Role of coronary artery spasm in symptomatic and silent myocardial ischemia

The revival of the concept of coronary spasm has stimulated research into coronary artery disease. Observations in patients with variant angina have substantially contributed to the appreciation of painless myocardial ischemia. However, the presence or absence of pain during ischemic episodes is not related to the cause of ischemia, because painless ischemia can be observed in variant angina (caused by spasm), in effort-induced angina (caused by increased myocardial demand) and in myocardial infarction (caused by thrombosis).Continuous monitoring initially of patients with variant angina and subsequently of patients with unstable and stable angina proved that often painful and painless ischemic episodes are caused by a transient impairment of regional coronary blood flow rather than by an excessive increase of myocardial demand. The transient impairment of coronary flow appears to be caused by dynamic stenosis of epicardial coronary arteries. This most often occurs at the site of atherosclerotic plaques encroaching on the lumen to a variable extent.Dynamic stenosis can be caused by 1) “physiologic” increase of coronary tone, as in stable angina, 2) spasm, as in variant angina, and 3) thrombosis, usually in combination with “physiologic” changes in tone or with spasm, or both, as in unstable angina. The mechanisms of spasm, as typically observed in variant angina, are different from those of “physiologic” increase of tone; they appear to be related to a local alteration that makes a segment of coronary artery hyperreactive to a variety of constrictor stimuli causing only minor degrees of constriction in other coronary arteries. The nature of this abnormality, which may remain stable for months and years, is yet unknown

Clinical and experimental evidences on the prothrombotic properties of neutrophils

Epidemiologic studies have shown that the neutrophil count correlates with the risk of myocardial infarction and stroke and identify patients more susceptible to reinfarction and in-hospital death. In particular, neutrophils action was initially associated to blood rheological changes, or to the effect of neutrophil-derived eicosanoids or proteases. Animal models indicate that platelet-leukocyte P-selectin dependent cross-talk contributes to fibrin deposition during in vivo thrombus formation. In fact, platelet P-selectin, through its leukocyte counter-receptor PSGL-1, determines the activation of leukocyte ?2 integrins, the binding of fibrinogen and the expression of tissue factor on leukocyte surface. Monocytes stimulated in vitro with LPS, PMA and P-selectin synthesize and express tissue factor. fMLP, P-selectin, TNFalpha and C5a are effective stimuli that trigger the synthesis and expression of biologically active tissue factor in neutrophils. The experimental evidence well agrees with clinical observations: patients with acute coronary syndromes, acute respiratory distress syndrome, antiphospholipid syndromes, giant cell arteritis and myeloproliferative syndromes have increased the expression of tissue factor on leukocyte surface. Moreover circulating neutrophils express mRNA codifying for fulllength and/or alternatively spliced tissue factor, suggesting a new important link between thrombosis and inflammation. All together, clinical and experimental evidence suggest that the leukocyte thrombogenic profile is a relevant player in patients with a high risk of thromboembolic events and possibly represents a suitable target for molecular intervention

Immune system activation follows inflammation in unstable angina: pathogenetic implications

AbstractObjectives. The aim of this study was to assess the relations between inflammation, specific immune response and clinical course in unstable angina (UA).Background. Several studies suggest that either inflammation and/or T-cell activation might have a pathogenetic role in UA, but neither their potential reciprocal connection nor their relation to the clinical course is known.Methods. Serum levels of C-reactive protein (CRP) (inflammation), IgG, IgA, IgM, C3, C4 (humoral immunity), IL-2 and the percentage of CD4+, CD8+ and CD3+/DR+ T-cells (cell-mediated immunity) were measured in 35 patients with UA and 35 patients with chronic stable angina (CSA) during a period of 6 months.Results. The CRP levels and the main specific immune markers (CD4+ and CD3+/DR+ cells, IL-2 and IgM) were higher in unstable than in stable angina. In UA, the serum levels of IgM and IL-2 and the percentage of double positive CD3+/DR+ significantly increased at 7 to 15 days, and returned to baseline at 6 months. The increment of circulating activated T cells (CD3+/DR+) in UA was inversely related to the admission levels of CRP (r = −0.63, p = 0.003) and associated with a better outcome.Conclusions. Our data suggest that the inflammatory component systemically detectable in UA may be antigen-related and that the magnitude of the immune response correlates with the clinical outcome of instability

Not So Mural Thrombus

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Impairment of myocardial perfusion and function during painless myocardial ischemia

Left ventricular (or pulmonary and systemic arterial) hemodynamics were measured for a mean of 13.6 hours during continuous electrocardiographic monitoring in 14 patients admitted to the coronary care unit because of angina at rest. Of 293 episodes of transient ST segment and T wave changes identified, 247 (84%) were completely asymptomatic. Sixty-three percent of asymptomatic episodes were associated with an elevation of the left ventricular end-diastolic or pulmonary artery diastolic pressure of 5 mm Hg or more; in 15% there were smaller elevations (2 to 4 mm Hg) and in 22% there were no changes or less than a 2 mm Hg elevation of pressure. The peak contraction and relaxation dP/dt (first deriviative of left ventricular pressure) were reduced to 100 mm Hg/s or more in 84 and 81 % of asymptomatic episodes, respectively. Great cardiac vein oxygen saturation measured in three patients showed an increased myocardial oxygen extraction similar to that seen in painful episodes, which preceded and accompanied asymptomatic electrocardiographic changes. These results indicate that asymptomatic electrocardiographic changes represent transient myocardial ischemia.Comparison of asymptomatic and symptomatic episodes revealed that asymptomatic episodes were generally shorter (253 ± 159 versus 674 ± 396 seconds, probability [p] < 0.001) and produced less impairment of left ventricular function: there were smaller elevations of left ventricular end-diastolic or pulmonary artery diastolic pressure (5.9 ± 5.0 versus 16.5 ± 6.9 mm Hg, p < 0.001), and smaller reductions of peak left ventricular contraction dP/dt (252 ± 156 versus 395 ± 199 mm Hg/s, p < 0.001) and relaxation dP/dt (259 ± 191 versus 413 ± 209 mm Hg/s, p < 0.001). In individual patients, however, asymptomatic and symptomatic episodes of similar duration and severity were observed. The duration and severity of ischemia appear important for the genesis of anginal pain, but additional factors must be involved

