were detected.

Conclusions And Relevance: Intensive SBP control led to large absolute differences in death and HF among patients with abnormal hscTnT and NTproBNP levels. These findings demonstrate that risk associated with elevation of these biomarkers is modifiable with intensive BP control. A prospective, randomized clinical trial is needed to evaluate whether these biomarkers may help guide selection of patients for intensive SBP lowering.

Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.
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http://dx.doi.org/10.1001/jamacardio.2021.3187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411355PMC
September 2021

Measured Versus Estimated Resting Metabolic Rate in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2021 Aug 4;14(8):e007962. Epub 2021 Aug 4.

University of Michigan Frankel Cardiovascular Center, Ann Arbor (T.M.C., T.M.K., D.P., S.L.H.).

Background: Obesity is common in heart failure with preserved ejection fraction (HFpEF), and a hypocaloric diet can improve functional capacity. Malnutrition, sarcopenia, and frailty are also frequently present, and calorie restriction could harm some patients. Resting metabolic rate (RMR) is an essential determinant of caloric needs; however, it is rarely measured in clinical practice. The accuracy of commonly used predictive equations in HFpEF is unknown.

Methods: RMR was measured with indirect calorimetry in 43 patients with HFpEF undergoing right heart catheterization at the University of Michigan, and among 49 participants in the SECRET trial (Study of the Effects of Caloric Restriction and Exercise Training in Patients With Heart Failure and a Normal Ejection Fraction); SECRET patients also had dual-energy X-ray absorptiometry body composition measures. Measured RMR was compared with RMR estimated using the Harris Benedict, Mifflin-St Jeor, World Health Organization, and Academy for Nutrition and Dietetics equations.

Results: All predictive equations overestimated RMR (by >10%, <0.001 for all), with mean (95% CI) differences Harris Benedict equation +250 (186-313), Mifflin-St. Jeor equation +169 (110-229), World Health Organization equation +300 (239-361), and Academy for Nutrition and Dietetics equation +794 (890-697) kcal/day. Results were similar across both patient groups, and the discrepancy between measured and estimated RMR tended to increase with body mass index. In SECRET, measured RMR was closely associated with lean body mass (ρ=0.74; by linear regression adjusted for age and sex: β=27 [95% CI, 18-36] kcal/day per kg, <0.001; r=0.56).

Conclusions: Commonly used predictive equations systematically overestimate measured RMR in patients with HFpEF. Direct measurement of RMR may be needed to effectively tailor dietary guidance in this population. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT00959660.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373809PMC
August 2021

Rehabilitation Intervention in Older Patients With Acute Heart Failure With Preserved Versus Reduced Ejection Fraction.

JACC Heart Fail 2021 10 7;9(10):747-757. Epub 2021 Jul 7.

Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Sections on Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

Objectives: This study assessed for treatment interactions by ejection fraction (EF) subgroup (≥45% [heart failure with preserved ejection fraction (HFpEF); vs <45% [heart failure with reduced ejection fraction (HFrEF)]).

Background: The REHAB-HF trial showed that an early multidomain rehabilitation intervention improved physical function, frailty, quality-of-life, and depression in older patients hospitalized with acute decompensated heart failure (ADHF).

Methods: Three-month outcomes were: Short Physical Performance Battery (SPPB), 6-min walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ). Six-month end points included all-cause rehospitalization and death and a global rank of death, all-cause rehospitalization, and SPPB. Prespecified significance level for interaction was P ≤ 0.1.

Results: Among 349 total participants, 185 (53%) had HFpEF and 164 (47%) had HFrEF. Compared with HFrEF, HFpEF participants were more often women (61% vs 43%) and had significantly worse baseline physical function, frailty, quality of life, and depression. Although interaction P values for 3-month outcomes were not significant, effect sizes were larger for HFpEF vs HFrEF: SPPB +1.9 (95% CI: 1.1-2.6) vs +1.1 (95% CI: 0.3-1.9); 6MWD +40 meters (95% CI: 9 meters-72 meters) vs +27 (95% CI: -6 meters to 59 meters); KCCQ +9 (2-16) vs +6 (-2 to 14). All-cause rehospitalization rate was nominally lower with intervention in HFpEF but not HFrEF [effect size 0.83 (95% CI: 0.64-1.09) vs 0.99 (95% CI: 0.74-1.33); interaction P = 0.40]. There were significantly greater treatment benefits in HFpEF vs HFrEF for all-cause death [interaction P = 0.08; intervention rate ratio 0.63 (95% CI: 0.25-1.61) vs 2.21 (95% CI: 0.78-6.25)], and the global rank end point (interaction P = 0.098) with benefit seen in HFpEF [probability index 0.59 (95% CI: 0.50-0.68)] but not HFrEF.

