Prognostic Importance of Pathophysiologic Markers in Patients With Heart Failure and Preserved Ejection Fraction

Abstract

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown. Methods and Results We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area change, and 34% had RV hypertrophy. During a median follow-up time of 18 months, 102 (24%) were hospitalized for HF and 175 (42%) experienced the composite end point of cardiovascular hospitalization or death. Decreased LV compliance, measured as reduced LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg (EDV20), and RV remodeling, as indicated by increased RV wall thickness, were the 2 pathophysiologic markers most predictive of worse outcomes: adjusted hazard ratio per 1 SD decrease in EDV20=1.39 (95% confidence interval [CI], 1.10–1.75; P=0.006), and hazard ratio per 1 SD increase in RV wall thickness=1.37 (95% CI, 1.16–1.61; P<0.001). These associations persisted after additional adjustment for markers of HF severity. By contrast, markers of LV relaxation, longitudinal LV systolic dysfunction, and ventricular-arterial coupling were not significantly associated with adverse outcomes. Conclusions In patients with HFpEF, reduced LV compliance and RV remodeling are the strongest pathophysiologic predictors of adverse outcomes.

Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial

“…Making the assessment that the dyspnea and fatigue of a patient with a preserved ejection fraction are attributed to heart failure rather than to the commonly associated comorbidities is notoriously difficult. [23][24][25][26][27][28][29][30] The additional protocol inclusion criterion in TOPCAT of either a prior hospitalization in which heart failure was a prominent feature or an elevated natriuretic peptide level was intended to both improve diagnostic certainty and to augment risk. The assumption that those with a prior hospitalization would have higher risk [31][32][33][34][35] was confirmed only for the patients randomized from the Americas, suggesting that the nonadjudicated qualifying hospitalization criterion enrolled different patient populations.…”

“…45,46 This lack of evidence-based guidelines for treatment of heart failure with preserved ejection fraction continues to be perpetuated because diagnostic uncertainties, diverse and poorly understood mechanistic underpinnings, lack of animal models, and heterogeneous phenotypes with relatively greater contribution of comorbidities are some of the heightened challenges to garnering the extensive resources needed to conduct outcome trials in these patients. [21][22][23][24][25][26][27][28]47 In the absence of definitive data and with no new outcome trial results in the near term, physicians and patients faced with this serious medical condition must use the best available information to guide their therapeutic decisions. The overall neutral finding of TOPCAT with the observation of fewer hospitalizations for heart failure in the patients assigned to spironolactone would generally be considered the most reliable result of the trial.…”

Pulmonary Hypertension in Heart Failure Preserved Ejection Fraction

“…44 Data from Mohammed et al, 41 obtained in 548 subjects with HFpEF with variable degree of PH and RV involvement, documented a worse prognosis for patients with PASP above the median (>47 mm Hg) and RV systolic dysfunction. Interestingly, RV systolic dysfunction was a significant predictor of mortality even after adjustment for age and PASP in a Cox regression model (Hazard Ratio=1.4, P=0.02; Figure 5).…”

“…6 Studies investigating the pattern of right heart function and geometry in PH-HFpEF are summarized in Table 1. [9][10][11]14,15,21,[40][41][42][43][44][45] In a report by Puwanant et al, 11 RV dysfunction, assessed by RV fractional area and tissue Doppler S prime, was not uncommon in patients with HFpEF although in a milder degree compared with HFrEF. Similar findings were reported by looking at RV global longitudinal early diastolic strain rate and systolic RV global longitudinal systolic strain.…”

Effective Arterial Elastance Is Insensitive to Pulsatile Arterial Load

“…45 Because E A is used along with end-systolic LV elastance as an index of ventricular-arterial coupling, our findings imply that this paradigm does not properly assess the effects of pulsatile load on the heart. The pressure-volume paradigm characterizes only limited aspects of ventricular-arterial coupling (such as energetic efficiency and SV changes), which is a much broader concept.…”