Immunosuppressive Therapy for Active Lymphocytic Myocarditis

Background— The beneficial effect of immunosuppressive treatment on myocarditis is still controversial, possibly because the immunologic and virological profile of potential candidates is largely unknown. Methods and Results— Out of 652 biopsied patients, 112 had a histological diagnosis of active lymphocytic myocarditis; 41 of these 112 patients were characterized by progressive heart failure despite conventional therapy and were treated with prednisone and azathioprine for 6 months. All were resubmitted to cardiac catheterization, angiography, and endomyocardial biopsy at 1 and 6 months and followed-up for 1 year. A total of 21 patients responded with prompt improvement in left ventricular ejection fraction from 25.7±4.1% to 47.1±4.4% and showed evidence of healed myocarditis at control biopsy. Conversely, 20 patients failed to respond and showed a histological evolution toward dilated cardiomyopathy: 12 remained stationary, 3 underwent cardiac transplantation, and 5 died. We retrospectively performed a polymerase chain reaction on frozen endomyocardial tissue for the most common cardiotropic viruses and assessed circulating serum cardiac autoantibodies. Viral genomes were present in biopsy specimens of 17 nonresponders (85%), including enterovirus (n=5), Epstein-Barr virus (n=5) adenovirus (n=4), both adenovirus and enterovirus (n=1), influenza A virus (n=1), parvovirus-B19 (n=1), and in 3 responders, who were all positive for hepatitis C virus. Cardiac autoantibodies were present in 19 responders (90%) and in none of the nonresponders. Conclusions— In patients with active lymphocytic myocarditis, those with circulating cardiac autoantibodies and no viral genome in the myocardium are the most likely to benefit from immunosuppression. The beneficial effect of immunosuppression in hepatitis C virus myocarditis suggests a relevant immunomediated component of damage

Delayed recovery of coronary resistive vessel function after coronary angioplasty

AbstractObjectives. The aim of this study was to use Doppler catheterization and sequential dynamic positron emission tomography (PET) to investigate the role and time course of abnormal coronary resistive vessel function in the impairment of the coronary vasodilator response (maximal/basal coronary blood flow) after successful coronary angioplasty.Background. The coronary vasodilator response may be impaired immediately after coronary angioplasty, despite successful dilation of a flow-limiting stenosis.Methods. Twelve men (mean age 52 ± 10 years) with singlevessel coronary artery disease and normal left ventricular function were studied. The coronary vasodilator response to intravenous dipyridamole (0.5 mg·kg−1over 4 min) was determined from intracoronary Doppler measurement of coronary How velocity, before and after successful angioplasty. Basal and maximal myocardial blood flow in the angioplasty region and a normal region were determined in nine patients with positron emission tomography with H215O at 1 day (PET1), 7 days (PET2) and 3 months (PET3) after angioplasty.Results. The coronary vasodilator response, measured by Doppler catheterization, was similar before and immediately after angioplasty, 1.63 ± 0.41 and 1.62 ± 0.55, respectively (p = NS). After angioplasty, in seven of nine patients without restenosis, basal myocardial blood flow at PET1, PET2and PET3was 0.98 ± 0.16, 0.94 ± 0.09 and 0.99 ± 0.13 ml·min−1·g−1, respectively, in the remote region and 1.19 ± 0.23 (p < 0.01 vs. remote region), 1.17 ± 0.19 (p < 0.01 vs. remote region) and 1.10 ± 0.08 ml·min-1·g−1(p = NS vs. remote region), respectively, in the angioplasty region. Myocardial blood flow after dipyridamole at PET1, PET2and PET3was 3.04 ± 0.68, 3.00 ± 0.71 and 3.00 ± 0.60 ml·ml·min−1g−1, respectively, in the remote region and 2.11 ± 0.80 (p < 0.01 vs. remote region), 2.28 ± 0.73 (p = NS vs. remote region) and 3.06 ± 0.86 ml · min−1· g−1(p = NS vs. remote region), respectively, in the angioplasty region. The coronary vasodilator response at PET1, PET2and PET3was 3.15 ± 0.85, 3.18 ± 0.68 and 3.08 ± 0.75, respectively, in the remote region and 1.80 ± 0.68 (p < 0.01 vs. remote region), 1.94 ± 0.49 (p < 0.01 vs. remote region) and 2.77 ± 0.74 (p = NS vs. remote region), respectively, in the angioplasty region.Conclusions. After successful angioplasty, basal myocardial blood flow is increased for ≥7 days in the angioplasty region, with a reduction in the dipyridamole · induced increase in maximal myocardial blood flow for ≥24 h after the procedure. Thus, the coronary vasodilator response is impaired for ≥7 days after angioplasty, indicating that there is abnormal resistive vessel function in the coronary vascular bed distal to a coronary artery stenosis that persists for 7 days to 3 months