Conclusions: Among older patients hospitalized with ADHF, compared with HFrEF those with HFpEF had significantly worse impairments at baseline and may derive greater benefit from the intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).
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http://dx.doi.org/10.1016/j.jchf.2021.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487922PMC
October 2021

Physical frailty in older patients with acute heart failure: From risk marker to modifiable treatment target.

J Am Geriatr Soc 2021 09 19;69(9):2451-2454. Epub 2021 Jun 19.

Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.

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http://dx.doi.org/10.1111/jgs.17306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440358PMC
September 2021

Relationships Between Objectively Measured Physical Activity, Exercise Capacity, and Quality of Life in Older Patients With Obese Heart Failure and Preserved Ejection Fraction.

J Card Fail 2021 06;27(6):635-641

Cardiology Section, Department of Internal Medicine, Wake Forest School of Medicine; Department of Geriatric Medicine, Sticht Center, Wake Forest University, Winston-Salem, North Carolina.

Background: The relationship between physical activity (PA), exercise capacity, and quality of life (QOL) in obese heart failure with preserved ejection fraction is poorly understood.

Methods And Results: This was an ancillary study to a clinical trial. Accelerometers were used to measure light PA, moderate to vigorous PA, total PA, PA energy expenditure, and steps. Peak VO, exercise time, and 6-minute walk distance, as well as QOL measures were obtained. Pearson correlations were performed to examine relationships between PA, exercise capacity, and QOL. Patients (n = 58) were 68.0 ± 5.7 years old, 78% female, 59% White, and obese (body mass index 39.1 ± 6.1 kg/m). Patients had low levels of objectively measured PA as well as decreased exercise capacity and poor QOL. Light PA (r = 0.32, P = .014) and steps per day (r = 0.30, P = .022) were modestly correlated with peak VO. All PA variables were modestly correlated with exercise time (r = 0.33-0.49, all P < .02) and 6-minute walk distance (r = 0.25-0.48, all P < .01). None of the PA variables were correlated with QOL.

Conclusions: PA variables were modestly correlated with measures of exercise capacity and were not significantly correlated with QOL. Our findings indicate that PA, exercise capacity, and QOL assess different aspects of the patient experience in older obese patients with heart failure with preserved ejection fraction.
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http://dx.doi.org/10.1016/j.cardfail.2020.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186734PMC
June 2021

The old man in room 802.

Authors:
Dalane W Kitzman

J Am Geriatr Soc 2021 08 20;69(8):2346-2347. Epub 2021 May 20.

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http://dx.doi.org/10.1111/jgs.17214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373765PMC
August 2021

Final Report of a Trial of Intensive versus Standard Blood-Pressure Control.

N Engl J Med 2021 05;384(20):1921-1930

The affiliations of the members of the writing committee are as follows: the Department of Epidemiology, School of Public Health (C.E.L.), and the Divisions of Preventive Medicine (C.E.L.) and Cardiovascular Disease (S.O.), Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham; the Clinical Applications and Prevention Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (L.J.F., J.A.C., J.K.S.); the Division of Nephrology and Hypertension, University of Utah, and Medical Service, Veterans Affairs Salt Lake City Health Care System, Salt Lake City (S.B., A.K.C.); the Department of Preventive Medicine, University of Tennessee Health Science Center (W.C.C., K.C.J.), and Medical Service, Veterans Affairs Medical Center (W.C.C.), Memphis; the Department of Biostatistics and Data Science (G.W.E., D.M.R., W.T.A.), the Division of Cardiovascular Medicine (D.W.K.) and Section of Nephrology (M.V.R.), Department of Internal Medicine, and the Sticht Center for Healthy Aging and Alzheimer's Prevention and Division of Geriatric Medicine (K.M.S., J.D.W.), Wake Forest School of Medicine, Winston Salem, NC; the Division of Nephrology and Hypertension, Louis Stokes Cleveland Veterans Affairs Medical Center (M.R.), and the Division of Nephrology and Hypertension, University Hospitals Cleveland Medical Center, Case Western Reserve University (M.R., J.T.W.), Cleveland; and the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans (P.K.W.).

