Gaetano Antonio Lanza

Primary Coronary Microvascular Dysfunction: Clinical Presentation, Pathophysiology, and Management

Myocardial ischemia is usually caused by abnormalities of epicardial coronary arteries. In the past 30 years, however, several studies have shown that abnormalities in coronary microcirculation may also cause or contribute to myocardial ischemia in several conditions. Accordingly, Camici and Crea1 have recently proposed a classification of coronary microvascular dysfunction (CMVD) based on the clinical setting in which it occurs (eg, obstructive coronary artery disease [CAD], cardiomyopathy, and systemic diseases) (Table 1). In these various conditions, CMVD can be caused by specific mechanisms related to the underlying disease. View this table: Table 1. Classification of CMVD According to its Pathogenetic Mechanisms (Derived From Camici and Crea 1 ) In a number of patients who present with angina attacks in the absence of any apparent cardiac or systemic disease, CMVD has been suggested to be the unique cause of symptoms. This condition is known as microvascular angina (MVA)2 and can be better defined as primary MVA to distinguish it from MVA occurring in the setting of specific diseases, which can be defined as secondary MVA. In clinical practice, primary MVA is usually suspected, by exclusion, in patients with sufficiently typical chest pain in whom, despite abnormalities of the ECG and/or stress test results indicative of myocardial ischemia, arteriography surprisingly fails to show fixed or dynamic obstructions in epicardial coronary arteries.3 Primary MVA, however, includes heterogeneous groups of patients, with different pathogenetic and pathophysiological mechanisms of CMVD, who might have different clinical implications and need different diagnostic and therapeutic approaches. In several previous studies, however, patients with different characteristics of chest pain, possibly related to different mechanisms of CMVD or even to nonischemic or noncardiac causes, have often been considered together, usually under the general descriptive term of chest pain with normal coronary arteries, which may have contributed to generate contrasting results …

Inflammation as a Possible Link Between Coronary and Carotid Plaque Instability

Background— Multiple complex stenoses, plaque fissures, and widespread coronary inflammation are common in acute coronary syndromes. A systemic cause of atherosclerotic plaque instability is also suggested by studies of ischemic cerebrovascular disease. We investigated the association between coronary and carotid plaque instability and the potential common causal role of inflammation. Methods and Results— The ultrasound characteristics of carotid plaques were evaluated retrospectively in patients scheduled for coronary bypass surgery, 181 with unstable and 92 with stable angina, and prospectively in a similar group of patients, 67 with unstable and 25 with stable angina, in whom serum C-reactive protein levels were also measured. The prevalence of carotid plaques was similar in the retrospective and prospective studies and >64% in both unstable and stable coronary patients. The prevalence of complex, presumably unstable carotid plaques was 23.2% in unstable versus 3.2% in stable patients (P <0.001) in the retrospective study and 41.8% versus 8.0% (P =0.002) in the prospective study. C-reactive protein levels were higher in patients with complex (7.55 mg/L) than in those with simple (3.94 mg/L; P <0.05) plaques or without plaques (2.45 mg/L; P <0.05). On multivariate analysis, unstable angina and C-reactive protein levels >3 mg/L were independently associated with complex carotid plaques (OR, 6.09; 95% CI, 1.01 to 33.72; P =0.039, and OR, 5.80; 95% CI, 1.55 to 21.69; P =0.009, respectively). Conclusions— In unstable angina, plaque instability may not be confined to coronary arteries, and inflammation may be the common link with carotid plaque instability. These observations may have relevant implications for understanding the mechanisms of acute widespread atherothrombotic plaque inflammation.

Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris

Management of unstable angina is largely determined by symptoms, yet some symptomatic patients stabilize, whereas others develop myocardial infarction after waning of symptoms. Therefore, markers of short-term risk, available on admission, are needed. The value of 4 prognostic indicators available on admission (pain in the last 24 hours, electrocardiogram [ECG], troponin T, and C-reactive protein [CRP]), and of Holter monitoring available during the subsequent 24 hours was analyzed in 102 patients with Braunwald class IIIB unstable angina hospitalized in 4 centers. The patients were divided into 3 groups: group 1, 27 with pain during the last 24 hours and ischemic electrocardiographic changes; group 2, 45 with pain or electrocardiographic changes; group 3, 30 with neither pain nor electrocardiographic changes. Troponin T, CRP, ECG on admission, and Holter monitoring were analyzed blindly in the core laboratory. Fifteen patients developed myocardial infarction: 22% in group 1, 13% in group 2, and 10% in group 3. Twenty-eight patients underwent revascularization: 37% in group 1, 35% in group 2, and 7% in group 2 (p <0.01 between groups 1 or 2 vs group 3). Myocardial infarction was more frequent in patients with elevated troponin T (50% vs 9%, p=0.001) and elevated CRP (24% vs 4%, p= 0.01). Positive troponin T or CRP identified all myocardial infarctions in group 3. Only 1 of 46 patients with negative troponin T and CRP developed myocardial infarction. Among the indicators available on admission, multivariate analysis showed that troponin T (p=0.02) and CRP (p=0.04) were independently associated with myocardial infarction. Troponin T had the highest specificity (92%), and CRP the highest sensitivity (87%). Positive results on Holter monitoring were also associated with myocardial infarction (p=0.003), but when added to troponin T and CRP, increased specificity and positive predictive value by only 3%. Thus, in patients with class IIIB unstable angina, among data potentially available on admission, serum levels of troponin T and CRP have a significantly greater prognostic accuracy than symptoms and ECGs. Holter monitoring, available 24 hours later, adds no significant information.

Mechanisms of Coronary Artery Spasm

The term coronary artery spasm (CAS) refers to a sudden, intense vasoconstriction of an epicardial coronary artery that causes vessel occlusion or near occlusion. Although CAS may be involved in other coronary syndromes, it represents the usual cause of variant angina. The variant form of angina was first described in 1959 by Prinzmetal et al,1 who used this term to indicate that angina attacks, unlike the most common form of effort angina, occurred at rest and were associated with ST-segment elevation, rather than ST-segment depression, on the ECG (Figure 1). Because myocardial ischemia occurred in the absence of any change in myocardial oxygen demand, the authors hypothesized that it was caused by an increased tonus of vessels at the level of coronary stenoses.1 Figure 1. (Top) ST-segment elevation in anterior leads, with reciprocal mild ST-segment depression in inferior leads and V6, during an angina attack in a patient with variant angina. (Bottom) Normalization of the ECG after spontaneous resolution of chest pain. Some years later, in fact, coronary angiography, performed during spontaneous angina attacks, demonstrated that CAS is the usual cause of variant angina.2–4 Coronary angiography also showed that CAS could occur at the site of a stenosis (either minor or severe) or in angiographically normal coronary arteries,5 usually at a localized segment of an epicardial artery (focal spasm) (Figure 2).6 However, sometimes CAS involves 2 or more segments of the same (multifocal spasm) or of different (multivessel spasm) epicardial coronary arteries, or may also involve diffusely one or multiple coronary branches.7 Figure 2. Occlusive spasm of the left circumflex coronary artery and near occlusive spasm of the left anterior descending coronary artery (arrows) during coronary angiography (left, top), associated with dramatic ST-segment elevation at monitoring ECG leads (left, bottom). Complete resolution of spasm (right, …

Relation between stress-induced myocardial perfusion defects on cardiovascular magnetic resonance and coronary microvascular dysfunction in patients with cardiac syndrome X.

