Beyond Congestion: The Wet-Cold Phenotype Drives Mortality in Obese HFpEF

Introduction: Re-evaluating the Hemodynamic Landscape of HFpEF

Heart failure with preserved ejection fraction (HFpEF) has long been considered a heterogeneous syndrome, often associated with comorbidities such as hypertension, diabetes, and notably, obesity. For years, the prevailing clinical assumption was that HFpEF was primarily a disease of diastolic dysfunction and congestion, where cardiac output remained relatively preserved—the so-called warm-wet or warm-dry phenotypes. However, recent evidence suggests that a significant subset of these patients may suffer from impaired flow, a finding that is particularly nuanced in the context of the obesity epidemic.

A landmark study by Jani et al., published in JACC: Heart Failure, provides a critical interrogation of this assumption. By characterizing predominantly overweight and obese HFpEF patients through invasive hemodynamic assessment, the researchers have identified a prevalent and under-recognized low-output phenotype that significantly drives adverse clinical outcomes. This discovery challenges the current diagnostic paradigms and suggests that we must look beyond ejection fraction to understand the true hemodynamic burden of HFpEF.

Background: The Obesity Paradox and Hemodynamic Challenges

Obesity is a primary driver of HFpEF, contributing to systemic inflammation, epicardial fat accumulation, and increased blood volume. Yet, the hemodynamic assessment of obese HFpEF patients is fraught with difficulty. Non-invasive measures, such as echocardiography, often provide suboptimal images or unreliable estimates of filling pressures due to body habitus. Even invasive right heart catheterization (RHC) can be complicated by high intrathoracic pressures, which may lead to overestimation of pulmonary capillary wedge pressure (PCWP) if not carefully corrected.

Furthermore, the “obesity paradox” in heart failure—where higher body mass index (BMI) is sometimes associated with better survival—has complicated the interpretation of risk. The study by Jani et al. aims to cut through this complexity by correlating direct hemodynamic measurements of congestion (PCWP) and perfusion (Cardiac Index) with long-term clinical mortality in a cohort where obesity is the rule rather than the exception.

Study Design and Methodology

The researchers analyzed a cohort of 227 patients referred to the Johns Hopkins HFpEF Clinic. All patients met the clinical criteria for HFpEF and underwent RHC to establish a definitive hemodynamic profile. The cohort was predominantly overweight or obese, reflecting the typical demographic of modern HFpEF populations.

Patients were categorized into four distinct hemodynamic phenotypes based on their PCWP and Cardiac Index (CI):

1. Dry-Warm: PCWP 2.2 L/min/m2
2. Wet-Warm: PCWP ≥15 mm Hg and CI >2.2 L/min/m2
3. Dry-Cold: PCWP <15 mm Hg and CI ≤2.2 L/min/m2
4. Wet-Cold: PCWP ≥15 mm Hg and CI ≤2.2 L/min/m2

The study utilized both the thermodilution and Fick methods for calculating cardiac output, ensuring a robust assessment of perfusion. The primary endpoint was all-cause mortality, with a median follow-up time of 39 months.

Clinical and Hemodynamic Phenotypes: A Four-Quadrant Analysis

The results revealed a striking distribution of phenotypes. Contrary to the belief that HFpEF is strictly a high-output or normal-output state, 34% of the cohort fell into the “cold” category (CI ≤ 2.2 L/min/m2).

Patients in the “cold” profile (comprising both dry-cold and wet-cold) were generally older (68 vs. 62 years) and more likely to be male compared to those in the “warm” profile. There was also a significantly higher prevalence of atrial fibrillation in the cold group, suggesting that rhythm disturbances and the loss of atrial kick may contribute significantly to reduced cardiac output in this population.

From a biochemical perspective, the “wet-cold” group—the most hemodynamically compromised—exhibited the highest levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), with a median of 469 pg/mL. They also demonstrated higher pulmonary vascular resistance (PVR) indices, indicating that the low-output state in HFpEF is often compounded by pulmonary vascular remodeling and right heart strain.

Key Findings: The Impact of Low Perfusion on Survival

The most significant finding of the study was the clear association between low cardiac perfusion and mortality. Kaplan-Meier survival analysis demonstrated that HFpEF patients with a low cardiac index had significantly worse outcomes.

