Diastolic HF: Target Comorbidities
It’s One of the Few Things That Seems to Work
ACCEL | Given the striking lack of effective therapies for managing patients with HFpEF (or ‘diastolic’ HF), two recent papers in JACC—both co-authored by Christopher M. O’Connor, MD, FACC Editor-in-Chief of JACC Heart Failure—offer insights that may provide new directions for therapy and disease management.
One paper focuses on noncardiac comorbidities.1 The fact that patients with HF typically have multiple comorbidities is not news, but the extent of the problem was highlighted in data from the Centers for Medicare & Medicaid Services, demonstrating that 55% of Medicare patients coded as having HF have >5 chronic comorbidities.2 Looking at the prevalence of specific comorbidities, O’Connor and colleagues focused on several of the most common: chronic obstructive pulmonary disease (COPD), anemia, diabetes mellitus (DM), renal disease, sleep-disordered breathing (SDB), and obesity.
Why Focus on Comorbidities?
Yes, comorbidities are almost universal in patients with HF, but guidelines provide little discussion of these comorbidities. This is not surprising given that so many are noncardiac in nature and the evidence base is sparse and mostly observational. Compared to patients with HFrEF, patients with preserved ejection fraction tend to have an increased burden of COPD, DM, and anemia, which are all associated with increased morbidity and mortality.
Because the development of novel HF therapies has slowed in recent years, and most contemporary HF trials have failed to improve outcomes above standard medical therapy, O’Connor et al. suggest the need for a critical reappraisal of treatment strategies in HF in which clinicians target comorbidities, in addition to targeting the underlying cardiac dysfunction. This approach may be particularly relevant for HFpEF patients for whom no therapies are available to reduce the substantial morbidity and mortality.
Another big factor: there is a bidirectional impact for many comorbidities. Here are some examples:
COPD: It is more prevalent in HFpEF and is associated with higher mortality risk than in patients with HFrEF. COPD drives inflammation, hypoxia, parenchymal changes, and airflow limitation leading to pulmonary congestion. In addition, it leads to abnormal left ventricular (LV) diastolic filling. Therapy for COPD, specifically, inhaled beta-agonists, can also complicate matters for patients with HF. Conversely, looking at HF specifics, elevated end-diastolic pressure and beta-blocker use may compromise lung function.
Anemia: Besides adverse remodeling, anemia produces cardiorenal effects and increases neurohormonal and inflammatory cytokines, all of which are deleterious in the setting of HF. Going the other way, HF produces inflammation, hemodilution, renal dysfunction, and metabolic abnormalities, all of which exacerbate anemia.
Diabetes: The growing incidence of DM in the U.S. can lead to diabetic cardiomyopathy, mitochondrial dysfunction, abnormal calcium hemostasis, oxidative stress, RAAS activation, atherosclerosis, and coronary artery disease (CAD). As for HF, it can cause incident and worsening DM via sympathetic and RAAS activation.
Renal dysfunction: It produces sodium and fluid retention, anemia, inflammation, RAAS and sympathetic activation that are met in return by HF that promotes cardiorenal syndrome through low cardiac output, accelerated atherosclerosis, inflammation, and increased venous pressure.
Sleep-disordered breathing: Obstructive sleep apnea (OSA) is estimated to affect ~10% of individuals; however, its prevalence in patients with cardiovascular disease is likely considerably higher (estimated 50% to 80%), although rigorous epidemiological data are still evolving. A recent issue of JACC included a state-of-the-art review on central sleep apnea (CSA)3, which is an important, independent risk factor for worsening HF and reduced survival in patients with HF. While less common than OSA, the situation is complicated by the fact that it is often not identified because its subtle findings often become lost in the signs and symptoms that typically accompany HF. In its corner, SDB in general produces hypoxia, systemic inflammation, sympathetic activation, arrhythmias, hypertension (pulmonary and systemic), right ventricular dysfunction, and worsening congestion. HF punches back with rostral fluid movement that may worsen pharyngeal obstruction and instability of the ventilatory control system.
