A Lack of Reserve

Introduction

Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr. Taqueti), who responds to the information, sharing her reasoning with the reader (regular type). A discussion by the authors follows.

Patient presentation: A 67-year-old woman presented to the emergency department with escalating exertional chest pressure and dyspnea over the preceding week. Her symptoms are progressive such that she can no longer walk up a flight of stairs without chest discomfort. Resting and taking sublingual nitroglycerin provided mild improvement. There was no associated lightheadedness, palpitations or nausea. Over the preceding year, she had been able to walk five blocks without chest discomfort, although she reported angina at higher exertion.

She has a history of coronary artery disease (CAD), diagnosed three years ago following stress myocardial perfusion imaging for evaluation of exertional chest pressure. Testing demonstrated a large area of inferior left ventricular (LV) ischemia, and she underwent percutaneous coronary intervention with placement of a drug-eluting stent to a 90% stenosis in the ostial right coronary artery (RCA). At the time of intervention, nonobstructive atherosclerotic plaques were noted in the mid RCA, proximal left anterior descending (LAD) artery, and proximal first diagonal branch artery. Six months following intervention, the patient was diagnosed with in-stent restenosis and underwent repeat coronary artery stenting. She continued to experience exertional chest pressure. Two weeks prior to presentation, she underwent repeat stress myocardial perfusion imaging with regadenoson single-photon emission computed tomography (SPECT), which demonstrated normal perfusion and LV systolic function. The patient’s medical history also includes hypertension, hyperlipidemia, diabetes, chronic kidney disease (CKD), obstructive sleep apnea (OSA) and osteoarthritis. She reported adherence to medications, including aspirin, clopidogrel, rosuvastatin, labetalol, hydralazine, isosorbide, metformin and insulin. She was a former smoker, and did not drink alcohol or use illicit drugs. She was a retired store clerk who lived with her daughter.

The patient’s examination demonstrated an obese older woman who appeared comfortable at rest. Her vital signs revealed a heart rate of 60 bpm, blood pressure of 164/82 mm Hg bilaterally, oxygen saturation of 98% on ambient air, and a body mass index of 39.8 kg/m². Jugular venous pressure was 8 cm and the apical impulse was normal in location and size. Auscultation revealed a regular rate and rhythm with normal S1 and S2 and clear lung fields bilaterally. Radial, femoral and dorsalis pedis pulses were of normal contour and intensity, and there was trace lower extremity pitting edema.

Dr. Taqueti: A diabetic woman with a history of stable ischemic heart disease (SIHD) presents with escalating exertional angina and a markedly decreased exercise tolerance. Although her symptoms are progressive, an acute coronary syndrome must be excluded. Additional causes of chest pain, including pulmonary embolism, vascular dissection, myo/pericarditis, tachyarrhythmia, structural heart disease, coronary and esophageal spasm, and anemia, should be considered.

Patient presentation (continued): A 12-lead ECG demonstrated normal sinus rhythm, prolonged QTc, criteria for LV hypertrophy, and nonspecific ST and T wave abnormalities (Figure 1), unchanged from prior tracings. Chest radiography was normal. Abnormal laboratory tests included glucose 217 mg/dL (reference 70–100), eGFR 46 mL/min (>60), hemoglobin 9.8 g/dL (11.5–16.4). Other labs, including electrolytes, N-terminal probrain natriuretic peptide, D-dimer, and thyroid-stimulating hormone, were normal. Three serial troponin T values measured over 24 hours were below assay. Recent lipid testing revealed a total cholesterol of 189 mg/dL, high-density lipoprotein 59 mg/dL, low-density lipoprotein (LDL) 117 mg/dL, triglycerides 140 mg/dL and a hemoglobin A1C of 8.4%. Transthoracic echocardiography demonstrated a small LV with mild concentric hypertrophy (12 mm wall thickness), LVEF of 0.65 without segmental wall motion abnormalities, grade II diastolic dysfunction, normal right ventricular size and systolic function, mild left atrial enlargement, normal valvular function, normal IVC size, and an estimated pulmonary artery systolic pressure of 36 mm Hg.

Figure 1.

A 12-lead electrocardiogram on admission demonstrated normal sinus rhythm at 60 beats per minute, prolonged QTc of 491 ms, criteria for LV hypertrophy, and nonspecific ST and T wave abnormalities.