Background: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected.

Methods: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure, <120 mm Hg) or a standard treatment target (systolic blood pressure, <140 mm Hg). The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. Additional primary outcome events occurring through the end of the intervention period (August 20, 2015) were adjudicated after data lock for the primary analysis. We also analyzed post-trial observational follow-up data through July 29, 2016.

Results: At a median of 3.33 years of follow-up, the rate of the primary outcome and all-cause mortality during the trial were significantly lower in the intensive-treatment group than in the standard-treatment group (rate of the primary outcome, 1.77% per year vs. 2.40% per year; hazard ratio, 0.73; 95% confidence interval [CI], 0.63 to 0.86; all-cause mortality, 1.06% per year vs. 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61 to 0.92). Serious adverse events of hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope were significantly more frequent in the intensive-treatment group. When trial and post-trial follow-up data were combined (3.88 years in total), similar patterns were found for treatment benefit and adverse events; however, rates of heart failure no longer differed between the groups.

Conclusions: Among patients who were at increased cardiovascular risk, targeting a systolic blood pressure of less than 120 mm Hg resulted in lower rates of major adverse cardiovascular events and lower all-cause mortality than targeting a systolic blood pressure of less than 140 mm Hg, both during receipt of the randomly assigned therapy and after the trial. Rates of some adverse events were higher in the intensive-treatment group. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.).
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http://dx.doi.org/10.1056/NEJMoa1901281DOI Listing
May 2021

Physical Rehabilitation for Older Patients Hospitalized for Heart Failure.

N Engl J Med 2021 07 16;385(3):203-216. Epub 2021 May 16.

From the Department of Internal Medicine, Sections of Cardiovascular Medicine (D.W.K., M.B.N., B.U.) and Gerontology and Geriatric Medicine (D.W.K., M.A.E.), and the Departments of Neurology (P.D.) and Biostatistics and Data Science (H.C., M.A.E.), Wake Forest School of Medicine, Winston-Salem, the Department of Orthopedic Surgery, Doctor of Physical Therapy Division (A.M.P.), the Department of Medicine, Division of Cardiology (R.J.M.), and the Department of Population Health Sciences (S.D.R.), Duke University School of Medicine, Durham, and Novant Health Heart and Vascular Institute, Charlotte (G.R.R.) - all in North Carolina; the Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University (D.J.W.), and the Department of Physical Therapy, Jefferson College of Rehabilitation Sciences at Thomas Jefferson University (L.A.H.) - both in Philadelphia; and Inova Heart and Vascular Institute, Fairfax, VA (C.M.O.).

Background: Older patients who are hospitalized for acute decompensated heart failure have high rates of physical frailty, poor quality of life, delayed recovery, and frequent rehospitalizations. Interventions to address physical frailty in this population are not well established.

Methods: We conducted a multicenter, randomized, controlled trial to evaluate a transitional, tailored, progressive rehabilitation intervention that included four physical-function domains (strength, balance, mobility, and endurance). The intervention was initiated during, or early after, hospitalization for heart failure and was continued after discharge for 36 outpatient sessions. The primary outcome was the score on the Short Physical Performance Battery (total scores range from 0 to 12, with lower scores indicating more severe physical dysfunction) at 3 months. The secondary outcome was the 6-month rate of rehospitalization for any cause.

