Daniela Degli Esposti

Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of Myocardial infarction in patients with arterial hypertension

A positive history of arterial hypertension (HBP) is present in as many as 30% of patients with acute myocardial infarction (AMI) and their clinical outcome could be greatly improved by drugs enhancing blood pressure control and preserving ventricular function. The aim of the present study was to evaluate the importance of a history of HBP on the clinical efficacy of early treatment with the angiotensin-converting enzyme (ACE) inhibitor zofenopril in patients with anterior AMI. We summarize the results of a post-hoc analysis of data from the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, which randomly evaluated the efficacy of zofenopril given within 24 h of symptom onset to patients with anterior AMI not undergoing thrombolysis. Of 1441 patients who entered the study, 565 (39.2%) had a history of HBP. The mean follow-up time was 12 months and the main outcome measures were 6-week combined occurrence of death and severe congestive heart failure (CHF) and 1-year mortality. After 6-week of treatment with zofenopril the relative risk of death or severe CHF was 0.60 (95% confidence interval [CI]: 0.45-0.81; 2P < .05) in the hypertensive group and 0.89 (0.74-1.08; 2P = .62) for normotensive patients, whereas the 1-year risk of death was 0.61 (95% CI: 0.23,0.89; 2P < .05) and 0.77 (95% CI: 0.52-1.17; 2P = .22), respectively. The 6-week prevalence of mild-to-moderate CHF was also significantly reduced by zofenopril in the hypertensive population (14.1% v 9.4%; 2P < .05). The present data suggest that treatment with zofenopril started within 24 h of the onset of anterior AMI could be highly beneficial in patients with a history of HBP.

Factors associated with the development of stable hypertension in young borderline hypertensives

Objectives To identify factors predisposing subjects to the development of stable hypertension and to estimate their relative importance in 70 young patients with borderline hypertension monitored for 10 years. Design Longitudinal evaluation of the incidence of stable hypertension [diastolic blood pressure (DBP) > 95 mmHg]. Methods Patients were examined at baseline by determination of resting blood pressure, intracellular sodium level and individual pressor response to mental arithmetic and to intravenous saline loading. They were re-examined after 10 years to assess the prevalence of established hypertension and the importance of some prognostic variables identified prospectively (age, sex, intracellular sodium level, baseline blood pressure, pressor response to stress and acute salt-sensitivity). Results The prevalence of sustained hypertension (DBP > 95 mmHg) was 35.8% after 10 years of follow-up study. Subjects developing hypertension were older (26.9±1.3 versus 21.0±1.8 years) and showed a higher percentage of family history of hypertension (92 versus 64%) and of acute salt-sensitivity (72 versus 53%). The pressor response to mental arithmetic was greater in patients who developed hypertension (systolic blood pressure 26.9±1 versus 22.7±0.9 mmHg, P=0.005 DBP = 16.6±0.8 versus 13.1±0.7 mmHg, P=0.005), who also showed higher levels of intracellular sodium (30.7±0.6 versus 27.3±0.5 mmol/kg, P=0.001). The same variables were found to be related to the development of hypertension in a multivariate analysis and the concomitant presence of 4–5 risk factors was associated with a reasonable predictive power for the identification of patients at high risk (sensitivity 72%, specificity 67%, predictive accuracy 76%). Conclusions The present study demonstrates that borderline hypertensives at high risk of stable hypertension can be identified by the concomitant evaluation of some clinical and cellular characteristics directly related to long-term development of high blood pressure.

