Incident Heart Failure in Chronic Inflammatory Diseases

Is it Time to Rethink Stage A Heart Failure?

Douglas L. Mann, MD

Disclosures

JACC Heart Fail. 2020;8(6):499-500. 

The observation that elevated levels of inflammatory biomarkers were detected in patients with acute and chronic heart failure (HF), regardless of left ventricular ejection fraction, suggested a previously unrecognized role for the activation of innate and adaptive immune responses in the pathogenesis of HF.[1] Although early attempts to target inflammation in phase III clinical trials were fraught and resulted in neutral or worsening clinical outcomes,[2] results of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) showed that treatment with canakinumab, an interleukin- 1β antagonist, reduced HF hospitalization and HF-related mortality in patients with evidence of systemic, elevated levels of high-sensitivity C-reactive protein levels,[3] thus providing the first clear demonstration that reducing inflammation improves clinical outcomes in selected patients. Given that backdrop, the results of the study by Prasada et al.[4] in this issue of JACC: Heart Failure, which investigated incident HF in patients with chronic inflammatory disease, are of considerable interest.

To determine the risks of incident HF among patients with a different chronic inflammatory diseases, Prasada et al.[4] analyzed the electronic health records of 18,217 patients with chronic inflammatory diseases and 19,315 patients without a chronic inflammatory disease, who were followed in a large urban medical center. Patients with known HF at baseline were excluded from the analysis. Rates of incident HF were determined by Kaplan-Meier analysis and were adjusted for age, sex, insurance status, baseline diabetes, and hypertension. The major findings of the study were that the rates of incident HF were strikingly different among patients with different chronic inflammatory diseases. The authors observed the following risk of incident HF (in rank order): systemic sclerosis (hazard ratio [HR]: 7.26; 95% confidence interval [CI]: 5.72 to 9.21; p < 0.01) > systemic lupus erythematosus (HR: 3.15; 95% CI: 2.41 to 4.11; p < 0.01) > rheumatoid arthritis (HR: 1.39; 95% CI: 1.13 to 1.71; p < 0.01), > HIV (HR: 1.28; 95% CI: 0.99 to 1.66; p = 0.06). There was no association of psoriasis or inflammatory bowel disease with incident HF, although patients with these chronic inflammatory diseases had higher C-reactive protein levels than control subjects. The predominant HF phenotype in systemic sclerosis and rheumatoid arthritis was HF with a preserved ejection fraction (HFpEF). In contrast, the phenotype for patients with systemic lupus erythematosus was mixed, with equal numbers of HFpEF and HF with a reduced ejection fraction (HFrEF). Interestingly, patients with HIV, who had a marginally increased risk of incident HF had the lowest left ventricular EF and the greatest LV dilation. In an exploratory analysis, the authors observed an association between higher C-reactive protein levels and higher risk of HF. Intriguingly, the risk of incident HF was less among patients with hypertension and diabetes than in patients with chronic inflammatory diseases.

Results of the study by Prasada et al.[4] confirm findings in prior studies that demonstrated an association between chronic inflammatory disease (e.g., rheumatoid arthritis) and the development of incident HF and, thus, provide further evidence that inflammation is a mechanism and not simply a biomarker of tissue injury in HF. What is important about this study, however, is the observation that the risk of incident HF was strikingly different among patients with different chronic inflammatory diseases and that the observed HF phenotype ranged from HFrEF to HFpEF, emphasizing the fact that the contribution of inflammation to the pathogenesis of HF is nuanced and context-dependent.[4] Beyond the novelty and importance of the findings, the results of the study by Prasada et al.[4] highlight the need to broaden the epidemiological spectrum of diseases that are considered Stage A HF. Current American College of Cardiology Foundation/American Heart Association/Heart Failure Society of America HF guidelines recommend aggressive treatment of hypertension and lipid disorders (Level of Evidence: A), as well as control of other conditions such as obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents (Level of Evidence: C) in order to prevent the development of the HF in these patient populations.[5] As noted above, Prasada et al.[4] showed that the risk of incident HF was less among patients with hypertension and diabetes than it was for patients with chronic inflammatory diseases, suggesting that chronic inflammatory disorders should be added to the growing list of Stage A diseases that culminate in Stages B and C HF.[4] Beyond that, the provocative results by Prasada et al.[4] also highlight another issue with respect to our current approach to Stage A HF. That is, the guidelines provide a Class I recommendation for modifying risk factors (e.g., hypertension and lipid disorders) that lead to the development of structural heart disease and incident HF, whereas the guidelines only provide a Class IIa recommendation for using biomarker-based screening to prevent the development of structural heart disease, insofar as the data in support of this later approach are limited. Given that it may not be possible currently to reduce risk factors for the development of many chronic inflammatory diseases, the study by Prasada et al.[4] highlights the need to focus on screening strategies to identify incident HF, as well as the need to understand whether conventional guideline-directed medical therapies will be effective in preventing Stages B and C HF in this unique group of patients. The best way to treat HF is to prevent it from ever developing. In order to prevent HF from developing, we will need to develop better tools for knowing whom to treat and when to treat them.

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