OBJECTIVES The purpose of this study was to investigate whether a direct relation can be demonstrated between myocardial perfusion defects detected during dobutamine stress test (DST) by cardiovascular magnetic resonance (CMR) and impairment of coronary microvascular dilatory function in patients with cardiac syndrome X (CSX). BACKGROUND Despite the fact that coronary microvascular dysfunction has been shown in most patients with CSX, the ischemic origin of CSX remains debated. No previous study assessed whether a strict relation exists between abnormalities in myocardial perfusion and coronary microvascular dysfunction in CSX patients. METHODS Eighteen CSX patients (mean age 58 +/- 7 years, 7 men) and 10 healthy control subjects (mean age 54 +/- 8 years, 4 men) underwent myocardial perfusion study by gadolinium-enhanced CMR at rest and at peak DST (maximal dose 40 microg/kg/min). Coronary flow response (CFR) to adenosine (140 microg/kg/min in 90 s) in the left anterior descending (LAD) coronary artery was assessed by high-resolution transthoracic echo-Doppler and expressed as the ratio between coronary flow velocity at peak adenosine and at rest. RESULTS At peak DST, reversible perfusion defects on CMR were found in 10 CSX patients (56%) but in none of the control subjects (p = 0.004). The CFR to adenosine in the LAD coronary artery was lower in CSX patients than in control subjects (2.03 +/- 0.63 vs. 3.29 +/- 1.0, p = 0.0004). The CSX patients with DST-induced myocardial perfusion defects in the LAD territory on CMR had a lower CFR to adenosine compared with those without perfusion defects in the LAD territory (1.69 +/- 0.5 vs. 2.31 +/- 0.6, p = 0.01). A significant correlation was found in CSX patients between CFR to adenosine and a DST perfusion defect score on CMR in the LAD territory (r = -0.45, p = 0.019). CONCLUSIONS Our data concurrently show DST-induced myocardial perfusion defects on CMR and reduced CFR in the LAD coronary artery territory in CSX patients, thus giving strong evidence that a dysfunction of coronary microcirculation resulting in myocardial perfusion abnormalities is present in these patients.

Abnormal Cardiac Adrenergic Nerve Function in Patients With Syndrome X Detected By [123I]Metaiodobenzylguanidine Myocardial Scintigraphy

BACKGROUND Previous studies have suggested that an abnormal cardiac adrenergic tone may have a pathophysiological role in syndrome X (effort angina, positive exercise testing, angiographically normal coronary arteries). METHODS AND RESULTS To evaluate cardiac adrenergic nerve function, we performed [123I]metaiodobenzylguanidine (MIBG) myocardial scintigraphy in 12 patients with syndrome X and 10 control subjects. Cardiac MIBG uptake was assessed by the heart/mediastinum (H/M) ratio and by an MIBG uptake defect score (higher values=lower uptake). In syndrome X patients, we also correlated MIBG scintigraphic findings with stress myocardial perfusion as assessed by 201Tl scintigraphy. An inferior MIBG defect was observed in only 1 control subject, whereas 9 patients (P<.01) showed MIBG defects. The heart was totally or almost totally invisible on MIBG images in 5 patients, and predominantly regional defects were observed in 4. The H/M ratio was lower (1.70+/-0.6 versus 2.2+/-0.3, P=.03) and MIBG uptake defect score higher (35+/-31 versus 4+/-2, P=.003) in syndrome X patients. Reversible stress thallium perfusion defects were found in 62% of patients with MIBG defects but in no patient with normal MIBG uptake. MIBG defects persisted unchanged in 7 patients at a 5+/-3-month follow-up study. CONCLUSIONS In this study, obvious defects in global and/or regional cardiac MIBG uptake, indicating an abnormal cardiac adrenergic nerve function, were detected in 75% of patients with syndrome X. These findings strongly support the cardiac origin of chest pain in syndrome X, although the mechanisms and the pathophysiological meaning of the abnormal cardiac MIBG uptake in these patients deserve further investigation.

Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X

The effects of a beta blocker (atenolol), a calcium antagonist (amlodipine), and a nitrate (isosorbide-5-mononitrate) on anginal symptoms in 10 patients with syndrome X were assessed in a crossover, double-blind, randomized trial. Only atenolol was found to significantly improve chest pain episodes, suggesting that it should be the preferred drug when starting pharmacologic treatment of patients with syndrome X.