Serum cholesterol levels, blood pressure response to stress and incidence of stable hypertension in young subjects with high normal blood pressure

Rationale Elevated serum cholesterol levels are common in patients with high blood pressure (BP) and could contribute to the progression of the hypertensive disease. Objective To determine whether serum cholesterol levels affect the BP response to mental stress (MA) and the development of stable hypertension in young subjects with high normal BP. Methods Seventy young (age < 45 years) high normal BP subjects with elevated (> 200 mg/dl, n = 49; HC) or normal (⩽ 199 mg/dl, n = 21; NC) serum cholesterol levels, and 20 normotensive normocholesterolaemic (serum cholesterol < 199 mg/dl; C) subjects undergoing standardized mental challenge (mental arithmetic) were followed up for 15 years according to a prospective, longitudinal, cohort study design conducted in an ambulatory setting. The main outcome measure was the evaluation of the 15-year incidence of stable hypertension (diastolic BP > 95 mmHg). Results After adjustment for age, resting BP, family history of high BP and body mass index at the study entry, high normal BP subjects with HC showed an enhanced BP reactivity to stress and a higher 15-year incidence of stable hypertension compared to high normal BP and NC subjects [relative risk (RR) = 2.1; 95% confidence interval (CI) = 1.7–5.5, P < 0.001] and controls (RR = 3.1; 95% CI = 1.4–5.3, P < 0.001). In a multivariate analysis of data the presence of high cholesterol levels was an independent predictor for the development of hypertension. Conclusion These data suggest that subjects with high normal BP and elevated serum cholesterol might have an exaggerated cardiovascular response to stress and have an increased risk for stable hypertension that can be detected at young age.

A review of the angiotensin-converting enzyme inhibitor, zofenopril, in the treatment of cardiovascular diseases

Based on preclinical and clinical findings, zofenopril appears to be an angiotensin-converting enzyme (ACE) inhibitor with high potency, significant tissue selectivity and a long duration of action. Its ancillary properties, such as antioxidant activity and cardiovascular (CV) protection, make this drug potentially suitable for the treatment, and possibly prevention, of several CV diseases. There is a large body of evidence that support a complex interaction between ACE inhibitors and CV disease. A review of the preclinical profile of zofenopril clearly suggest that such interaction can be even more complex and could involve some drug-specific properties directly involved in the definition of the overall clinical profile of zofenopril as emerged from randomised clinical trials. In particular, zofenopril combines the feature of an effective ACE inhibitor, with plasma and tissue activity, along with that of an antioxidant compound, and both these characteristics can contribute to its capacity of controlling hypertension and improving the prognosis of patients with coronary artery disease. The results of The Survival of Myocardial Infarction Long term Evaluation (SMILE) trials have demonstrated that the early administration of zofenopril to patients with acute myocardial infarction is associated with a significant reduction in the 6-week occurrence of major CV events (death and congestive heart failure) in high-risk patients with anterior non-thrombolysed myocardial infarction, and this effect is enhanced in some higher-risk subgroups of patients, such as those with a history of diabetes or arterial hypertension.

Hemodynamic and neurohumoral profile in patients with different types of hypertension in pregnancy

Hypertension in pregnancy is a frequent disorder that includes a spectrum of conditions. We aimed at comparatively evaluating the hemodynamic, echocardiographic and biohumoral profile of a sample of pregnant Caucasian women with different form of pregnancy-related hypertension. We enrolled 39 non-hypertensive pregnant women (NP), 26 with Chronic HBP in pregnancy (CH), 24 with gestational hypertension (G-PIH), and 33 with pre-eclampsia. We recorded and compared blood pressure (BP), echocardiographic parameters, resting plasma renin activity (PRA) and plasma aldosterone (PA), Plasma levels of atrial (ANP) and brain natriuretic peptide (BNP). PE patients had a significantly higher BP than either G-PIH or NP patients. PE patients had also significantly lower cardiac output than NP, G-PIH and CH. In comparison to NP patients, the total peripheral vascular resistance was 61% higher in PE women and 38% higher in CH patients. All echographic parameters were significantly more altered in PE patients when compared with NP, in respect to any other form of hypertension. Either ANP (+35%) and BNP (+40%) were significantly higher in PE patients than in controls. The PRA was reduced in PE and CH patients when compared either with NP (−38 and −35%, respectively) or G-PIH (−47 and −43%, respectively). On the basis of our data, we can conclude that PE is the gestation associated hypertension with the largest anatomical, functional and biohumoral involvement, and so it has to be involved in a more intensive monitoring and evaluation.