Results: A total of 349 patients underwent randomization; 175 were assigned to the rehabilitation intervention and 174 to usual care (control). At baseline, patients in each group had markedly impaired physical function, and 97% were frail or prefrail; the mean number of coexisting conditions was five in each group. Patient retention in the intervention group was 82%, and adherence to the intervention sessions was 67%. After adjustment for baseline Short Physical Performance Battery score and other baseline characteristics, the least-squares mean (±SE) score on the Short Physical Performance Battery at 3 months was 8.3±0.2 in the intervention group and 6.9±0.2 in the control group (mean between-group difference, 1.5; 95% confidence interval [CI], 0.9 to 2.0; P<0.001). At 6 months, the rates of rehospitalization for any cause were 1.18 in the intervention group and 1.28 in the control group (rate ratio, 0.93; 95% CI, 0.66 to 1.19). There were 21 deaths (15 from cardiovascular causes) in the intervention group and 16 deaths (8 from cardiovascular causes) in the control group. The rates of death from any cause were 0.13 and 0.10, respectively (rate ratio, 1.17; 95% CI, 0.61 to 2.27).

Conclusions: In a diverse population of older patients who were hospitalized for acute decompensated heart failure, an early, transitional, tailored, progressive rehabilitation intervention that included multiple physical-function domains resulted in greater improvement in physical function than usual care. (Funded by the National Institutes of Health and others; REHAB-HF ClinicalTrials.gov number, NCT02196038.).
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http://dx.doi.org/10.1056/NEJMoa2026141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353658PMC
July 2021

Associations of Cardiac Mechanics With Exercise Capacity: The Multi-Ethnic Study of Atherosclerosis.

J Am Coll Cardiol 2021 Jul 13;78(3):245-257. Epub 2021 May 13.

Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address:

Background: Lower exercise capacity, as measured by 6-minute walk distance (6MWD), is associated with incident heart failure (HF). Among those without HF, the associations of measures of cardiac function with 6MWD are unclear, and may provide insight regarding the risk of incident HF.

Objectives: The purpose of this study was to understand the relationships between cardiac function and exercise capacity.

Methods: This study evaluated the associations of cardiac mechanics with 6MWD in the sixth examination of the Multi-Ethnic Study of Atherosclerosis. Echocardiography (2-dimensional, Doppler, and speckle-tracking) was performed at rest and after passive leg raise to evaluate functional reserve after intravascular volume challenge.

Results: Of 2,096 participants without HF (mean age 73 years, 48% men, 58% non-White), individuals with lower (worse) left atrial (LA) reservoir strain were older and had higher blood pressure. Lower resting LA reservoir strain (β coefficient per SD decrease: -5.0; 95% confidence interval [CI]: -8.8 to -1.3 m; p = 0.009), inability to augment LA reservoir strain after passive leg raise (β coefficient per SD decrease: -5.8; 95% CI: -9.1 to -2.5 m; p < 0.001), and lower right atrial reservoir strain (β coefficient per SD decrease: -4.4; 95% CI: -7.8 to -1.1 m; p = 0.01) were associated with shorter 6MWD. Worse left ventricular (LV) diastolic function was also associated with lower 6MWD. There were no independent associations of measures of LV systolic function (global longitudinal strain, circumferential strain, ejection fraction) with 6MWD.

Conclusions: Among individuals without HF, worse biatrial function, lack of LA functional reserve, and worse LV diastolic function were associated with reduced submaximal exercise capacity. Therapies aimed to improve these functional domains may increase exercise capacity and prevent HF.
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http://dx.doi.org/10.1016/j.jacc.2021.04.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299435PMC
July 2021

Temporal Trends and Factors Associated With Cardiac Rehabilitation Participation Among Medicare Beneficiaries With Heart Failure.

JACC Heart Fail 2021 07 12;9(7):471-481. Epub 2021 May 12.

Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, California, USA. Electronic address:

Objectives: The purpose of this study was to assess temporal trends and factors associated with cardiac rehabilitation (CR) enrollment and participation among Medicare beneficiaries after the 2014 Medicare coverage expansion.

Background: CR improves exercise capacity, quality of life, and clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). In 2014, Medicare coverage for CR was expanded to include chronic HFrEF.

Methods: Among Medicare beneficiaries from quarter (Q) 1 2014 to Q2 2016, 11,696 patients from 14,258 hospitalizations with primary discharge diagnosis of HF were identified. Patients with HF with preserved ejection fraction were excluded. Quarterly CR participation rates among hospitalized HF patients within 6 months of discharge were identified through outpatient administrative claims. The predictors of CR participation were assessed with the use of a multivariable logistic regression model that included patient- and hospital-level characteristics. A secondary analysis to assess participation rates of CR after outpatient encounters for HF was performed.

