Sergio L. Chierchia

Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: Evaluation of the protective role of the metabolic modulator trimetazidine

OBJECTIVES We sought to assess the effects of heparin and the potential protective effects of trimetazidine (TMZ) on exercise performance, plasma nitric oxide (NO), endothelin-1 (ET-1) and free fatty acid (FFA) release in patients with stable coronary artery disease (CAD). BACKGROUND Heparin has been shown to reduce the ischemic threshold in patients with CAD. Trimetazidine may affect myocardial substrate utilization by shifting energy production from FFA to glucose oxidation. METHODS In four consecutive days, nine patients with CAD each received one of the following four regimens: 1) one tablet of placebo the evening before and at 8 AM and 4 PM on the day of the study, 10 ml of saline in a bolus 10 min before exercise, followed by an infusion of the same preparation; 2) placebo at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; 3) 20 mg TMZ at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; or 4) TMZ at the same times as in the first regimen, 10 ml of saline 10 min before exercise, followed by an infusion of the same preparation. RESULTS During placebo (test 2), heparin reduced the time to 1-mm ST-segment depression and prolonged the recovery time, as compared with the results of test 1. When heparin was administered after TMZ (test 3), the time to 1-mm ST-segment depression and the recovery time were similar to those recorded during saline (test 1). Finally, compared with all study phases, TMZ during saline (test 4) prolonged the time to 1 mm. No changes in NO release were found, whereas ET-1 was decreased at peak exercise and during recovery, when the patients were receiving TMZ (tests 3 and 4). Free fatty acids increased after heparin, both with placebo and TMZ. CONCLUSIONS In patients with CAD, heparin reduces the ischemic threshold. Trimetazidine reduces the effects of heparin, probably by inhibiting FFA oxidation and enhancing glucose metabolism. The concomitant novel observation of reduced ET-1 release is likely to be also dependent on TMZ-induced improvement of endothelial metabolism or reduction of myocardial ischemia.

Evidence that apolipoprotein(a) phenoptype is a risk factor for coronary artery disease in men < 55 years of age

Whereas the importance of plasma lipoprotein(a) [Lp(a)] levels as a risk factor for premature coronary artery disease (CAD) is certain, it is not clear if the apolipoprotein(a) [apo(a)] phenotype plays an additional and independent role. To investigate the possible effect of apo(a) phenotype on premature CAD (in patients < 55 years of age), plasma Lp(a) concentrations, the apo(a) phenotypes, and their relation with many recognized CAD risk factors were examined in 96 non-diabetic male patients with angiographically defined CAD and in 83 age-matched male control subjects with no angiographic evidence of CAD. Results demonstrate that patients with premature CAD are characterized by higher Lp(a) levels (24 +/- 21 vs 17 +/- 15 mg/dl, p < 0.01) and a higher frequency of S2 phenotype (32% vs 15%, p < 0.01). Patients with an S2 phenotype exhibited significantly higher plasma Lp(a) concentrations than control subjects with the same isoform (37 +/- 22 vs 22 +/- 17 mg/dl, p < 0.05). A significant correlation was found between apo B and Lp(a) levels in patients with an S2 phenotype. In addition, patients had a low frequency of S1 and S4, and a high frequency of double-band phenotypes of apo(a). Multivariate analysis did not demonstrate an independent role for apo(a) phenotype as a risk factor for premature CAD. In conclusion, CAD patients < 55 years of age have a very different pattern of apo(a) phenotypes than subjects with no angiographic evidence of CAD; this study confirms the hypothesis that apo(a) phenotype may play an additional role in the etiology of premature CAD.

Time dependence of residual tissue viability after myocardial infarction assessed by [18F]fluorodeoxyglucose and positron emission tomography

Areas of myocardial infarction may retain glycolytic activity and this finding is indicative of tissue viability and predictive of functional recovery after revascularization. In order to assess the relation between the time elapsed from the occurrence of acute myocardial infarction and persistence of myocardial metabolic activity in the infarcted tissue, we prospectively studied 65 patients with previous myocardial infarction diagnosed clinically and by electrocardiographic (Q wave) and enzymatic criteria. All patients underwent coronary angiography and contrast left ventriculography, evaluation of regional myocardial glucose metabolism (in the fasting state) by positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), and assessment of myocardial perfusion by single photon emission computed tomography (SPECT) with technetium-99m methoxyisobutyl isonitrile (99mTc-MIBI). Based on the regional metabolic and perfusion findings, patients were divided into 2 groups, depending on the absence (group 1, 26 patients) or presence (group 2, 39 patients) of [18F]FDG uptake in the underperfused regions. Areas of underperfusion at rest, consistent with the clinically identified myocardial infarction site, were observed in all patients. Severity of coronary artery disease, presence of collaterals, number of hypocontractile segments, and wall motion score did not differ significantly in the 2 groups. The time elapsed from the infarction was significantly greater (1,860 +/- 1,333 days) in group 1 than in group 2 (92 +/- 115 days; p < 0.0001). Exercise caused an increase in severity and/or extent of resting perfusion abnormalities in a greater proportion of patients of group 1 (53% vs 23%).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of myocardial perfusion and viability with technetium-99m methoxyisobutylisonitrile and thallium-201 rest redistribution in chronic coronary artery disease