Anti-ischemic effects of angiotensin-converting enzyme inhibitors : A future therapeutic perspective

Summary: The renin‐angiotensin system and angiotensin‐converting enzyme (ACE) are increasingly being implicated in the pathogenesis of coronary artery disease and its sequelae and the potential of ACE inhibitors to protect the heart is a topic that has emerged recently as a matter for scientific discussion. Experimental and clinical studies have shown the beneficial effects of ACE inhibitors on the metabolism, function and structure of healthy and damaged hearts and these data support the concept of both primary and secondary cardioprotection with this class of drugs. Animal studies have demonstrated the potential beneficial effects of ACE inhibition at a variety of sites, including improvement of endothelial function, inhibition of platelet aggregation, prevention of atherosclerotic lesions and inhibition of myointimal proliferation, extending the concept to a more general definition of cardiovascular protection with ACE inhibitors involving both the heart and the vessels. ACE inhibitors prevent stimulation of smooth muscle cell angiotensin‐II (A‐II) receptors, thereby blocking both contractile and proliferative actions of A‐II. In addition, ACE inhibition of kininase inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level ACE inhibition shifts the balance of ongoing mechanisms in favour of those promoting vasodilatory, anti‐aggregatory, antithrombotic and antiproliferative effects. Although these data have not all been validated in human studies, the reduction of ischemic events in studies of ACE inhibition in left ventricular dysfunction (LVD) and, more recently, also in patients without LVD, cannot be explained solely by improved hemodynamics, and it is possible that actions on the endothelium, the atherosclerotic process and platelets are at least in part responsible. So, the available data underlie the potential benefits of ACE inhibition in the field of ischemic heart disease and atherosclerosis; the results of ongoing studies in humans looking more directly at the influence of ACE inhibitors in this setting are awaited with interest.

Long-term clinical experience with zofenopril

Angiotensin-converting enzyme inhibitors are extensively used to improve clinical outcome of patients with several cardiovascular diseases. Zofenopril proved to be very effective in patients with coronary artery disease and myocardial infarction, thanks to its unique effective mechanism of action for improving blood pressure control, left ventricular function and myocardial ischemia burden, as well as angiotensin-converting enzyme inhibition. The SMILE project involved more than 3500 patients with coronary artery disease and demonstrated that zofenopril treatment may reduce mortality and morbidity in patients with myocardial infarction, also when combined with acetyl salicylic acid and to a greater extent than lisinopril and ramipril. In addition, the results of the SMILE-ISCHEMIA study have demonstrated an interesting anti-ischemic effect of zofenopril, and these properties largely contribute to the overall clinical benefit of the drug. The effects of zofenopril on blood pressure control and cardiovascular protection clearly support its primary role for prevention and treatment of cardiovascular diseases.

β-blockade in Hypertension and congestive heart failure

Hypertension is common and increases the risk of death from coronary artery disease and cerebral vascular disease. The reason for treating hypertension is to prevent the long-term complications of this disorder. Many studies of antihypertensive therapy have produced only modest reductions in coronary events; in particular, with the use of beta-blockers. Clinical trials and meta-analyses have shown a lesser effect of these drugs on primary prevention of coronary events, cardiovascular and total mortality with respect to other antihypertensive approaches based on the use of low-dose diuretic therapy, especially in the elderly, even if the reduction of stroke and heart failure (HF) were similar. New beta-blockers with vasodilating properties due to the capacity to enhance the release of endothelial nitric oxide, then lessening a contributory mechanism to the pathogenesis of atherosclerosis as endothelial damage and dysfunction, seem to possess considerable potential in the treatment of hypertension, particularly in terms of improvement of cardiovascular outcome of patients. In HF, there is now considerable interest in the therapeutic use of beta-blockade. Some recent clinical trials have demonstrated conclusive evidence of the beneficial effects of beta-blocker therapy on survival in chronic HF. As a result of these data, beta-blocker therapy has become part of standard therapy for patients with chronic HF, in addition to angiotensin-converting enzyme-inhibitors and diuretics. The treatment is, in general, well tolerated. There are, however, some unanswered questions. One is whether some beta-blockers may be better than others. The major mortality benefit is probably a class-effect of beta1-adrenoceptor blockade, but the differences between beta-blockers might be clinically relevant. For example, it is under debate whether ancillary properties of some beta-blockers, such as the capability of exerting antioxidant effects or enhancing the nitric oxide production, may contribute to the clinical effects of these drugs. Future clinical trials will report over the next few years and help to answer the question about differences in mortality effects among types of beta-blocking agents, thus correctly defining the precise role of these drugs in the wide spectrum of cardiovascular disease.

