Guía Europea de Prevención Cardiovascular en la Práctica Clínica (y II) / Spanish adaptation of the European Guidelines on Cardiovascular Prevention (and II)

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Sustained benefit at 10-14 years follow-up after thrombolytic therapy in myocardial infarction.

AIMS: To investigate whether the benefit of thrombolytic therapy was sustained beyond the first decade. We report the 10-14 year outcome of 533 patients who were randomized to treatment with intracoronary streptokinase or to conventional therapy during the years 1980-1985. METHODS AND RESULTS: Details of survival and cardiac events were obtained from the civil registry, from medical records or from the patient's physician. At follow-up, 158 patients (59%) of the 269 patients allocated to thrombolytic treatment and only 129 patients (49%) of the 264 conventionally treated patients were alive. The cumulative 1-, 5- and 10-year survival rates were 91%, 81% and 69% in patients treated with streptokinase and 84%, 71% and 59% in the control group, respectively (P=0.02). Reinfarction during 10-years of follow-up was more frequent after thrombolytic therapy, particularly during the first year. Coronary bypass surgery and coronary angioplasty were more frequently performed after thrombolytic therapy. At 10 years approximately 30% of the patients were free from subsequent cardiac events. Independent determinants of mortality were elderly age, indicators of impaired residual left ventricular function, multivessel disease and an inability to perform an exercise test at the time of hospital discharge. CONCLUSION: Improved survival after thrombolytic therapy is maintained beyond the first decade. Age, left ventricular function, multivessel disease and an inability to perform an exercise test were independent predictors for long-term mortality, as they are predictors for early mortality.

A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.

Thrombomodulin is an endothelial cell surface receptor that transforms the procoagulant thrombin into an anticoagulant. A mutation in the thrombomodulin gene is a potential risk factor for venous and arterial thrombosis. We screened a region within the coding sequence of the thrombomodulin gene by single-strand conformation polymorphism analysis (SSCP) in a pilot study of 104 patients with myocardial infarction and 104 age, sex and race matched controls. We identified a 127G to A mutation in the gene, which predicts an Ala25Thr substitution, in 2 out of 104 patients (1 man and 1 woman) with myocardial infarction but in no controls. We assessed the risk of myocardial infarction associated with the mutation in a larger "Study of Myocardial Infarctions Leiden" (SMILE). Among 560 men with a first myocardial infarction before the age of 70, 12 were carriers of the Ala25Thr substitution. In a control group of 646 men, frequency-matched for age, seven were carriers of the Ala25Thr substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls suggesting risk associated with the mutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1]. In patients aged below 50, the predicted risk was almost seven times increased (OR 6.5, CI 0.8-54.2). In the presence of additional risk factors, such as smoking and a metabolic risk factor, the predicted risk increased to 9-fold (OR 8.8. CI 1.8-42.2) and 4-fold (OR 4.4, CI 0.9-21.3), respectively. While not conclusive, these results strongly suggest that the Ala25Thr substitution is a risk factor for myocardial infarction, especially in young men, and when in the presence of additional risk factors.

A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men.

Several studies have examined the relation between factor VII and coronary artery disease by measuring factor VII levels in plasma and some found an association between high levels and disease. This suffers problems of interpretation concerning the causality of high factor VII levels, because factor VII levels may be affected by atherogenic risk factors and may become elevated as a consequence of atherosclerosis. We investigated the association between a genetic variant (353Arg-->Gln), shown to be related to factor VII levels, and myocardial infarction in a large case-control study, including 560 cases and 644 controls. Individuals carrying the 353Arg-Arg genotype seemed to have a lower risk of myocardial infarction (odds ratio 0.80 [95% confidence interval 0.60-1.061). In this study, we confirmed higher factor VII antigen and activity level in 529 men homozygous for the 353Arg allele compared with 115 men carriers of the 353Gln allele (around 20% higher). Our results indicate that a genetic propensity to high factor VII levels is not associated with the risk of myocardial infarction. Since we confirmed the association of the 353Arg-Arg genotype with higher factor VII levels, we conclude that high levels of factor VII are not a causal determinant of myocardial infarction.

Comparison between regional myocardial perfusion reserve and coronary flow reserve in the canine heart.

