Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction

Figures

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  Figure 1.. Graphical abstract and study scheme. Overview of the study design linking invasive cardiopulmonary exercise testing (iCPET), metabolomics, and genomics. In the MGH-ExS (Massachusetts General Hospital Exercise Study) iCPET cohort of patients with heart failure (HF) with preserved ejection fraction (HFpEF; n=820), we quantified 7 organ-specific exercise physiological deficits and peak Vo2, derived metabolite signatures for each deficit, and related these signatures to clinical outcomes. The relation of these signatures with clinical-demographic features, cardiac magnetic resonance imaging, and incident HF was measured in MESA (Multi-Ethnic Study of Atherosclerosis; n=6345). We also mapped deficit-implicated metabolites to tissue-specific genetic variation in ≈2 million individuals with HF and in the largest genome-wide association studies of HFpEF comorbidities to evaluate shared metabolic mechanisms of HFpEF pathophysiology.

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  Figure 2.. Heterogeneity in cardiac, vascular, pulmonary, and peripheral mechanisms quantified during exercise in HFpEF. A, The 7 invasive cardiopulmonary exercise testing (iCPET)–derived exercise physiological deficits with abnormal thresholds for each deficit as indicated. B, Joint prevalence of physiological deficits in the heart failure with preserved ejection fraction (HFpEF) iCPET cohort. Each participant was first classified as having or not having each of the 7 exercise deficits based on the abnormal thresholds shown in A, and these binary classifications were then used to construct the UpSet plot. Vertical bars represent the number of participants exhibiting each specific combination of deficits (shown only for combinations occurring in ≥10 individuals). Horizontal bars indicate the total number of participants meeting criteria for each individual deficit, and colored dots denote which deficits are present within each combination. C, Heat map in which each row represents 1 patient with HFpEF and each column represents 1 of the 7 exercise deficits. For every patient, the measured value of each deficit was converted into a percentage of the predicted normal value so that all deficits…

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  Figure 3.. Physiological deficits are linked to progressive decline in functional capacity and clinical outcomes in HFpEF. A, Association of each exercise physiological deficit with two adjudicated outcomes: cardiovascular hospitalization or all-cause mortality, and heart failure hospitalization or all-cause mortality among participants with heart failure (H) with preserved ejection fraction (HFpEF) in the invasive cardiopulmonary exercise testing (iCPET) cohort. Hazard ratios (HRs) were estimated from Cox models adjusted for age, sex, and body mass index (BMI). B, Each patient with HFpEF had the number of exercise physiological deficits quantified across all 7 deficits, and was then assigned to a single group based on the total deficit count (0, 1, 2, 3, 4, or ≥5). Deficits were determined from the abnormal thresholds shown in Figure 2A. The plot displays peak oxygen consumption (Vo2) for patients within each deficit-count group, with each dot representing an individual patient. Boxplots display median, interquartile range, and overall distribution. One-way ANOVA suggested significant differences across all groups (P<0.0001). C, Prognostic association of compound physiological deficits in…

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  Figure 4.. Metabolic correlates of physiological deficits in HFpEF. A, Joint metabolite-deficit associations across the 7 deficits from linear regression models built in invasive cardiopulmonary exercise testing (iCPET) participants with heart failure with preserved ejection fraction (HFpEF) adjusted for age and sex. B, This result shown graphically through a heat map of estimated regression coefficients of metabolite-deficit associations, subset to metabolites significantly associated with ≥4 clinical phenotypes. HN and HP in metabolite name are hydrophobic interaction liquid chromatography (HILIC) negative and HILIC positive, respectively. *False discovery rate (FDR) <0.05. Full regression results are available in Supplementary Data File 1. C, Metabolites (FDR <0.05) related to peripheral (arteriovenous oxygen content difference [Cavo2]) and central (pulmonary capillary wedge pressure/cardiac output [PCWP/CO] slope) deficits. MVV indicates maximum voluntary ventilation; PVR, pulmonary vascular resistance; and VE, minute ventilation.

