Abstract
Background
Coronary microvascular dysfunction (CMD) is increasingly implicated in heart failure, but reversal with guideline-directed medical therapy (GDMT) is rarely documented using invasive physiology.
Case Summary
A 53-year-old man presented with paroxysmal nocturnal dyspnea. Electrocardiography showed precordial ST–T changes; brain natriuretic peptide was 419 pg/mL; left ventricular ejection fraction 35% with anteroseptal hypokinesis. Coronary angiography revealed intermediate proximal left anterior descending artery disease with nonischemic fractional flow reserve (0.84). Invasive indices indicated CMD (mean transit time [Tmn] 2.41/0.70 s; coronary flow reserve [CFR] 3.4; index of microvascular resistance [IMR] 59). After GDMT, left ventricular ejection fraction normalized (63%), and brain natriuretic peptide fell to 4.0 pg/mL at 3 months. Repeat physiology showed restored microvascular function (Tmn 0.84/0.20 s; CFR 4.2; IMR 15); fractional flow reserve remained nonischemic (0.82).
Discussion
Marked improvement in IMR/CFR supports CMD—rather than epicardial stenosis—as the principal driver of the initial ischemic phenotype. GDMT may enhance microvascular vasodilator tone and myocardial energetics, improving CMD.
Take-Home Message
Contemporary GDMT may favorably modulate the coronary microcirculation; improvement in CMD may parallel clinical recovery.
Key words: coronary microvascular dysfunction, heart failure, ischemic cardiomyopathy
Visual Summary
History of Presentation
A 53-year-old man was admitted with a 2-month history of exertional dyspnea and a 2-week history of paroxysmal nocturnal dyspnea. Chest radiography demonstrated marked cardiomegaly (cardiothoracic ratio 58%) and bilateral pleural effusions (Figure 1A). The 12-lead electrocardiogram showed ST–T abnormalities in the precordial leads (Figure 2A). Laboratory testing revealed a mildly elevated high-sensitivity troponin T (0.027 ng/mL) and an elevated brain natriuretic peptide (BNP) level of 419 pg/mL. Hemoglobin A1c was 8.8%. Transthoracic echocardiography showed mild left ventricular (LV) hypertrophy with a regional wall-motion abnormality in the anteroseptal wall, with left ventricular ejection fraction of 35% (Video 1).
Figure 1.
Serial Chest Radiographic Changes
(A) Baseline chest radiograph demonstrating marked cardiomegaly with bilateral pleural effusions. (B) Chest radiograph at 3-month follow-up showing a reduced cardiothoracic ratio and resolution of effusions.
Figure 2.
Serial Electrocardiographic Changes
(A) Baseline 12-lead electrocardiography (ECG) showing precordial ST–T abnormalities. (B) ECG at 3-month follow-up demonstrating normalization of the precordial ST–T changes.
Past Medical History
The patient's past medical included hypertension, dyslipidemia, and type 2 diabetes mellitus. He had been receiving medications until 2 years prior, when he discontinued therapy because of financial constraints. His father had a history of myocardial infarction. He previously smoked 20 cigarettes/day but quit 7 years ago. He reported heavy alcohol intake, approximately 90-100 g ethanol/day.
Differential Diagnosis
Based on the presentation and initial testing, he was diagnosed with heart failure with reduced ejection fraction (HFrEF). Ischemic cardiomyopathy was the leading consideration; alcoholic cardiomyopathy and cardiac amyloidosis were considered secondary differentials.
Investigations and Management
Guideline-directed medical therapy (GDMT) was initiated, consisting of dapagliflozin 10 mg/day, sacubitril/valsartan 200 mg/day, spironolactone 25 mg/day, bisoprolol 2.5 mg/day, and azosemide 30 mg/day. After 1 week, he was clinically euvolemic and compensated.
We performed coronary angiography, demonstrating only intermediate stenosis in the proximal left anterior descending artery (LAD) with a fractional flow reserve (FFR) of 0.84 (hyperemia induced with 4 mg nicorandil) (Figure 3). Angiography was notable for slow flow in both right and left coronary systems, suggestive of elevated microvascular resistance (Video 2). Invasive coronary function testing in the LAD was therefore performed using a Pressure Wire X (Abbott, IL, USA) and the CoroFlow (Abbott, IL, USA) system. Resting and hyperemic mean transit times (Tmn) were 2.41 s and 0.70 s, respectively; coronary flow reserve (CFR) was 3.4, and the index of microvascular resistance (IMR) was 59—consistent with increased minimal microvascular resistance (Figure 4A).
Figure 3.
Coronary Angiography Depicting an Intermediate Stenosis of the Proximal Left Anterior Descending Artery
Figure 4.
