Practical Cardiovascular Medicine. Elias B. Hanna

flow-limiting stenosis, ischemia occurs.¹

      Supply ischemia is typically caused by ≥50% diameter stenosis of the left main coronary artery or ≥70% diameter stenosis of the major epicardial vessels. However, a 40–70% stenosis may be functionally significant, i.e., may impede maximal coronary flow during stress. The functional significance of a fixed lesion depends not only on the luminal narrowing, but also on:¹

       The size of the territory supplied by the vessel: a 50% proximal LAD stenosis is often significant, whereas a 50% diagonal or distal LAD stenosis may not be. A larger flow translates into a larger percentage of flow drop across the stenosis.

       Lesion length, as resistance across a stenosis correlates with (viscosity × length)/radius⁴ (Poiseuille law).

       Amount of viable myocardium.

       Degree of coronary distensibility at the lesion site. As such, for the same luminal stenosis, a large necrotic core or positive remodeling increases the functional significance.²

      Therefore, stress imaging may be useful to assess the functional significance of a borderline lesion. Also, in the cath lab, fractional flow reserve (FFR), i.e., the relative drop in flow across a lesion, may be invasively measured. FFR consists of assessing the pressure drop across a lesion using a coronary pressure wire; this pressure drop corresponds to a flow drop in patients with maximal microcirculatory hyperemia that exhausts autoregulation (flow = pressure/microvascular resistance). A flow drop ≥20%, i.e., FFR flow ratio ≤0.80, implies functional significance. In the FAME trial of multivessel PCI, 35% of 50–70% stenoses, 80% of 70–90% stenoses, and almost all stenoses >90% were functionally significant (FFR ≤0.80).³ This highlights the limitations of angiography even for stenoses of 70–90%.

      B. Vasospastic angina (Prinzmetal angina) or dynamic coronary obstruction

      It was initially hypothesized by Prinzmetal and then demonstrated in an old series that vasospasm and vasospastic angina often occur at the site of a significant atherosclerotic obstruction in patients with significant CAD.^4,5. CAD was not only significant but frequently unstable.⁵ Later reports suggest that vasospasm is also a common diagnosis in patients with angina and no significant CAD, men or women.⁶ Even in patients with normal or near-normal coronary arteries, atherosclerosis is documented at the site of vasospasm, and, in fact, vasospasm correlates with the atherosclerotic burden at this site.^7,8 Vasospasm may be related to vasoconstrictors released by platelets and leukocytes at the atherosclerotic site, or endothelial dysfunction and abnormal vasomotor response induced by atherosclerosis.⁷ Paradoxical vasoconstriction may occur during exercise, adrenergic stimulation (stress), or cold exposure. Approximately 60% of patients only have symptoms at rest or mild activity without exertional limitation, sometimes in a cyclic nocturnal pattern; in those patients, angina only occurs when the dynamic component exacerbates the fixed obstruction.⁵ On the other hand, many patients have exertional angina, whether from the CAD itself or from the exertional vasospasm, and some patients only have exertional angina.⁶ Vasospastic angina is classically more severe than fixed-threshold angina, as the episodic obstruction is totally or subtotally occlusive, with more frequent arrhythmia, high-grade AV block, or syncope during the episodes. While characteristically more common in women, some series suggest that vasospasm is as common in men.^9,10

      C. Angina secondary to severely increased demands

      This is seen with severe LV hypertrophy, severe HTN, valvular heart disease, HF, marked tachycardia, or metabolic disorders (anemia or hyperthyroidism). Some of these patients have underlying significant CAD, but many do not, angina being completely explained by the severely increased demands.

      Note on coronary flow physiology

      Because of systolic compression of the microcirculation, the LV receives blood mainly during diastole (>80% of the left coronary flow occurs in diastole). Tachycardia, in addition to increasing O₂ demands, reduces myocardial O₂ supply by reducing diastolic time.

      As opposed to the LV, the RV is thin and does not compress its microcirculation as much in systole, which explains why its flow is not as affected by systole. Approximately 50% of the right coronary-to-RV flow occurs in systole.

      The LV coronary blood flow is directly related to the pressure gradient between DBP and LVEDP (coronary perfusion pressure) and inversely related to the microvascular resistance; the latter depends on myocardial stiffness, and, thus, on LVEDP as well (flow = delta pressure/microvascular resistance). An increase in LVEDP reduces coronary flow, even in the absence of a coronary stenosis.

      Since the RV receives significant flow during systole, the coronary blood flow of the RV is partly related to the gradient between SBP and RV systolic pressure, not just DBP and RVEDP.

II. Diagnostic approach

      A. Clinical features of typical angina

      Typical angina is characterized by three features:

      1 Retrosternal or epigastric discomfort; neck/jaw/arm pain.

      2 Occurrence with exertion or emotional stress.

      3 Quick relief by rest or nitroglycerin (within 30 s – 5 min). A prolonged pain (>20 min), or a delay to relief with rest or nitroglycerin (>5 min) usually implies one of two extremes: acute MI or non-cardiac pain.

Angina is precipitated by walking uphill, in the cold, or after a meal.^* Nausea or diaphoresis during pain increases the likelihood of angina. Postprandial angina is often a marker of severe, sometimes multivessel CAD. As opposed to biliary colic or peptic ulcer disease, angina occurs immediately after the meal and is exacerbated by postprandial physical activity. Nocturnal angina may imply severe CAD vs. vasospasm on top of fixed CAD; the increased venous return in the recumbent position increases O₂ demands and triggers ischemia in patients with critical, sometimes multivessel, CAD. Rest angina without an exertional component may be seen in patients with significant CAD whose angina is mainly triggered by a vasospastic reduction of O₂ supply (although many of the latter patients also have exertional angina). Dyspnea may be an angina equivalent and may indicate extensive CAD with secondary increase in LVEDP during ischemic spells; however, dyspnea is very non-specific compared to chest pain. “Warm-up” angina is angina that starts with the onset of activity and improves with further exertion (e.g., in the morning); it suggests a very severe stenosis, with collaterals that get recruited during exertion and a myocardium that adapts to ischemia (ischemic preconditioning).

Figure 3.1 Clinical probability of CAD.

      * Combination of diabetes, smoking, or hyperlipidemia (LDL >160–190 mg/dl), especially when all three are present.¹⁷

      B. Pre-test clinical probability of significant CAD

The presence of all three features defines typical (definite) angina, while two features define possible angina, and chest pain without any additional feature defines non-anginal chest pain. The combination of (1) angina features, (2) age and sex, and (3) risk factors establishes the probability of CAD (Diamond-Forrester and Duke classifications, combined in Figure 3.1).^11-13 Note that typical angina is defined by its relation to exertion, not by a description of “chest heaviness” or arm radiation.

      In addition,