Results: Overall, only 611 (4.3%) and 349 (2.2%) eligible patients participated CR after primary hospitalization or outpatient visit for HF, respectively. There was a modest, statistically significant increase in CR participation after HF admissions (2.8% in Q1 2014; 5.0% in Q2 2016; p < 0.001) without significant increase after outpatient visits for HF (2.6% to 3.8%; p = 0.21). Younger age, male sex, nonblack race, previous cardiovascular procedures, and hospitalization at hospitals with available CR facilities were all independently associated with CR participation.

Conclusions: CR participation among eligible Medicare beneficiaries with HFrEF was low with minimal increase since 2014 Medicare coverage decision. Sex, race, and institution-dependent variables were independent predictors of CR participation.
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http://dx.doi.org/10.1016/j.jchf.2021.02.006DOI Listing
July 2021

Left atrial structure and function of the amyloidogenic V122I transthyretin variant in elderly African Americans.

Eur J Heart Fail 2021 08 9;23(8):1290-1295. Epub 2021 Jun 9.

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.

Aims: African-American carriers of the transthyretin (TTR) valine-to-isoleucine substitution (V122I) are at increased risk of heart failure, yet many have relatively subtle abnormalities of left ventricular (LV) function. We sought to explore the influence of this mutation on left atrial (LA) structure and function in this population.

Methods And Results: We assessed 1225 genotyped African-Americans (age range, 67-89 years) participating in the Atherosclerosis Risk in Communities study who underwent echocardiography and were in sinus rhythm at study Visit 5 (2011 to 2013). Six LA parameters [LA maximum/minimum volume index, ejection fraction, and LA reservoir, conduit, and contractile longitudinal strains (LS)] were compared between V122I TTR variant carriers (n = 46) and non-carriers (n = 1179). LA minimum volume index was significantly greater and LA contractile LS was worse in carriers than non-carriers (19.5 ± 10.6 mL/m vs. 16.3 ± 8.4 mL/m ; 15.0 ± 5.8% vs. 16.8 ± 5.7%, respectively, both P < 0.05). Carriers had a significantly higher number of LA abnormalities than non-carriers (1.8 ± 2.2 vs. 1.1 ± 1.6, P = 0.009). The number of subjects with at least four LA abnormalities was significantly increased among carriers compared with non-carriers (27% vs. 12%; odds ratio 2.43; 95% confidence interval 1.06-5.58 after adjusting for age, sex, body mass index, and LV wall thickness and global LS).

Conclusions: Left atrial enlargement and dysfunction were common in V122I TTR carriers with sinus rhythm than non-carriers, suggesting that abnormalities of LA function may represent early markers of subclinical disease in these individuals.
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http://dx.doi.org/10.1002/ejhf.2200DOI Listing
August 2021

The other striated muscle: The role of sarcopenia in older persons with heart failure.

J Am Geriatr Soc 2021 07 17;69(7):1811-1814. Epub 2021 Apr 17.

Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.

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http://dx.doi.org/10.1111/jgs.17160DOI Listing
July 2021

Relationship of physical function with quality of life in older patients with acute heart failure.

J Am Geriatr Soc 2021 07 10;69(7):1836-1845. Epub 2021 Apr 10.

Section of Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States.

Background: Older patients with acute decompensated heart failure (ADHF) have severely impaired physical function (PF) and quality of life (QOL). However, relationships between impairments in PF and QOL are unknown but are relevant to clinical practice and trial design.

Methods: We assessed 202 consecutive patients hospitalized with ADHF in the multicenter Rehabilitation Therapy in Older Acute HF Patients (REHAB-HF) Trial. PF measures included Short Physical Performance Battery (SPPB) and 6-min walk distance (6MWD). Disease-specific QOL was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). General QOL was assessed by the Short Form-12 (SF-12) and EuroQol-5D-5L. PF was evaluated as a predictor of QOL using stepwise regression adjusted for age, sex, race, and New York Heart Association class.