Obesity: In terms of the epidemic that continues to grow, we know that obesity leads to inflammation, reduced physical activity and deconditioning, hypertension, metabolic syndrome, and DM leading to—well, see above. In what may be the defining example of a vicious circle in cardiology, HF produces fatigue and dyspnea that may limit activity and a spectrum of metabolic disorders that complicate weight loss and may lead to nutritional deficiencies in spite of the excess caloric intake. What about the obesity paradox and the fact that a higher weight may be associated with better outcomes compared with HF patients? That may be true compared with patients with cardiac cachexia and/or nutritional deficiencies, but O’Connor et al. point to associations between obesity and metabolic syndrome, glucose intolerance, and diabetes that seem to explain, in part, the link between increased body weight and adverse events in certain circumstances.
HF by Phenotype:
The second recent paper by O’Connor and colleagues looked at the clinical implications of chronic heart failure phenotypes. The authors start by emphasizing that the contemporary classification of HF leaves a lot to be desired. Its classification relies not on pathogenesis (our understanding of which has improved greatly in recent years) but rather on imprecise measures that may lead to overlapping diagnostic labels and misclassification. For example, chronic HF is still clinically defined along subjective measures of functional status, arbitrary LVEF cut-points (thus the distinction of preserved vs. reduced EF), or stages (A to D), despite the increasing recognition that these constructs provide inadequate phenotyping of the syndrome.
There’s that word again: phenotyping. As O’Connor put it, “Look at what oncologists do: they phenotype, they genotype, they biomarker type their patients and then they get signals in those subgroups and they move the therapy forward.”
O’Connor and others used cluster analysis to explore clinical phenotypes in chronic HF patients. They evaluated 45 baseline clinical variables from 1,619 participants in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, producing four specific clusters (TABLE). The patients in these clusters varied considerably among measures of age, sex, race, symptoms, comorbidities, HF etiology, socioeconomic status, quality of life (QOL), cardiopulmonary exercise testing parameters, and biomarker levels.
The findings are important for several reasons. Measurement of LVEF—the methodology most commonly used to describe HF—was one of a handful of variables that was statistically identical across all four patient clusters; this emphasizes the need for improved descriptions of HF subtypes.
There were two clusters of patients with HF as a result of ischemic cardiomyopathy (clusters one and three) that differed dramatically in frequency and intensity of angina symptoms (prevalence: 11% vs. 97%). Consequently, despite having objective measures of milder disease and far higher rates of revascularization procedures, patients in cluster three had a greater risk of hospitalization and the poorest QOL.
Despite higher rates of rehospitalization, the mortality rates for cluster three patients were 40% lower than cluster one patients. This suggests that novel strategies to improve angina symptoms in this patient subtype might be clinically helpful.
They also identified a cluster of patients who tended to be young, obese African Americans with nonischemic cardiomyopathy. Despite objective evidence of milder disease on the basis of cardiopulmonary exercise testing and HF biomarkers, these patients had high rates of hospitalization and low QOL scores.
Finally, the findings shed light on the shortcomings of clinical trials in patients with HF: a mechanistically sound therapeutic intervention might not show efficacy when tested on a disease state with large phenotypic variations in etiology, clinical features, and natural history.
- Mentz RJ, Kelly JP, von Lueder TG, et al. J Am Coll Cardiol. 2014;64:2281-93.
- Centers for Medicare & Medicaid Services. Chartbook. 2012 Ed. Baltimore, MD:Centers for Medicare & Medicaid Services, 2012.
- Costanzo M, Khayat R, Ponikowski P, et al. J Am Coll Cardiol. 2015;65:72-84.
- Ahmad T, Pencina MJ, Schulte PJ, et al. J Am Coll Cardiol. 2014;64:1765-74.
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