Serial Changes in Coronary Microvascular Function
Invasive coronary physiology at (A) index hospitalization and (B) 3-month follow-up, illustrating interval improvement in microvascular function.
Three months after the index hospitalization, 99mTc-pyrophosphate scintigraphy and cardiac magnetic resonance were obtained to evaluate for specific cardiomyopathies. 99mTc-pyrophosphate imaging did not suggest cardiac amyloidosis, and cardiac magnetic resonance imaging showed no late gadolinium enhancement.
Despite ongoing alcohol use and worsening glycemic control (hemoglobin A1c 9.1%), left ventricular systolic function had completely recovered (left ventricular ejection fraction 63%), with resolution of regional wall-motion abnormalities (Video 3). In parallel, BNP levels decreased to 4.0 pg/mL, the cardiothoracic ratio improved to 49% on chest radiography, and previously observed ST–T abnormalities had resolved (Figure 1B, Figure 2B). In view of this recovery, invasive coronary function testing was repeated. Resting and hyperemic Tmn were 0.84 s and 0.20 s, respectively; CFR was 4.2, and IMR was 15, consistent with normalization of microvascular function (Figure 4B, Video 4). Despite the increased hyperemic flow, FFR of the LAD was 0.82.
Discussion
The myocardium is an energetically demanding tissue that relies on uninterrupted ATP generation to sustain systole and diastole. To meet this requirement, the heart flexibly oxidizes multiple substrates (fatty acids, glucose, lactate, ketone bodies, pyruvate, and branched-chain amino acids), with mitochondrial oxidative phosphorylation providing the dominant ATP supply; consequently, myocardial oxygen consumption is among the highest of any organ. Because the myocardium extracts ∼70%-80% of delivered oxygen at rest, increases in oxygen demand are met primarily by augmenting coronary blood flow rather than extraction. This supply–demand matching is governed by a hierarchically organized autoregulatory network within the coronary microcirculation that dynamically modulates microvascular resistance.1 Mounting evidence links coronary microvascular dysfunction (CMD) to the development and progression of several heart-failure phenotypes.2
In the present case, ischemic cardiomyopathy due to epicardial disease was initially suspected based on precordial ST–T changes, a regional wall-motion abnormality, and multiple risk factors. However, FFR across the intermediate proximal LAD lesion remained nonischemic. At the index study, hyperemic coronary flow was depressed (hyperemic Tmn 0.70 s), raising the possibility that flow-dependent pressure loss across the epicardial stenosis was underestimated. Three months later, hyperemic flow normalized (hyperemic Tmn 0.20 s) while FFR remained nonischemic, arguing against a major contribution of the LAD stenosis to left-ventricular dysfunction. By contrast, the combination of reduced hyperemic flow and elevated IMR supported a diagnosis of CMD. Normalization of hyperemic flow and IMR paralleled the resolution of electrocardiographic abnormalities, recovery of regional function, and reduction in BNP, implicating CMD—at least in part—in the pathogenesis of HFrEF in this patient. These observations are consistent with prior reports associating CMD with impaired contractile reserve, adverse remodeling, and worse outcomes in HFrEF.3,4
The mechanism by which CMD improved in this case is likely multifactorial, but GDMT for HFrEF is a plausible driver. Neprilysin inhibition increases vasodilatory peptides (eg, bradykinin and atrial natriuretic peptide); bradykinin induces potent endothelium-dependent vasodilation ex vivo, and atrial natriuretic peptide receptors are expressed in the coronary microvasculature, suggesting a direct microvascular effect.5,6 Clinical analyses have further linked angiotensin receptor–neprilysin inhibitor therapy with reduction in troponin levels and better outcomes in heart failure patients, findings that may reflect enhanced microvascular vasodilation.7 In addition, sodium–glucose cotransporter-2 inhibitors improve mitochondrial energetic efficiency, reduce resting coronary flow, and thereby increase CFR.8 Collectively, these data support the hypothesis that contemporary GDMT contributed to the reversible CMD observed in our patient. Routine follow-up invasive coronary function testing is not standard practice in heart failure. The clinical yield is greatest at the index study, where invasive endotyping (“functional” vs “structural” CMD) can direct targeted therapy and set expectations for response. Selective serial testing may be considered in patients with persistent or discordant symptoms, diagnostic ambiguity, or in research settings to document the physiological reversibility of CMD in response to treatment.