Results: Participants were 72 ± 8 years, 54% women, 55% minority race, 52% with reduced ejection fraction, and body mass index 33 ± 9 kg/m . Participants had severe impairments in PF (6MWD 185 ± 99 m, SPPB 6.0 ± 2.5 units) and disease-specific QOL (KCCQ Overall Score 41 ± 21 and Physical Score 47 ± 24) and general QOL (SF-12 Physical Score 28 ± 9 and EuroQol Visual Analog Scale 57 ± 23). There were modest, statistically significant correlations between 6MWD and KCCQ Overall, KCCQ Physical Limitation, and SF-12 Physical Scores (r = 0.23, p < 0.001; r = 0.30, p < 0.001; and r = 0.24, p = 0.001, respectively); and between SPPB and KCCQ Physical and SF-12 Physical Scores (r = 0.20, p = 0.004, and r = 0.19, p = 0.007, respectively). Both 6MWD and SPPB were correlated with multiple components of the EuroQol-5D-5L. 6MWD was a significant, weak predictor of KCCQ Overall Score and SF-12 Physical Score (estimate = 0.05 ± 0.01, p < 0.001 and estimate = 0.05 ± 0.02, p = 0.012, respectively). SPPB was a significant, weak predictor of KCCQ Physical Score and SF-12 Physical Score (estimate = 1.37 ± 0.66, p = 0.040 and estimate = 0.54 ± 0.25, p = 0.030, respectively).

Conclusion: In older, hospitalized ADHF patients, PF and QOL are both severely impaired but are only modestly related, suggesting that PF and QOL provide complementary information and assessment of both should be considered to fully assess clinically meaningful patient-oriented outcomes.
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http://dx.doi.org/10.1111/jgs.17156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273137PMC
July 2021

Conversion between the Modified Mini-Mental State Examination (3MSE) and the Mini-Mental State Examination (MMSE).

Alzheimers Dement (Amst) 2021 31;13(1):e12161. Epub 2021 Mar 31.

Department of Psychiatry & Behavioral Medicine Wake Forest School of Medicine Winston-Salem North Carolina USA.

Background: The Modified Mini-Mental State Examination (3MSE) and the Mini-Mental State Examination (MMSE) are two commonly used instruments for assessing cognitive function. Although conversion between 3MSE and MMSE is useful in applications such as integrative data analysis, there are limited published reports on the topic. Our objective is to provide a dual tool: (1) an item-level conversion tool to score responses for deriving both 3MSE and MMSE measures, and (2) cross-walk tables to facilitate quick conversion between 3MSE and MMSE.

Methods: An SAS program tool allows scoring of 3MSE item-level responses into MMSE score. Using integrated data sets (n = 8346), actual 3MSE and MMSE scores obtained from the same individuals were linked to form cross-walk tables.

Results: An SAS conversion program was made available. Cross-walk tables were derived. Validation sample shows bias is -0.11 (standard deviation = 1.02) in 3MSE→MMSE; the converse had substantially large bias.

Discussion: The 3MSE→MMSE conversion table can be used in clinical practice and legacy system data.
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http://dx.doi.org/10.1002/dad2.12161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010479PMC
March 2021

Association of Left Ventricular Systolic Function With Incident Heart Failure in Late Life.

JAMA Cardiol 2021 May;6(5):509-520

Department of Medicine, Cardiovascular Medicine Division, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Limited data exist regarding the association of subtle subclinical systolic dysfunction and incident heart failure (HF) in late life.

Objective: To assess the independent associations of subclinical impairments in systolic performance with incident HF in late life.

Design, Setting, And Participants: This study was a time-to-event analysis of participants without heart failure in the Atherosclerosis Risk in Communities (ARIC) study, a prospective, community-based cohort study, who underwent protocol echocardiography at the fifth study visit (January 1, 2011, to December 31, 2013). Findings were validated independently in participants in the Copenhagen City Heart Study (CCHS). Data analysis was performed from June 1, 2018, to February 28, 2020.

Exposures: Left ventricular ejection fraction (LVEF), longitudinal strain (LS), and circumferential strain (CS) measured by 2-dimensional and strain echocardiography.