Diameter stenosis and flow reserve are indices of morphological and functional severity of coronary artery stenosis. Flow reserve can be determined at coronary arterial or at myocardial level. In the presence of functional collateral circulation, coronary flow reserve and myocardial perfusion reserve may differ. We studied coronary flow, coronary flow reserve and myocardial perfusion reserve in an open chest dog model with intact collateral circulation, before and after induction of coronary artery stenosis. Coronary flow was determined with perivascular ultrasonic flow probes and myocardial perfusion reserve from digital angiographic images, in the stenotic as well as the adjacent non-stenotic coronary arteries. Before induction of a stenosis, a significant correlation existed between coronary flow reserve and myocardial perfusion reserve of the left anterior descending (r = 0.59; P < 0.005) and the left circumflex arteries (r = 0.84, P < 0.005). In stenotic arteries, coronary flow reserve and myocardial perfusion reserve decreased significantly (P < 0.005), but in the adjacent non-stenotic arteries coronary flow reserve was not affected. Myocardial perfusion reserve in the non-stenotic adjacent left anterior descending artery decreased significantly (P < 0.05) and no correlation was found between coronary flow reserve and myocardial perfusion reserve, whereas in the adjacent non-stenotic left circumflex artery there was no statistically significant decrease (4.1 +/- 1.6 --> 3.5 +/- 1.4) but there was a good correlation between coronary flow reserve and myocardial perfusion reserve (r = 0.85; P < 0.005). This study demonstrates that, in the presence of a stenosis and functioning collateral circulation, coronary flow reserve is not a reliable predictor of myocardial perfusion reserve; both parameters provide mutually complementary information.

Autonomic, ischaemic, circadian and rhythmic factors as causes of the spontaneous variability of ventricular arrhythmias.

Ventricular arrhythmias present with strongly varying intensity. This spontaneous variability makes it difficult to use one of the existing arrhythmia grading systems for risk or therapy efficacy studies. We attempted to explain the variability by the changing autonomic, ischaemic, circadian, and rhythmic factors. Four (two learning, two test) 24-h Holter tapes were made within one month in 31 patients with chronic frequent ventricular ectopic beats of miscellaneous aetiology and under constant drug regimen. The data were segmented into 5-min episodes, in which ectopy (dependent variable) was measured, together with heart rate, amount of heart rate variability, fraction low-frequency heart rate variability, ST depression, and clock time (independent variables). Forty-three percent of the fluctuations in arrhythmia incidence could be explained with a multiple regression procedure, and more than 50% of the variance in arrhythmia incidence could be explained in 36% of the cases. Our study demonstrates that much of the spontaneous variability of ventricular arrhythmias can be attributed to the varying conditions. This method of dealing with arrhythmia variability might lead to an alternative to the current arrhythmia grading systems used in risk and drug efficacy studies.

The acute effects of intravenous nisoldipine on left ventricular function within 24 h after acute myocardial infarction.

Nisoldipine is a calcium antagonist with potent coronary vasodilating effects in patients with chronic stable angina pectoris. We studied the acute effects of nisoldipine in six patients within 24 h (mean 14 +/- 4 h) after the onset of myocardial infarction. Nisoldipine was administered as a 4.5 micrograms kg-1 intravenous bolus over 3 min followed by intravenous infusion of 0.2 microgram kg-1 min-1 during 60 min. Radionuclide angiography, cardiac output and intra-arterial blood pressure measurements were performed before and during nisoldipine. Left ventricular ejection fraction increased from 48.3 +/- 10.3% to 55.3 +/- 11.8% (P = 0.034) during nisoldipine infusion. Regional wall motion score changed during nisoldipine infusion from 3.3 +/- 2.5 to 1.8 +/- 2.6 (P = 0.027). Cardiac output increased from 5.5 +/- 1.0 to 7.3 +/- 1.3 l min-1 (P = 0.0001). Heart rate increased from 78 +/- 12 to 88 +/- 11 beats.min-1 (P = 0.004). Mean arterial blood pressure decreased from 91.7 +/- 20.2 to 78.7 +/- 13.1 mmHg (P = 0.038). The rate-pressure product did not change significantly during nisoldipine infusion. It is concluded that nisoldipine improves global and regional left ventricular function in patients with acute myocardial infarction within the first 24 h. Our findings suggest that this effect is achieved without increasing myocardial oxygen demand.

Silent myocardial ischemia after acute myocardial infarction.

Silent ischemia after myocardial infarction has definite prognostic significance but should be interpreted within the context of other prognostic indicators. The rationale for therapeutic intervention is based on the prognostic implications of silent ischemia and the potentially deleterious effect of repeated episodes of ischemia on the integrity of the left ventricle. We measured parameters of ischemia in 20 patients who showed asymptomatic ischemic ST-T changes on exercise testing in the early phase after myocardial infarction. After diltiazem administration, a reduction of exercise-induced ST-T depression from 2.3 +/- 0.8 to 0.7 +/- 0.6 mm (p less than 0.01) occurred, and regional wall-motion score at exercise, determined by radionuclide angiography, improved significantly (p less than 0.02). These and other observations warrant further studies in which the duration, severity and frequency of the ischemic episodes should be quantified and correlated with prognosis after myocardial infarction.