We compare thallium-201 rest redistribution and fluorine-18 fluorodeoxyglucose ([18F]FDG) for the assessment of myocardial viability within technetium-99m methoxyisobutylisonitrile (MIBI) perfusion defects in 27 patients with chronic stable coronary artery disease. The following studies were performed: (1) stress99mTc-MIBI, (2) rest99mTc-MIBI, (3)201T1 rest-redistribution single-photon emission tomography, (4) [18F]FDG positron emission tomography. The left ventricle was devided into 11 segments on matched tomographic images. The segment with the highest activity at stress was taken as the reference (activity=100%). Perfusion defects at99mTc-MIBI rest were classified as severe (activity<50%), moderate (activity 50%–60%) or mild (activity 60%–85%). Uptakes of [18F]FDG and rest-redistributed201Tl were recognized as significant if they exceeded 50% of that in the reference segment. Among the 33 segments with severe99mTc-MIBI rest perfusion defects, 21 had significant [18F]FDG and 10 significant rest-redistributed201Tl uptake. As regards the 37 segments with moderate defects, [18F]FDG was present in 29 and201Tl in 31, while of the 134 segments with mild defects, 128 showed [18F]FDG uptake, and 131,201Tl uptake. In conclusion, there is an inverse relationship between the severity of99mTc-MIBI perfusion defects and the uptake of rest-redistributed201Tl and [18F]FDG. Both tracers are adequate markers of viability in mild and moderate defects; in severe defects201Tl might underestimate the presence of viability as assessed by [18F]FDG.

Septal panniculitis induced by atenolol: A case report

The authors report a case of septal panniculitis induced by atenolol in a patient with coronary artery disease. Several tender, erythematous, suppurated subcutaneous nodules appeared over the metacarpal-phalanx and interphalanx joints of both hands. Hematology indicated a transient inflammatory immunomediated disorder, with an increase of cytotoxic suppressor lymphocytes and presence of antinuclear antibodies. The dramatic inflammatory involvement of the subcutaneous connective tissue could have eventually progressed toward fibrosis, if atenolol had not been withdrawn. This raises the possibility that retroperitoneal fibrosis, a recognized adverse effect of beta blockers, may just represent the terminal phase of undetected connective tissue inflammation occurring in districts not easily explorable before overt manifestations of the disease. Since retroperitoneal fibrosis has already been associated with migratory panniculitis and described as mesenteric panniculitis, it is tempting to speculate that these manifestations originate from the same mechanisms.

Reverse perfusion pattern of Tc-99m MIBI heralding the development of myocardial infarction

In a patient with sporadic atypical chest pain associated with dyspnea, stress Tc-99m MIBI imaging showed normal perfusion and inferoposterior hypoperfusion on the resting study. Although this reverse perfusion pattern was considered artifactual, the patient later had an acute myocardial infarction involving the same areas. Postinfarction stress Tc-99m MIBI imaging showed a nonreversible defect in the same area that, in the earlier study, showed a reverse perfusion pattern. The authors hypothesize that partial stenosis of the related artery with some nontransmural myocardial necrosis at the time of the initial study may be a possible cause of this peculiar Tc-99m MIBI perfusion pattern.

Regional glucose utilization in infarcted and remote myocardium : Its relation to coronary anatomy and perfusion

We studied the relationship between coronary anatomy, perfusion and metabolism in myocardial segments exhibiting transient and persistent perfusion defects on stress/rest 99Tcm-MIBI single photon emission tomography in 35 patients (31 males, 4 females, mean age 56 +/- 7 years) with a previous myocardial infarction. Quantitative coronary angiography and assessment of myocardial perfusion reserve and glucose metabolism were performed within 1 week of one another. Perfusion was assessed by SPET after the intravenous injection of 740 MBq of 99Tcm-MIBI at rest and after exercise. Regional myocardial glucose metabolism was assessed by position emission tomography at rest (200 MBq of 18F-2-deoxyglucose, FDG) after an overnight fast with no glucose loading. All 35 patients exhibited persistent perfusion defects consistent with the clinically identified infarct site, and 27 (77%) also showed various degrees of within-infarct FDG uptake; 11 patients developed exercise-induced transient perfusion defects within, or in the vicinity of, 15 infarct segments and resting FDG uptake was present in 10 of these segments (67%). Five patients also showed exercise-induced transient perfusion defects in nine segments remote from the site of infarct: resting FDG uptake was present in six of these regions (67%). Finally, nine patients had increased glucose uptake in non-infarcted regions not showing transient perfusion defects upon exercise testing and perfused by coronary arteries with only minor irregularities. Our results confirm the presence of viable tissue in a large proportion of infarct sites. Moreover, FDG uptake can be seen in regions perfused by coronary arteries showing minor irregularities, not necessarily resulting in detectable transient perfusion defects on a MIBI stress scan. Since the clinical significance of such findings is not clear, further studies should be conducted to assess the long-term evolution of perfusion, function and metabolism in non-revascularized patients of those remote areas which are apparently normally perfused, but show abnormal fasting FDG uptake after myocardial infarction. Such studies may have important implications for the management of post-infarct patients, as the preservation of coronary vasodilator reserve and myocardial metabolism in remote myocardium may be seen as an additional goal in the treatment of such patients.