Main Outcomes And Measures: Main outcomes were incident adjudicated HF and HF with preserved and reduced LVEF at a median follow-up of 5.5 years (interquartile range, 5.0-5.8 years). Cox proportional hazards regression models adjusted for demographics, hypertension, diabetes, obesity, smoking, coronary disease, estimated glomerular filtration rate, LV mass index, e', E/e', and left atrial volume index. Lower 10th percentile limits were determined in 374 participants free of cardiovascular disease or risk factors.

Results: Among 4960 ARIC participants (mean [SD] age, 75 [5] years; 2933 [59.0%] female; 965 [19%] Black), LVEF was less than 50% in only 76 (1.5%). In the 3552 participants with complete assessment of LVEF, LS, and CS, 983 (27.7%) had 1 or more of the following findings: LVEF less than 60%, LS less than 16.0%, or CS less than 23.7%. Modeled continuously or dichotomized, worse LVEF, LS, and CS were each independently associated with incident HF. The adjusted hazard ratio (HR) per SD decrease in LVEF was 1.41 (95% CI, 1.29-1.55); the HR for LVEF less than 60% was 2.59 (95% CI, 1.99-3.37). Similar findings were observed for continuous LS (HR, 1.37; 95% CI, 1.22-1.53) and dichotomized LS (HR, 1.93; 95% CI, 1.46-2.55) and for continuous CS (HR, 1.39; 95% CI, 1.22-1.57) and dichotomized CS (HR, 2.30; 95% CI, 1.64-3.22). Although the magnitude of risk for incident HF or death associated with impaired LVEF was greater using guideline (HR, 2.99; 95% CI, 2.19-4.09) compared with ARIC-based limits (HR, 1.88; 95% CI, 1.58-2.25), the number of participants classified as impaired was less (104 [2.1%] based on guideline thresholds compared with 692 [13.9%] based on LVEF <60%). The population-attributable risk associated with LVEF less than 60% was 11% compared with 5% using guideline-based limits, a finding replicated in 908 participants in the CCHS.

Conclusions And Relevance: These findings suggest that relatively subtle impairments of systolic function (detected based on LVEF or strain) are independently associated with incident HF and HF with reduced LVEF in late life. Current recommended assessments of LV function may substantially underestimate the prevalence of prognostically important impairments in systolic function in this population.
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http://dx.doi.org/10.1001/jamacardio.2021.0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970394PMC
May 2021

Chronic Ca/Calmodulin-Dependent Protein Kinase II Inhibition Rescues Advanced Heart Failure.

J Pharmacol Exp Ther 2021 Jun 15;377(3):316-325. Epub 2021 Mar 15.

Department of Cardiology, the First Affiliated Hospital of Kunming Medical University, Kunming, China (Y.L.); Department of Cardiology, Harbin Medical University Cancer Hospital, Harbin, China (Q.S.); Department of Internal Medicine, Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Y.L., Q.S., H.-J.C., T.L., X.Z., M.F.C., D.H., D.K., D.Z., C.-P.C.); Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China (T.L.); and Department of Cardiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China (X.Z.)

Ca/calmodulin-dependent protein kinase II (CaMKII) is upregulated in congestive heart failure (CHF), contributing to electrical, structural, and functional remodeling. CaMKII inhibition is known to improve CHF, but its direct cardiac effects in CHF remain unclear. We hypothesized that CaMKII inhibition improves cardiomyocyte function, [Ca] regulation, and -adrenergic reserve, thus improving advanced CHF. In a 16-week study, we compared plasma neurohormonal levels and left ventricular (LV)- and myocyte-functional and calcium transient ([Ca]) responses in male Sprague-Dawley rats (10/group) with CHF induced by isoproterenol (170 mg/kg sq for 2 days). In rats with CHF, we studied the effects of the CaMKII inhibitor KN-93 or its inactive analog KN-92 ( = 4) (70 µg/kg per day, mini-pump) for 4 weeks. Compared with controls, isoproterenol-treated rats had severe CHF with 5-fold-increased plasma norepinephrine and about 50% decreases in ejection fraction (EF) and LV contractility [slope of LV end-systolic pressure-LV end-systolic volume relation (E)] but increased time constant of LV relaxation (). They also showed significantly reduced myocyte contraction [maximum rate of myocyte shortening (dL/dt)], relaxation (dL/dt), and [Ca] Isoproterenol superfusion caused significantly fewer increases in dL/dt and [Ca] KN-93 treatment prevented plasma norepinephrine elevation, with increased basal and acute isoproterenol-stimulated increases in EF and E and decreased in CHF. KN-93 treatment preserved normal myocyte contraction, relaxation, [Ca], and -adrenergic reserve, whereas KN-92 treatment failed to improve LV and myocyte function, and plasma norepinephrine remained high in CHF. Thus, chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system, restoring normal LV and cardiomyocyte basal and -adrenergic-stimulated contraction, relaxation, and [Ca], thereby playing a rescue role in advanced CHF. SIGNIFICANCE STATEMENT: We investigated the therapeutic efficacy of late initiation of chronic Ca/calmodulin-dependent protein kinase II (CaMKII) inhibition on progression of advanced congestive heart failure (CHF). Chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system and restored normal intrinsic cardiomyocyte basal and -adrenergic receptor-stimulated relaxation, contraction, and [Ca] regulation, leading to reversal of CHF progression. These data provide new evidence that CaMKII inhibition is able and sufficient to rescue a failing heart, and thus cardiac CaMKII inhibition is a promising target for improving CHF treatment.
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http://dx.doi.org/10.1124/jpet.120.000361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140392PMC
June 2021

