OECAD is highly prevalent among patients with HFpEF. In the ESC Heart Failure Long-Term Registry, approximately 24% had a primary etiology of ischemic heart disease, with 13% of percutaneous coronary intervention (PCI) and 9% of coronary artery bypass graft (CABG). However, this likely underestimates the true prevalence, because many cases of asymptomatic or subclinical ischemia may go undetected without formal imaging. For example, among patients with HFpEF who underwent coronary angiography, a total of 68% were found to have angiographically confirmed OECAD. In a large observational cohort of HF patients undergoing coronary computed tomography angiography (CCTA), asymptomatic coronary atherosclerosis was present in over 78% of patients with HFpEF. Moreover, the extent of OECAD was independently associated with an increased risk of cardiovascular death, nonfatal myocardial infarction (MI), and HF hospitalization during follow-up, and OECAD is recognized as a significant risk factor for the development of HFpEF. These findings firmly establish CAD as a common and potentially modifiable factor in the HFpEF population.

CMD is even more prevalent than OECAD among patients with HFpEF and may be particularly important in women and those without traditional cardiovascular risk factors. ^,, Obstructive or nonobstructive CAD are present in up to 81% of HFpEF patients. ^,

The PROMIS-HFpEF study (Prospective Comparison of Angiographic CMD and Outcomes in HFpEF) employed adenosine stress transthoracic Doppler echocardiography to quantify coronary flow reserve (CFR) in 202 prospectively enrolled patients [14]. Remarkably, 75% of these patients had a CFR <2.0, which was strongly associated with symptoms, impaired functional capacity, and higher N-terminal pro–B-type Natriuretic Peptide (NT-proBNP). Other studies using positron emission tomography (PET) to assess CFR have confirmed this high prevalence. Taqueti et al. demonstrated that 53% of HFpEF patients had CFR <2.0, and that reduced flow reserve correlated independently with hospitalization and mortality. In a 2023 systematic review and meta-analysis including 10 studies and 822 patients with HFpEF, the pooled prevalence of CMD in HFpEF was 71% (95% confidence interval (CI) 0.63 to 0.79). In the subgroup analysis, the prevalence of CMD was 79% (95% CI, 0.71 to 0.87) by invasive measurement and 66% (95% CI, 0.54 to 0.77) by noninvasive measurement and 67% (95% CI, 0.52 to 0.82) with CFR < 2.0 and 75% (95% CI, 0.71 to 0.79) with CFR < 2.5. These data emphasize that CMD is not a rare epiphenomenon, but rather a dominant component of HFpEF.

Flow-limiting epicardial stenoses reduce coronary perfusion pressure, especially during exertion, leading to repetitive subendocardial ischemia. In contrast to HFrEF, where infarction and necrosis dominate, ischemia in HFpEF tends to be more chronic, patchy, and sublethal, leading to low-grade injury and fibrosis rather than overt scarring. ^,, Such low-grade ischemia activates pro-fibrotic signaling cascades including transforming growth factor beta, galectin-3, and connective tissue growth factor, which enhance fibroblast proliferation and matrix cross-linking. These changes increase left ventricular diastolic stiffness, promote concentric hypertrophy, and reduce compliance. ^, Moreover, myocardial ischemia reduces nitric oxide bioavailability and raises levels of endothelin-1 (ET-1), both of which compromise vascular function and promote vasoconstriction, creating a feedback loop that further intensifies the ischemic condition. ^,

CMD refers to structural and functional abnormalities of small coronary arterioles, resulting in impaired vasodilation, elevated microvascular resistance, and reduced CFR. Prior studies suggest that CMD arises from endothelial dysfunction with reduced nitric oxide bioavailability, increased oxidative stress, chronic inflammation, capillary rarefaction, and neuro-humoral dysregulation. Also, histological evidence from endomyocardial biopsies and autopsy studies has demonstrated significantly reduced capillary density in the myocardium of HFpEF patients with CMD, supporting the concept that microvascular rarefaction contributes to myocardial stiffening and fibrosis. In addition, CMD has been associated with altered myocardial metabolism, including increased reliance on fatty-acid oxidation, mitochondrial inefficiency, and elevated myocardial oxygen consumption, which may further exacerbate energetic mismatch in HFpEF. Importantly, CMD may also contribute to left-atrial dysfunction due to atrial ischemia, which in turn elevates left-ventricular filling pressures during exertion and impairs exercise capacity. These hemodynamic consequences are increasingly recognized as central to the pathophysiology of CMD-driven HFpEF. ^,

Patients with HFpEF and CAD should receive standard anti-anginal therapies for ischemia relief, although evidence for outcome benefit in HFpEF is limited. Beta-blockers remain first-line to reduce myocardial oxygen demand and control heart rate; observational data suggest beta-blockers may confer a survival benefit in HFpEF. However, no dedicated HFpEF trial has proven that beta-blockers reduce mortality. This underscores the fact that beta-blockers are primarily used to treat coexisting conditions, such as angina, atrial fibrillation, and hypertension.