Critically, the “wet-cold” phenotype represented the highest risk group. These patients suffer from the dual burden of congestion and poor systemic perfusion. Even after accounting for potential overcorrection of hemodynamic data due to BMI, the low-output state remained a potent independent predictor of death. This suggests that the “cold” phenotype is not merely a statistical artifact of how cardiac index is calculated in obese individuals but represents a genuine physiological failure of the heart to meet the metabolic demands of the body.

Interestingly, 68% of the wet-cold patients were on beta-blocker therapy. While beta-blockers are a cornerstone of HFrEF (reduced ejection fraction) management, their role in HFpEF is less clear and sometimes controversial. In a patient with an already depressed cardiac index, the negative chronotropic and inotropic effects of beta-blockers might further exacerbate the low-output state, potentially contributing to the poor outcomes observed in this subgroup.

Mechanistic Insights: Why Low Output Occurs in HFpEF

The identification of a low-output state in HFpEF necessitates a deeper look at the underlying biology. Several factors may contribute:

1. Chronotropic Incompetence: Many HFpEF patients cannot appropriately increase their heart rate during stress, which, when combined with a fixed or limited stroke volume, results in a failure to increase cardiac output.
2. Impaired Inotropic Reserve: Despite a “normal” ejection fraction at rest, the HFpEF heart may have subclinical systolic dysfunction that becomes apparent under hemodynamic loading or during exercise.
3. Pulmonary Hypertension: High PVR, as seen in the wet-cold group, increases right ventricular afterload, leading to right heart dysfunction and decreased left ventricular filling (preload), which subsequently lowers systemic output.
4. Atrial Fibrillation: The high prevalence of AFib in the cold group suggests that the loss of coordinated atrial contraction is a major contributor to low flow in HFpEF.

Clinical Implications for Practice

These findings have immediate implications for the management of HFpEF, particularly in specialized clinics.

First, the study underscores the value of right heart catheterization. While non-invasive testing is the first line, RHC remains the gold standard for identifying the specific hemodynamic phenotype. Clinicians should be particularly vigilant when treating patients who present with traditional signs of congestion but fail to improve with diuretics alone; these patients may be “cold” and require a different therapeutic approach.

Second, the high mortality of the wet-cold group suggests that we need to reconsider our therapeutic priorities. For a patient in a low-output state, aggressive diuresis must be balanced with strategies to maintain or improve perfusion. This might include heart rate optimization (especially in the context of AFib) or, in selected cases, the cautious withdrawal of medications that depress cardiac output.

Expert Commentary: Addressing the Diagnostic Gap

Experts in the field note that the “low-output HFpEF” phenotype is often a diagnostic blind spot. Because the ejection fraction is normal, clinicians may prematurely rule out pump failure as a cause of the patient’s symptoms. This study provides the evidence needed to broaden the clinical definition of heart failure severity in HFpEF beyond filling pressures.

However, limitations must be acknowledged. This was a single-center study at a specialized HFpEF clinic, which may introduce referral bias. The patients seen at Johns Hopkins may represent a more advanced or complex subset of the general HFpEF population. Additionally, while the study links the cold phenotype to mortality, it does not provide a randomized trial of specific interventions for this group. Further research is needed to determine if tailored therapies—such as those targeting pulmonary vascular resistance or heart rate—can improve survival in the wet-cold obese HFpEF patient.

Conclusion: A Call for Precise Hemodynamic Characterization

The work of Jani et al. serves as a powerful reminder that HFpEF is not a benign condition, nor is it a uniform one. In a predominantly overweight and obese population, over one-third of patients exhibit a low-output hemodynamic state that is associated with significantly increased mortality.

Recognizing the “wet-cold” phenotype is essential for risk stratification and clinical decision-making. As the medical community moves toward precision medicine, the integration of detailed hemodynamic profiling will be vital in developing targeted therapies that address both the congestion and the perfusion deficits that define this high-risk HFpEF population.

References

1. Jani VP, Vaishnav J, Vungarala S, et al. Congestion and Low Cardiac Output Hemodynamic Phenotype Drives Outcomes in Overweight and Obese HFpEF. JACC Heart Fail. 2025 Nov;13(11):102586. doi: 10.1016/j.jchf.2025.102586.
2. Borlaug BA. Evaluation and Management of Heart Failure with Preserved Ejection Fraction. Nat Rev Cardiol. 2020;17(9):559-573.
3. Reddy YNV, et al. Hemodynamic Heterogeneity of Heart Failure With Preserved Ejection Fraction. Circulation. 2018;137(13):1413-1425.