Determinants and consequences of heart rate and stroke volume response to exercise in patients with heart failure and preserved ejection fraction.

Eur J Heart Fail 2021 05 22;23(5):754-764. Epub 2021 Mar 22.

Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

Aims: A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO - heart rate and stroke volume - and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses.

Methods And Results: Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39-56% of patients with HFpEF and 3-56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m , healthy participants: +24 ± 12 mL/m , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF.

Conclusion: The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.
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http://dx.doi.org/10.1002/ejhf.2146DOI Listing
May 2021

Comparison of the Relation of Carotid Intima-Media Thickness With Incident Heart Failure With Reduced Versus Preserved Ejection Fraction (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

Am J Cardiol 2021 06 3;148:102-109. Epub 2021 Mar 3.

Section of Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina; Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, Maryland; Department of Pediatrics, Saint Joseph University Medical Center, Paterson, New Jersey; Department of Medicine, Lundquist Institute, Torrance, California; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA; Kaiser Permanente Health Research Institute, Seattle, Washington; Johns Hopkins University School of Medicine, Baltimore, Maryland; Ultrasound Reading Center, Tufts Medical Center, Boston, Massachusetts; National University of Ireland and National Institute for Prevention and Cardiovascular Health, Galway, Ireland.

Increased carotid intima-media thickness (cIMT) is associated with heart failure (HF) in previous studies, but it is not known whether the association of cIMT differs between HF with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We studied 6699 participants (mean age 62 ± 10 years, 47% male, and 38% white) from the Multi-Ethnic Study of Atherosclerosis (MESA) with baseline cIMT measurements. We classified HF events as HFrEF (EF <50%) or HFpEF (EF ≥ 50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios (HR), and 95% confidence intervals (CI) for the association between the IMT Z-score (measured maximum IMT of Internal Carotid (IC) and Common Carotid (CC) sites as the mean of the maximum IMT of the near and far walls of right and left sides), and incident HFrEF or HFpEF. Models were adjusted for covariates and interim coronary artery disease (CAD) events. A total of 191 HFrEF and 167 HFpEF events occurred during follow-up. In multivariable analysis, each 1 standard deviation increase in the measured maximum IMT (Z-score) was associated with both HFrEF and HFpEF in the unadjusted and demographically adjusted models [HR, 95% CI 1.57 (1.43 to 1.73)] and [HR, 95% CI 1.61 (1.47 to 1.77)] but not in the fully adjusted models [HR, 95% CI 1.11 (0.96 to 1.28)] and [HR, 95% CI 1.13 (0.98 to 1.30)]. In conclusion, cIMT was significantly associated with incident HF, but the association is partially attenuated with adjustment for demographic factors and becomes non-significant after adjustment for other traditional heart failure risk factors and interim CAD events. There was no difference in the association of IMT measures with HFrEF versus HFpEF.
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http://dx.doi.org/10.1016/j.amjcard.2021.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113133PMC
June 2021
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