Dr. Taqueti: This patient has CAD with prior revascularization and multiple cardiac comorbidities, which place her at a high pretest probability for progression of ischemic heart disease. She has no evidence of acute myocardial injury and no signs of decompensated heart failure. Nonetheless, she is obese with suboptimally controlled hypertension, diabetes and LDL cholesterol, along with anemia, CKD and OSA. Despite a preserved LVEF, she has LV hypertrophy and diastolic dysfunction. Although recent vasodilator stress testing with SPECT imaging was reported to be normal, important caveats may limit this test’s sensitivity for diagnosing ischemia in the higher risk, symptomatic patient. These include technical issues, such as caffeine intake resulting in ineffective vasodilator stress, or diagnostic limitations, such as multivessel CAD leading to diminished ability to detect relative perfusion defects, so-called “balanced ischemia.” After confirming stable renal function, non-urgent diagnostic coronary angiography with fractional flow reserve (FFR) assessment would be reasonable to evaluate for progression of epicardial CAD and resultant flow-limiting ischemia.

Patient presentation (continued): Invasive coronary angiography revealed patent left main, LAD and left circumflex arterial systems (Figure 2A). The ostial RCA had a 30% in-stent restenosis with no waveform change upon engagement and good contrast reflux, and the mid RCA had a 60% stenosis (Figure 2B). FFR assessment of the latter via administration of intracoronary adenosine was 0.88. The patient’s coronary anatomy appeared similar when compared to that from angiography two years prior.

Figure 2.

Invasive coronary angiography demonstrated patent left main, left anterior descending and left circumflex arterial systems with nonobstructive plaque (A), and a right coronary artery with an ostial 30% in-stent restenosis and a mid 60% stenosis (B). Upon engagement of the right coronary artery, there was good contrast reflux and no waveform change; fractional flow reserve assessment of the mid right coronary artery was normal at 0.88.

Dr. Taqueti: This patient has angina with no obstructive CAD. Invasive anatomical and functional assessments with contrast angiography and FFR, respectively, demonstrated that her epicardial coronary plaques have not progressed to flow-limiting stenoses and are therefore unlikely to explain her symptoms. Transient coronary vasospasm, may coexist with nonobstructive plaque, but is less likely to be responsible for this patient’s progressive exertional angina with minimal rest symptoms. Although her plaques are nonobstructive, she has diffuse atherosclerosis in the presence of obesity, diabetes and diastolic dysfunction, all of which are associated with small-vessel disease and coronary microvascular dysfunction (CMD).

The small vessels of the coronary circulation cannot be imaged directly, either invasively or noninvasively, and have not been a traditional focus of cardiovascular management. With increasing utilization of advanced imaging techniques, such as stress cardiac positron emission tomography (PET) and possibly magnetic resonance imaging (CMR), absolute blood flow integrated over the entire coronary circulation (e.g. from epicardial to microvascular vessels) can be quantified during stress and rest, and their ratio calculated into a coronary flow reserve (CFR). Observational data have shown that impaired CFR identifies patients at risk, independently of traditional factors, including LV dysfunction, ischemia, hypertension, obesity and diabetes. Together with standard semi-quantitative myocardial perfusion, ventricular function and ECG data, quantitative myocardial blood flows and CFR may be useful to diagnose diffuse global ischemia in this patient, which could explain her angina, provide further risk stratification and, potentially, guide further therapy.

Patient presentation (continued): Noninvasive imaging with cardiac PET was performed pre- and post-stress testing with regadenoson. The patient tolerated the study without symptoms, ECG changes or arrhythmia. LVEF was normal at 0.55. Perfusion images demonstrated a medium-sized, mild inducible perfusion defect along the apical inferior and mid anteroseptal/inferoseptal LV segments, reflecting 4.4% ischemic LV myocardium (Figure 3A). Absolute stress myocardial blood flows and, concordantly, CFR was reduced in all coronary territories (Figure 3B). Specifically, CFR_LAD 1.35, CFR_LCx 1.63, CFR_RCA 1.23, CFR_LV 1.40 (reference CFR ≥2).

Figure 3.

Noninvasive PET myocardial perfusion imaging with quantification of myocardial blood flow and coronary flow reserve. Stress perfusion images demonstrated a medium-sized, mild inducible perfusion defect along the apical inferior and mid anterosepta/inferoseptal LV segments with some transient ischemic dilatation (A). Absolute stress myocardial blood flows and CFR was reduced in all coronary territories (B) with global CFR 1.40 (arrow, reference CFR ≥2).

Dr. Taqueti: This patient has mild regional ischemia visible on semi-quantitative perfusion imaging, corresponding to typical territories of the distal posterior descending artery and septal perforator branches. However, there is also some evidence of transient ischemic dilatation and severely reduced stress myocardial blood flows and reserve. These are high-risk findings, which have been associated with worse cardiovascular prognosis, including greater risk of death, even without concomitant obstructive CAD. This patient has SIHD and severely impaired CFR, likely from a combination of diffuse atherosclerosis and small-vessel ischemia from associated CMD.

