Gender differences in the effects of cardiovascular drugs.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression.

BACKGROUND AND PURPOSE: Recent clinical data suggest beneficial effects of ivabradine, a specific heart rate (HR)-lowering drug, in heart failure patients. However, the mechanisms responsible for these effects have not been completely clarified. Thus, we investigated functional/molecular changes in I(f), the specific target of ivabradine, in the failing atrial and ventricular myocytes where this current is up-regulated as a consequence of maladaptive remodelling. EXPERIMENTAL APPROACH: We investigated the effects of ivabradine (IVA; 10 mg·kg(-1) ·day(-1) for 90 days) on electrophysiological remodelling in left atrial (LA), left ventricular (LV) and right ventricular (RV) myocytes from post-mycardial infarcted (MI) rats, with sham-operated (sham or sham + IVA) rats as controls. I(f) current was measured by patch-clamp; hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms and microRNA (miRNA-1 and miR-133) expression were evaluated by reverse transcription quantitative PCR. KEY RESULTS: Maximal specific conductance of I(f) was increased in MI, versus sham, in LV (P < 0.01) and LA myocytes (P < 0.05). Ivabradine reduced HR in both MI and sham rats (P < 0.05). In MI + IVA, I(f) overexpression was attenuated and HCN4 transcription reduced by 66% and 54% in LV and RV tissue, respectively, versus MI rats (all P < 0.05). miR-1 and miR-133, which modulate post-transcriptional expression of HCN2 and HCN4 genes, were significantly increased in myocytes from MI + IVA. CONCLUSION AND IMPLICATION: The beneficial effects of ivabradine may be due to the reversal of electrophysiological cardiac remodelling in post-MI rats by reduction of functional overexpression of HCN channels. This is attributable to transcriptional and post-transcriptional mechanisms.

Efficacy of ivabradine in combination with Beta-blocker versus uptitration of Beta-blocker in patients with stable angina.

PURPOSE: The antianginal and anti-ischemic efficacy of the selective I (f) inhibitor ivabradine is established in patients with stable angina in monotherapy and in combination with other antianginals, including beta-blocker. This pilot study compared the antianginal and anti-ischemic efficacy and hemodynamic profile of ivabradine plus 5 mg bisoprolol versus those of 10 mg bisoprolol in patients with stable angina. PATIENTS AND METHODS: Twenty-nine patients with stable angina and moderate left ventricular systolic dysfunction already on bisoprolol 5 mg od were randomized into 2 groups. Group 1 (n = 17) received ivabradine (5-7.5 mg bid) in addition to bisoprolol 5 mg od, while in group 2 (n = 12) bisoprolol was uptitrated first to 7.5 mg and then 10 mg od. Patients underwent a treadmill test, 6-minute walking test, and echocardiography at baseline and after 2 months. RESULTS: Mean resting heart rate decreased in both groups, from 76.6 ± 4.6 bpm to 59.3 ± 2.5 bpm (P < 0.001) in group 1 and from 75.9 ± 3.0 bpm to 60.5 ± 2.3 bpm (P = 0.002) in group 2. The effect on resting heart rate did not differ significantly between the two groups. However, more patients became asymptomatic in group 1 than in group 2. Addition of ivabradine also improved exercise capacity, as shown by the results of the 6-minute walking and exercise tolerance tests, whereas in group 2 neither parameter was significantly affected. Chronotropic reserve significantly improved with ivabradine, but not with bisoprolol 10 mg. CONCLUSIONS: These results suggest that combining ivabradine with low dose bisoprolol in stable angina patients produces additional antianginal and anti-ischemic benefits and improves chronotropic reserve.

Effect of heart rate reduction by ivabradine on left ventricular remodeling in the echocardiographic substudy of BEAUTIFUL.

