It is with great interest that we read the paper written by Isaacs et al entitled “Impacts of Mitral Annular Calcification on Heart Failure with Preserved Ejection Fraction” published in the American Journal of Cardiology.
Heart failure with preserved ejection fraction (HFpEF) remains the metaphorical “wild west” of heart failure in contrast to the well-mapped territory of heart failure with reduced ejection fraction (HFrEF). Classically HFpEF has been understood to be driven by states of systemic inflammation and aging such as hypertension, obesity, diabetes, amyloidosis, and chronic kidney disease. These states ultimately lead to impaired ventricular relaxation and reduced preload, thus heart failure with preserved systolic function.
In recent years, the role of mitral annular calcification (MAC) has become implicated in clinical sequala of HFpEF. , However, there remains a large gap in the literature examining the interplay between MAC and HFpEF. Isaacs et al aim to address this in their recent publication. They also aim to investigate how BMI influences the relationship between MAC and HFpEF.
To do this, Isaacs et al designed a series of 3 observational studies. They built their study cohorts using data from TriNetX US Collaborative Network, a deidentified system that collects from 71 healthcare organizations. Exclusion criteria included rheumatic mitral disease, HFrEF, and combined diastolic and systolic heart failure. The authors first queried for all patients greater than age 50 in the TriNetX system from January 1, 2020, to December 31, 2023. Every patient had at least 1 full year of follow-up data and a recorded BMI. Patients were stratified by the presence of MAC based on ICD codes.
For each of the 3 studies, a propensity score match with a 1:1 technique was performed. They matched on demographic and comorbidities including race, sex, diabetes, smoking history, ischemic heart disease, cerebrovascular disease, hypertensive disease, hyperlipidemia, chronic kidney disease, atrial fibrillation/flutter, and sleep apnea. BMI was additional matching factor in the first 2 studies only.
In Study 1, they examined how MAC impacted subsequent HFpEF development. All hospitalized patients from 2020 to 2023 without prior heart failure were stratified by presence or absence of MAC. Their risk of developing HFpEF at years 1 and 2 was examined. The final propensity matched cohorts included 10,628 patients in each cohort. Patients with MAC were at higher risk of developing HFpEF (HR 3.80, p <0.0001), HFrEF (HR 2.189, p <0.0001), and all types of heart failure failure (HR 2.795, p <0.0001) at the 1-year follow-up.
In Study 2, they examined how a MAC diagnosis in patients with HFpEF impacted cardiovascular outcomes 1-year later. The goal of Study 2 was to understand the impact of MAC in patients who have already developed HFpEF. The final propensity matched cohorts included 3,117 patients in each cohort. HFpEF patients with MAC were found to have a higher risk of heart failure related hospitalizations (HR 1.24, p <0.0001) compared to HFpEF patients without MAC. Additionally, HFpEF and MAC patients were found to have a higher risk of all-cause hospitalization (HR 1.34, p <0.0001) and were at greater risk of developing other tracked cardiovascular outcomes. These outcomes included higher risk of ICU admission, prosthetic valve replacement, pacemaker placement, ischemic heart disease, cerebrovascular disease, aortic stenosis, acute renal failure, and cardiogenic shock.
In Study 3, the authors further examined the cohorts in Study 1 to explore how BMI impacted the observed interaction between MAC and HFpEF. They looked at the 1-year incidence of HFpEF in patients with and without MAC after stratifying patients by BMI quintiles. A BMI of 20 to 24.9 was used as the reference quintile. They found that the incidence of HFpEF in the non-MAC group was low. They also observed a “j-shaped” curve across BMI quintiles in the non-MAC group, meaning that the incidence of all heart failure, but particularly HFpEF, was greater in the BMI <20 and ≥35. In the MAC group, there was a greater incidence of developing HFpEF, with little impact from BMI, except in the BMI ≥35 group. Thus, they conclude that the presence of MAC increases the risk of developing HFpEF more than obesity.
This paper draws strength from its large sample size and its excellent propensity scoring allowing for control of many confounders. Additionally, the authors thoughtfully excluded cofounding diagnoses (i.e., rheumatic mitral valve disease and ESRD) from the initial cohorts.
This paper has limitations to consider. First, their data draws from electronic medical records coded across many different healthcare systems, leaving the analysis vulnerable to biases from different coding practices and data-entry inaccuracies. Secondly, the severity of MAC cannot be distinguished in the dataset. Finally, the TriNetX system is known to underestimate mortality counts, thus the role of MAC on HFpEF mortality outcomes is unknown. However, the authors opted instead to examine rates of future hospitalization, which serves as a potential marker for increased disease severity and increased health care resource utilization.
Futures studies examining the mechanisms behind these observations, the impact of MAC on mortality in HFpEF, and what role severity of MAC has on HFpEF are warranted.
We applaud the authors again on performing the largest to date observational study demonstrating how the presence of MAC significantly increases the risk of HFpEF, predicts worse cardiovascular outcomes in patients who already have developed HFpEF, and serves as an important clinic marker for HFpEF likely to an even greater extent than obesity.
CRediT authorship contribution statement
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