Haemodynamic profile of young subjects with transient tinnitus

Abstract Objective: Our objective was to contribute to drawing a haemodynamic profile of healthy subjects prone to labyrinthine disorders of functional origin. The aim was to determine if some haemodynamic aspects could characterize young people with a history of transient tinnitus, considered as an early symptom of cochlear damage possibly derived from hypoperfusion. In one year we studied 60 consecutive subjects (28 ± 5.2, range 18–40 years): 24 who experienced transient tinnitus, and 36 without tinnitus. Exclusion criteria were a history of audiological and otological impairment, ear surgery, and known cardiac abnormalities. A clinical and echographic cardiac evaluation was performed, with assessment of blood pressure, heart rate, and left ventricular structure and function. Results: All results were within the normal range in both groups. The tinnitus group had a slightly lower body mass index (BMI) (p = 0.05) and body surface area (BSA) (p <0.05), while age, blood pressure and heart rate were similar in the two groups. Tinnitus subjects showed reduced diastolic and systolic left ventricular internal dimensions (p = 0.01 and 0.02, respectively) and left ventricular end-diastolic volume (p = 0.02). Left ventricular mass (LVM) related to height 2.7 and observed LVM were reduced in tinnitus subjects (both p = 0.02), while LVM related to BSA had a less marked reduction (p = 0.04), and predicted LVM and appropriate LVM showed only a borderline statistically significant reduction (p = 0.05). Functional systolic left ventricular aspects were similar in the two groups apart from a lower stroke volume in tinnitus subjects compared with the no-tinnitus group (p = 0.03), and no differences were observed in diastolic function indexes between the two groups. Conclusion: Subjects with a history of transient tinnitus, although presenting normal echocardiographic parameters, seem to have smaller somatic and cardiac structural characteristics, which could be less adequate in maintaining peripheral perfusion. In particular, a terminal circle district such as the cochlear one could thus show its stress through tinnitus. This observation indirectly supports the theory of a cochlear origin of tinnitus in a number of cases and is reminiscent of what happens in hypertension and heart failure.

Post-partum evaluation of maternal cardiac function after severe preeclampsia.

Abstract Objective: To evaluate the post-partum maternal cardiac function in patients with history of severe preeclampsia. Methods: A series of women with previous singleton pregnancy complicated by severe preeclampsia underwent transthoracic echocardiography at 6–12 months from delivery. A group of women with previous uncomplicated pregnancy was selected as controls. Results: Sixteen women with history of severe preeclampsia were enrolled in the study group whereas 18 patients were selected as controls. In the study group systolic (p = 0.002) and diastolic blood pressure (p = 0.044) were significantly higher. Significant differences were observed in systolic left ventricular (LV) parameters, such as cardiac output (p = 0.034), LV mass indexed to BSA (p = 0.024) and longitudinal contraction, expressed by tissue Doppler (TD) S1 wave, which resulted relatively impaired in former preeclamptic women (p = 0.049). As regards as diastolic parameters, pulsed Doppler A-wave velocity was increased (p = 0.036). TD E-wave velocity was significantly lower in study group (p < 0.001) and E/E1 ratio (E = peak early diastole transmitral wave velocity/E1 = peak early diastolic velocity at mitral valve annulus at TD) was higher respect to controls (p < 0.001). Conclusions: LV contractility and diastolic function, although within normal reference ranges, show slight but significant impairment among women who experienced a severe preeclampsia. TD seems to be a sensible tool to identify these precocious signs of potential LV dysfunction.