Currently, there are no therapies specifically targeting CMD, and the evidence base for its management is lacking. As in her counterpart with obstructive CAD, this patient requires aggressive medical therapy and risk factor reduction, including more optimal management of blood pressure, lipids, weight, glycemia, and OSA, with an age-appropriate workup for anemia. Beyond this, objective testing provides diagnostic and prognostic clarification, which may help to avoid costly and potentially harmful additional testing, and to better define disease for the future of tailored management. Efforts are ongoing to more precisely phenotype these patients with nonobstructive CAD and CMD, many of whom are women, to determine which interventions may be effective. Newer therapies targeting residual cholesterol and inflammatory risk, neurohormonal activation and glucose handling in the kidneys, and even surgical weight loss, may demonstrate improved outcomes in this sector of patients.

Patient presentation (continued): Lisinopril was added and hydralazine, discontinued. Carvedilol was used in place of labetalol. Isosorbide therapy was continued, but with an extended release formulation at 240 mg daily. Rosuvastatin was increased to 40 mg daily. Nutrition, exercise and weight-loss counseling were provided. She was discharged from the hospital with improved blood pressures and decreased exertional angina. An overnight polysomnography study was arranged for continuous-positive airway pressure therapy titration. Strategies for improved glycemic management, including bariatric surgery, were discussed with the patient and her endocrinologist. She was ultimately started on empagliflozin, a sodium-glucose co-transporter 2 inhibitor. Three months later, her symptoms of intermittent exertional angina were better controlled, allowing her to be more active with improved quality of life. She was screened for inclusion in the NHLBI-sponsored Cardiovascular Inflammation Reduction Trial (CIRT) and CIRT-CFR, but despite being a diabetic with SIHD, did not meet inclusion criteria for obstructive multivessel CAD and was not enrolled.

Dr. Taqueti: This case illustrates some of the current challenges, but also exciting prospects ahead for diagnosis and management of patients with ischemia and no obstructive CAD (INOCA). As evident here, this represents a significant unmet need, particularly prevalent among female heart disease patients. Defining CAD not only as an anatomical problem, but also a functional one for which modern tools can be leveraged in future clinical trials to interrogate the full extent of the coronary circulation, may lead us to a more complete understanding of the pathobiology of ischemic heart disease, with the goal of improving outcomes for all.

Discussion

The clinical evaluation of symptomatic patients, particularly women, with SIHD can be challenging due to their varying clinical presentation, clinical risk factor burden, high degree of comorbidity, and increased risk of major ischemic heart disease events. This case illustrates a clinical scenario not infrequently encountered in clinical practice, but one in which our understanding of the relevant disease pathophysiology, diagnosis, prognosis and management is evolving with emerging data.¹ In doing so, it highlights the following points for discussion.

First, INOCA is common, and may be present in up to 50% of symptomatic patients referred for evaluation of suspected CAD. It can occur in both women and men, although it is more prevalent in women.^{2, 3} It can also occur in patients with prior history of obstructive CAD who may have persistent symptoms despite adequate revascularization. As such, it requires a high index of suspicion and access to an adequate diagnostic toolbox. Patients can be referred without much benefit for costly repeated testing with traditional approaches lacking sensitivity for diagnosis of small vessel disease. Some patients may even be asked to discontinue ostensibly appropriate therapies because of apparently normal results (i.e., “clean coronaries”) or abnormal testing perceived to represent false positive findings.

Second, INOCA is associated with elevated cardiovascular morbidity and mortality, particularly in women,⁴ and is highly comorbid with common conditions such as hypertension, diabetes, and obesity. These patients are at increased risk for adverse cardiovascular events, including acute coronary syndromes, heart failure with preserved ejection fraction,⁵ and death from plaque erosion, impaired coronary vasoreactivity, and microvascular dysfunction with resultant ischemia.

Finally, despite its prevalence and associated cardiovascular risk, many questions remain unanswered, particularly in terms of patient management. As in the patient presented, this may be especially relevant in patients with adequately-revascularized but residual (nonobstructive) CAD who may already be on reasonable guideline-directed medical therapies for secondary prevention, and for whom coronary revascularization is not an option for symptomatic improvement or ischemic-burden reduction.⁴ There are no effective therapies specifically targeting CMD, and trials with agents such as calcium-channel blockers and ranolazine have been disappointing. Ongoing efforts are focused on defining the distinct clinical syndrome of INOCA as well as identifying current knowledge gaps and next steps for developing evidence-based therapies.

Conclusion

In patients with refractory angina despite optimal revascularization, CMD may be the culprit. This case illustrates the challenges associated with diagnosing and managing patients with INOCA, an increasingly recognized clinical syndrome with associated poor prognosis, for which previous management approaches have led to underwhelming results, and for which new evidence-based approaches are needed.