Metoprolol-induced reduction in postinfarction mortality: pooled results from five double-blind randomized trials.

Several postinfarction trials have evaluated the effect of secondary prophylaxis with different beta-blockers. Although so called meta-analysis of the results from all the trials have shown a beneficial effect of postinfarction beta-blockade, many of the individual studies have shown inconclusive results, mainly due to low statistical power. In order to obtain an evaluation of the merits of postinfarction therapy with metoprolol, data from the five available studies with metoprolol have been pooled into one database. In the total material 5474 patients (4353 men, 1121 women) have been studied during double-blind therapy with metoprolol 100 mg twice daily or matching placebo. The follow-up ranges from 3 months to 3 years. In total 4732 patient years of observation have been obtained. In total there were 223 deaths in the placebo-treated patients as compared to 188 deaths in the metoprolol-treated patients (P = 0.036), which corresponds to mortality rates of 97.0 and 78.3 per 1000 patient years, respectively. The mortality reduction was found both in men and women. As has been reported from individual postinfarction beta-blocker trials, the pooled results showed a marked reduction in sudden deaths (104 in the placebo group, 62 in the metoprolol group, P = 0.002). In a Cox regression model the influence of sex, age and smoking habits on the effect of metoprolol was evaluated. None of these factors influenced the metoprolol effect significantly. It is concluded that metoprolol therapy after acute myocardial infarction reduces the total number of deaths, and especially sudden cardiac deaths. The mortality reduction was independent of gender, age and smoking habits. Available data support a continuous beneficial effect.

Influence of angiotensin converting enzyme inhibition on pump function and cardiac contractility in patients with chronic congestive heart failure.

Eleven patients with coronary artery disease and chronic heart failure were studied before and three months after the angiotensin converting enzyme inhibitor enalapril was added to their frusemide medication. The following were measured: left ventricular pressure and volume with transient occlusion of the inferior vena cava, radionuclide angiography, and hormone concentrations in plasma. As in other reported studies, the clinical condition of the patients improved and their exercise tolerance increased moderately. Addition of enalapril reduced end diastolic and systolic pressure, reduced ventricular volume, and concomitantly increased the ejection fraction. The end systolic pressure-volume relation shifted to the left as it did in a similar animal study. In the animal study unloading by a vasodilator did not induce a leftward shift, so it can be inferred that in the present study unloading combined with a decrease in the angiotensin concentration was instrumental in remodelling the heart. Though unloading was expected to have a beneficial effect on the oxygen supply/demand ratio of the heart, the patients still showed the same drop in the ejection fraction during exercise as they did before treatment with enalapril, and early diastolic filling did not improve. Normally, regression of cardiac dilatation is only found if pump function improves; the present study showed that unloading in combination with angiotensin converting enzyme inhibition reshapes the ventricle without improving intrinsic pump function.

Cardiac remodelling and myocardial contractility in patients with congestive heart failure treated with furosemide and enalapril.

Eleven patients with congestive heart failure class II-IV (NYHA) caused by ischemic heart disease were studied before and three months after adding enalapril to their treatment with furosemide. After an infarction the heart dilates gradually, mainly as a result of slippage of myocardial fiber bundles. It is known that the addition of an ACE-inhibitor to the medical treatment unloads the heart and gradually, within a period of 3 months, reduces heart size. Objectives of this study were to demonstrate remodelling by recording diastolic pressure-volume relations before and after treatment. The study addresses the question of whether regression of dilation, induced by the ACE-inhibitor treatment, improves the oxygen supply-demand ratio and, as a result, the contractility of the heart muscle. Treatment resulted in a reduction of vascular resistance (1479 to 1182 dyn.s.cm-5, p less than 0.05) and of the left ventricular end-diastolic (130 to 108 ml per m2 body surface area, p less than 0.05) and end-systolic (102 to 81 ml per m2 body surface area, p less than 0.01) volume index. The slope of the end-systolic pressure-volume relation, measured using vena cava occlusion and beat-to-beat recording of pressure and volume loops, remained unchanged. Indices of oxygen-supply demand ratio such as a drop of ejection fraction during exercise and parameters of active diastolic relaxation also did not change. Addition of an ACE-inhibitor induces regression of ventricular dilation, but no indications were found that it improves the condition of the cardiac muscle.