Cardiac syndrome X: a critical overview and future perspectives.

The classic definition of cardiac syndrome X (CSX) seems inadequate both for clinical and research purposes and should be replaced with one aimed at including a sufficiently homogeneous group of patients with the common plausible pathophysiological mechanism of coronary microvascular dysfunction. More specifically, CSX should be defined as a form of stable effort angina, which, according to careful diagnostic investigation, can reasonably be attributed to abnormalities in the coronary microvascular circulation.

Prognostic role of heart rate variability in patients with a recent acute myocardial infarction

A low heart rate variability (HRV) has been shown to be a powerful predictor of cardiac events in patients surviving an acute myocardial infarction (MI), but it is not clear yet which among the HRV parameters has the best predictive value. Time domain and frequency domain HRV was assessed on 24-hour predischarge Holter recording of 239 patients with a recent MI. Patients were followed up for 6 to 54 months (median 28), during which 26 deaths (11%) occurred, 19 of which were cardiac in origin and 12 were sudden. Most HRVs did not show any difference between patients with or without mortality end points, but the average low-frequency and low-frequency/high-frequency ratio was lower in patients with events. However, when dichotomized according to cut points that maximized the risk of sudden death, several HRVs were significantly predictive of clinical end points. Overall, the mean of the standard deviations of all RR intervals for all 5-minute segments and the standard deviation of the mean RR intervals for all 5-minute segments were the time domain variables most significantly associated with mortality end points, whereas very low frequency was the most predictive frequency domain variable. Compared with the best time domain variables, very low frequency showed a better sensitivity (0.27 to 0.42 vs 0.19 to 0.33) for end points with only a small loss in specificity (0.92 vs 0.96). On multivariate Cox proportional analysis, a left ventricular ejection fraction <40% and a number of ventricular premature beats > or = 10/hour were the most powerful independent predictors for all end points, whereas no HRV was independently associated with the events. A low frequency/high frequency ratio < 1.05 only had a borderline association with sudden death (RR = 2.86, p = 0.076). Our data show a strong association between HRV and mortality in patients surviving a recent MI, with a slight better sensitivity of frequency domain analysis. In our study, however, HRV did not add independent prognostic information to more classic prognostic variables (e.g., left ventricular function and ventricular arrhythmias).

Angina pectoris and normal coronary arteries: cardiac syndrome X

Among patients undergoing coronary angiography because of angina typical enough to suggest coronary artery disease, 10–30% are found to have “normal” or “near normal” epicardial coronary arteries at angiography. A group of these patients presents features of “cardiac syndrome X”, which is typically characterised by: However, several groups of patients presenting with angina pectoris and normal coronary arteries do not fall into the strict definition of syndrome X, including those with predominant rest angina, those with hypertension or diabetes, or those with lack of ischaemic-like ECG changes during angina. It is still largely unknown whether the pathogenesis of angina in these various subsets of patients is different from that of angina in patients with typical syndrome X. Nevertheless, patients with typical and non-typical syndrome X have frequently been pooled together, thus making comparisons among different studies rather problematic. Therefore, a consensus document on the definition, classification, and management of patients with angina and normal coronary arteries would be very useful. Syndrome X is characterised by two major abnormalities, which may combine variously to determine the individual clinical picture: (1) coronary microvascular dysfunction; and (2) abnormal cardiac pain sensitivity. ### Microvascular dysfunction Since its first description it was suggested that, in syndrome X, angina is caused by myocardial ischaemia determined by a dysfunction of small resistance coronary artery vessels (< 500 μm) not visible at coronary angiography, a condition defined as “microvascular angina”.1 The occurrence of myocardial ischaemia in these patients is indicated by transient ST segment depression and reversible perfusion defects …