This case lacks invasive hemodynamic data; right-heart catheterization was not performed in either study, so LV filling pressures and cardiac output could not be quantified. Elevated LV filling pressures can depress CFR by lowering the effective transmural driving pressure—an effect that is modest at rest but more pronounced during hyperemia.9 Higher filling pressures correlated inversely with CFR, and physiologic studies have shown that reductions in LV filling pressure improve CFR primarily by augmenting hyperemic flow, with little change in resting flow.10 Mechanistically, coronary autoregulation maintains relatively high resting microvascular resistance, so incremental extravascular compression from elevated filling pressure exerts limited additional effect at rest, whereas during hyperemia—when microvascular resistance falls—the same increment can meaningfully blunt flow. In the present case, the index study was performed after clinical compensation, and CFR was measured at rest, so we anticipate only a modest resting impact of filling pressure. The abnormally slow hyperemic flow (hyperemic Tmn 0.70 s) and elevated IMR (59) at baseline could, in part, reflect persistently elevated LV filling pressure despite clinical compensation; however, the prolonged resting Tmn (2.41 s) is unlikely to be explained by loading conditions alone and is more consistent with intrinsic microvascular dysfunction. At 3 months, improvements in hyperemic flow and IMR may reflect a combination of microvascular recovery and hemodynamic unloading, whereas normalization of resting flow again argues for genuine microvascular improvement. We acknowledge that, without contemporaneous right-heart catheterization, these pathophysiologic inferences remain probabilistic rather than definitive.
Outcome and Follow-Up
The subsequent 6-month clinical course was uneventful. Beta-blocker therapy was titrated to bisoprolol 5 mg/day, and azosemide was discontinued. Electrocardiography showed normal sinus rhythm without ischemic ST–T changes. Follow-up echocardiography demonstrated normal LV function with no regional wall-motion abnormalities.
Conclusions
This case highlights the potential role of CMD in the pathogenesis of HFrEF. Although the mechanisms underlying the reversible impairment remain uncertain, to our knowledge, this is the first report in which reversible CMD was quantified with invasive coronary function testing during contemporary GDMT, with subsequent normalization paralleling recovery of LV function and resolution of potentially ischemic ECG changes.
Disclosures of Artificial Intelligence Programs
During the preparation of this work, the authors used ChatGPT to improve language and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Take-Home Messages
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In heart failure with reduced ejection fraction, coronary microvascular dysfunction can be a principal—and reversible—driver of ischemia; guideline-directed therapy may normalize index of microvascular resistance/coronary flow reserve in parallel with left-ventricular functional recovery.
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Serial invasive coronary physiology helps differentiate epicardial from microvascular pathology and provides an objective marker of treatment response.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
Visual Summary.
| Timeline | Events |
|---|---|
| Day 1 | 53-year-old man presented with exertional dyspnea and paroxysmal nocturnal dyspnea. ECG showed precordial ST–T abnormalities. BNP was elevated, and transthoracic echocardiography demonstrated reduced LVEF (35%) with anteroseptal hypokinesis. |
| Day 1 | GDMT for HFrEF was initiated, including ARNI, SGLT2 inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and diuretic therapy. |
| 1 Week | Coronary angiography revealed intermediate proximal LAD stenosis. Fractional flow reserve was nonischemic (FFR 0.84). Angiography showed slow coronary flow, suggesting elevated microvascular resistance. Invasive coronary function testing demonstrated coronary microvascular dysfunction with prolonged mean transit time and elevated IMR, with preserved CFR (Tmn 2.41/0.70 s; CFR 3.4; IMR 59). |
| 3-Month follow-up | Clinical status markedly improved. LVEF normalized to 63%, BNP decreased to normal levels, and ECG abnormalities resolved. |
| 3-Month follow-up | Repeat invasive coronary physiology showed normalization of microvascular function (Tmn 0.84/0.20 s; CFR 4.2; IMR 15) with persistently nonischemic FFR (0.82). |
Appendix
Baseline Transthoracic Echocardiography Demonstrating Anteroseptal Regional Wall-Motion Abnormality With an Left Ventricular Ejection Fraction of 35%
Baseline Coronary Angiography Showing Slow Flow in the Left Coronary System
Transthoracic Echocardiography at 3-Month Follow-Up Demonstrating Resolution of Regional Wall-Motion Abnormality With a Left Ventricular Ejection Fraction of 63%
Coronary Angiography at 3-Month Follow-Up Demonstrating Normalization of Flow in the Left Coronary System
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Associated Data
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Supplementary Materials
Baseline Transthoracic Echocardiography Demonstrating Anteroseptal Regional Wall-Motion Abnormality With an Left Ventricular Ejection Fraction of 35%
Baseline Coronary Angiography Showing Slow Flow in the Left Coronary System
Transthoracic Echocardiography at 3-Month Follow-Up Demonstrating Resolution of Regional Wall-Motion Abnormality With a Left Ventricular Ejection Fraction of 63%
Coronary Angiography at 3-Month Follow-Up Demonstrating Normalization of Flow in the Left Coronary System