Other heart rate-lowering agents have shown neutral results in HFpEF. The If-channel inhibitor ivabradine, which benefits HFrEF with tachycardia, did not improve diastolic function or exercise capacity in HFpEF.

Metabolic anti-anginals have also been tested. Ranolazine, a late sodium current inhibitor, was hypothesized to improve diastolic function. In the RALI-DHF trial, a 14-day course of ranolazine in HFpEF led to acute hemodynamic improvements (lower left ventricular end-diastolic pressure and pulmonary capillary wedge pressure) but no sustained change in diastolic relaxation or natriuretic peptides. Thus, ranolazine may relieve filling pressures transiently but without proven long-term benefit in HFpEF.

Nitrates, traditionally used for angina, surprisingly showed no benefit in HFpEF. The NEAT-HFpEF trial evaluated long-acting nitrates (isosorbide mononitrate) in HFpEF and found no improvement in exercise tolerance.

Beyond symptom control, several pharmacologic therapies target disease processes common to CAD and HFpEF (endothelial dysfunction, adverse remodeling, inflammation). Statins are advised in HFpEF patients with CAD risk factors given their well-known cardiovascular benefits. While no HFpEF-specific statin trial exists, meta-analyses of observational studies suggest statin therapy may improve survival in HFpEF. One analysis reported statin use was associated with lower all-cause mortality (odds ratio [95% CI] = 0.690 [0.493 to 0.965], p = 0.030) in HFpEF populations. Similarly, another study confirmed statins significantly reduced mortality in HFpEF. Thus, statins are indicated to modify atherosclerotic disease and potentially favorably impact HFpEF outcomes.

Blockade of the renin–angiotensin–aldosterone system (RAAS) has yielded mixed results in HFpEF. Large trials of RAAS blockers (e.g., PEP-CHF, I-PRESERVE, CHARM-Preserved) did not clearly improve primary outcomes in HFpEF. A meta-analysis found no mortality reduction with RAAS blockers in randomized HFpEF trials (relative risk 1.02, 95% CI 0.93-1.11), but observational studies suggested improved survival (relative risk 0.91, 95%CI 0.87 to 0.95). The angiotensin receptor–neprilysin inhibitor sacubitril/valsartan has also been evaluated in HFpEF. The PARAGON HF trial narrowly missed its primary endpoint: sacubitril/valsartan reduced total HF hospitalizations and cardiovascular death by 13% compared to valsartan alone, but this did not reach statistical significance. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was shown in FINEARTS-HF to reduce total HF events and cardiovascular death composite by 16% in HFpEF. Early evidence supports its potential benefit in HFpEF, including CAD subgroups, though further phenotype-specific analysis is needed.

Sodium-glucose co-transporter 2 inhibitors have demonstrated the most consistent benefit. Empagliflozin reduced HF hospitalizations in EMPEROR-Preserved, while dapagliflozin achieved similar results in DELIVER, with efficacy independent of CAD status. ^,

CMD is prevalent in HFpEF and contributes to exercise intolerance. Targeted therapies for CMD in HFpEF are under investigation, though results to date have been largely negative or neutral. Inorganic nitrite (INDIE-HFpEF) did not improve peak VO₂ or NT-proBNP. Sildenafil failed to improve functional capacity in RELAX, and endothelin receptor antagonists (e.g., macitentan) have shown no benefit, with safety concerns in trials like SERENADE.

In CAD-HFpEF patients with flow-limiting stenoses, complete revascularization is associated with improved survival and fewer HF hospitalizations. On the other hand, more recent studies have cast doubt on the idea that an invasive strategy offers any mortality benefits. A 2022 propensity-matched analysis compared an initial invasive approach (angiography ± PCI/CABG) versus conservative medical therapy in HFpEF with CAD. Over 5 years, an invasive strategy did not reduce all-cause death or cardiovascular hospitalization compared to medical therapy alone.