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  Figure 5.. Genes implicated by the deficit metabolome map to genome-wide signals in HF and HFpEF comorbidities by TWAS. A, Quantile-quantile plot of observed and expected P values for each included tissue (see Methods) in transcriptome-wide association studies (TWASs) of the largest genetic study in heart failure (HF; ≈2 million participants). B, Heat map of the TWAS effect size from the HF TWAS (more positive=higher HF risk) for genes that were significant at 5% false discovery rate in at least 1 tissue (FDR; per tissue) and within top 20 for each tissue (ranked by product of significance level and effect size; see Methods). An effect size of 0 was entered for those genes for which a TWAS model was not able to be constructed to facilitate cluster visualization. C, Intersects between significant genes (at 5% FDR) across tissues in the HF TWAS. Red arrow denotes the intersect of all tissues, with the 7 corresponding genes labeled (Table 3 provides ontology). D through F, Quantile-quantile plots for genes implicated by the deficit metabolome in diabetes (D), creatinine (E), and body mass index (F), demonstrating enriched signals for these HF with preserved ejection fraction (HFpEF)…

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  Figure 6.. Survival analysis of metabolic signatures of physiological deficits in HFpEF. Forest plots of association hazards from Cox models comparing the least absolute shrinkage and selection operator–based metabolite signatures of each deficit against our 2 coprimary outcomes: composite cardiovascular event or all-cause mortality and composite heart failure (HF) event or all-cause mortality. Cavo2 indicates arteriovenous oxygen content difference; CO, cardiac output; CV, cardiovascular; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; MVV, maximum voluntary ventilation; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; VE, minute ventilation; and Vo2, oxygen consumption.

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  Figure 7.. Relation of metabolic signatures of physiological deficits derived in HFpEF iCPET sample to key clinical-demographic risk factors for HFpEF in MESA. Stacked bar plot (top) depicts variance in each metabolite score explained by key demographic and clinical risk factors, estimated by type I sums of squares from multivariable regression models. Heat map (bottom) depicts associations between metabolic signatures and these risk factors as mean standardized differences in metabolic signatures comparing presence and absence of dichotomous characteristics or per 1-SD increment in continuous characteristics, estimated with linear regression and adjusted for study site. Cavo2 indicates arteriovenous oxygen content difference; CO, cardiac output; HFpEF, heart failure with preserved ejection fraction; iCPET, invasive cardiopulmonary exercise testing; MESA, Multi-Ethnic Study of Atherosclerosis; MVV, maximum voluntary ventilation; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; VE, minute ventilation; and Vo2, oxygen consumption. *P<0.05. **P<0.01. ***P<0.001.

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  Figure 8.. Clinical-structural associations of metabolic signatures of physiological deficits in MESA. A, Standardized mean difference in cardiac characteristics per 1-SD increment in metabolic signatures, estimated with linear regression and adjusted for study site, age, sex, and self-reported race and ethnicity. Sample sizes varied by cardiovascular magnetic resonance imaging (CMR) parameter: n=4684 for left ventricular (LV) ejection fraction (LVEF), LV mass indexed by body surface area (LVMi), and LV mass-to-volume ratio; and n=4007 for maximum left atrial volume indexed by body surface area (LAVi); B, Results of survival analysis for all-cause HF and HF with preserved ejection fraction (HFpEF)–specific hazards. Standardized hazard ratios (HRs) were estimated with Cox models in 6345 participants in MESA (Multi-Ethnic Study of Atherosclerosis) with 441 incident HF cases (any subtype) adjudicated over a median of 18.6 years. Forest plot shows results for analyses adjusted for study site, age, sex, and self-reported race and ethnicity (model 1) and further adjusted for traditional cardiovascular risk factors (model 2; see Supplementary Data File 1). Complete results of these analyses are…