Improvement of left ventricular function in silent ischemia following myocardial infarction, after administration of diltiazem.

In a group of 72 patients with acute myocardial infarction who underwent a maximal symptom-limited predischarge exercise test in conjunction with radionuclide angiography, 25 (35%) showed greater than 1 mm asymptomatic ST-T-segment depression during exercise. All 25 patients underwent repeated exercise radionuclide angiography 2 days later, 2 h after oral intake of 120 mg diltiazem. Double product was not significantly different before and after diltiazem both at rest and during exercise. Maximal ST-T-segment depression after diltiazem was reduced from 2.4 +/- 0.9 mm to 0.8 +/- 0.6 mm (p less than 0.01). Left ventricular ejection fraction (LVEF) at rest was (before diltiazem) 52.1 +/- 8.9% and (after diltiazem) 55.1 +/- 12.3% (NS). During exercise, LVEF improved after diltiazem from 42.8 +/- 12.1% to 49.1 +/- 10.8% (p less than 0.05). Regional wall motion score (1 = normal, 2 = hypokinetic, 3 = akinetic, 4 = dyskinetic) at rest before diltiazem was 9.9 +/- 2.3 and, after diltiazem, was 9.0 +/- 1.9 (NS). During exercise, regional wall motion score improved after diltiazem from 5.9 +/- 1.3 to 4.2 +/- 1.2 (p less than 0.02). We conclude that diltiazem has acute beneficial effects on asymptomatic ST-T-segment depression and on global and regional left ventricular function in post-infarction patients with silent ischemia.

Diagnostic significance of gadolinium-DTPA (diethylenetriamine penta-acetic acid) enhanced magnetic resonance imaging in thrombolytic treatment for acute myocardial infarction: its potential in assessing reperfusion.

The diagnostic value of gadolinium-DTPA (diethylenetriamine penta-acetic acid) enhanced magnetic resonance imaging in patients treated by thrombolysis for acute myocardial infarction was assessed in 27 consecutive patients who had a first acute myocardial infarction (14 anterior, 13 inferior) and who underwent thrombolytic treatment and coronary arteriography within 4 hours of the onset of symptoms. Magnetic resonance imaging was performed 93 hours (range 15-241) after the onset of symptoms. A Philips Gyroscan (0.5 T) was used, and spin echo measurements (echo time 30 ms) were made before and 20 minutes after intravenous injection of 0.1 mmol/kg gadolinium-DTPA. In all patients contrast enhancement of the infarcted areas was seen after Gd-DTPA. The signal intensities of the infarcted and normal values were used to calculate the intensity ratios. Mean (SD) intensity ratios after Gd-DTPA were significantly increased (1.15 (0.17) v 1.52 (0.29). Intensity ratios were higher in the 17 patients who underwent magnetic resonance imaging more than 72 hours after the onset of symptoms than in the 10 who underwent magnetic resonance imaging earlier, the difference being significantly greater after administration of Gd-DTPA (1.38 (0.12) v 1.61 (0.34). When patients were classified according to the site and size of the infarcted areas, or to reperfusion (n = 19) versus non-reperfusion (n = 8), the intensity ratios both before and after Gd-DTPA did not show significant differences. Magnetic resonance imaging with Gd-DTPA improved the identification of acutely infarcted areas, but with current techniques did not identify patients in whom thrombolytic treatment was successful.

[Safety and efficacy of thrombolysis during ambulance transportation of patients with an acute heart infarct]. / De veiligheid en effectiviteit van trombolyse tijdens ambulancetransport van patiënten met een acuut hartinfarct.

We studied the safety and efficacy of thrombolytic therapy for acute myocardial infarction initiated prior to ambulance transport. Intravenous streptokinase with 5 X 10(5) IU (SK-i.v.) was started in 40 patients (group A) before transport and 36 patients (group B) after transport. In all patients immediate coronary angiography was performed, followed by intracoronary streptokinase. Infarct size was assessed from cumulative release of alpha-hydroxybutyrate dehydrogenase. No procedure-related complications were seen during transport. The time to SK-i.v. was 70 minutes in group A versus 125 minutes in group B. At first visualisation the infarct-related vessel was patent in 23 patients (58%) in group A and in 6 patients (17%) in group B (p less than 0.001). For anterior wall infarction we found a 32% smaller infarct size in group A (p less than 0.05). We conclude that SK-i.v. during ambulance transport is safe, increases early reperfusion and leads to a further reduction of infarct size which is significant in anterior wall infarction.