AIMS: Occlusive coronary artery disease (CAD) is associated with left ventricular (LV) remodeling, LV systolic dysfunction, and heart failure. The BEAUTIFUL Echo substudy aimed to evaluate the effects of heart rate reduction with ivabradine on LV size (primary end-point: change in LV end-systolic volume index [LVESVI]) and function and the cardiac biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: The substudy was carried out in 86 centers participating in the BEAUTIFUL study. 2D echocardiography was performed at baseline, and after 3 and 12 months in patients with stable CAD and LV systolic dysfunction receiving ivabradine or placebo at the same time-points. All data were read and analyzed centrally. Of 525 patients completing the study, 426 had adequate echocardiographic readings (n = 220 ivabradine; n = 206 placebo). Treatment with ivabradine was associated with a decrease in the primary end-point LVESVI (change from baseline to last value, -1.48 ± 13.00 mL/m(2)) versus an increase with placebo (1.85 ± 10.54 mL/m(2)) (P=0.018). There was an increase in LV ejection fraction with ivabradine (2.00 ± 7.02%) versus no change with placebo (0.01 ± 6.20%) (P=0.009). Reduction in LVESVI was related to the degree of heart rate reduction with ivabradine. There were no differences in any other echocardiographic parameters or NT-proBNP. Change in LVESVI was related to the log change in NT-proBNP in the ivabradine group only (r = 0.18, P = 0.006). CONCLUSIONS: Our observations suggest that ivabradine may reverse detrimental LV remodeling in patients with CAD and LV systolic dysfunction.

Effects of treatment strategy on endothelial function.

A large body of evidence indicates that endothelial dysfunction is a characteristic of patients with arterial hypertension. As functional abnormalities lead to impaired endothelium-dependent vasodilation, this early step of atherogenesis is potentially reversible. In addition to reducing blood pressure, the major families of anti-hypertensive drugs have a number of pleiotropic effects that could improve endothelial function. In particular, the renin-angiotensin system plays an important role in the pathogenesis of both arterial hypertension and endothelial dysfunction, and so drugs capable of limiting the dangerous effects of this hormonal axis, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors, could help prevent/delay/reverse the atherosclerotic process. New third-generation ß-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.

Differences in the effect of angiotensin-converting enzyme inhibitors on the rate of endothelial cell apoptosis: in vitro and in vivo studies.

AIM: An imbalance between endothelial apoptosis and regeneration is one of the initiating events in atherosclerosis. Angiotensin-converting enzyme (ACE) inhibition corrects the endothelial dysfunction observed in coronary artery disease, and this could be the consequence of a reduction in the rate of endothelial apoptosis. The aim of this study was to investigate the effect of different ACE inhibitors on endothelial apoptosis. METHODS: We examined the effect of five ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) on the rate of endothelial apoptosis, either in vitro in human umbilical vein endothelial cells (HUVECs), using a serum deprivation method to induce apoptosis, or in vivo in rats, inducing apoptosis via endotoxic shock with Escherichia coli lipopolysaccharides (LPS). RESULTS: We were unable to detect any significant effect of ACE inhibition on the rate of in vitro endothelial apoptosis at concentrations ranging from 5 x 10(-8) to 10(-6) M. In contrast, chronic in vivo administration of ACE inhibitors to rats at dosages that had similar hypotensive effects reduced the rate of LPS-induced apoptosis significantly for perindopril (P < 0.001) and nonsignificantly for the other ACE inhibitors. The order of potency of the ACE inhibitors tested was perindopril > ramipril >> quinapril = trandolapril = enalapril, with significant differences between perindopril and quinapril (P < 0.01), trandolapril (P < 0.001), and enalapril (P < 0.001). The difference between perindopril and ramipril did not reach significance. CONCLUSION: Our experiments suggest differences between ACE inhibitors in terms of inhibition of endothelial apoptosis in vivo.

Therapeutic modulation of the nitric oxide: all ace inhibitors are not equivalent.

The properties of the angiotensin-converting enzyme (ACE) inhibitors have largely been attributed to a class effect. However, this opinion is now increasingly challenged in view of the findings from recent clinical trials, which have demonstrated differential effects of ACE inhibitors, in particular with respect to secondary cardiovascular prevention outcomes. In this experimental study, Sprague-Dawley rats were treated with five different ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) at equihypotensive doses. All ACE inhibitors increased endothelial nitric oxide synthase (eNOS) protein expression and activity in the aorta (both P<0.0001 versus vehicle) and in cardiac myocytes (both P<0.05 versus vehicle). A highly significant effect was observed with perindopril when compared with vehicle in the modulation of eNOS protein expression and activity in aorta (22.52+/-1.09 versus 9.12+/-0.57 AU microg(-1) protein and 1.59+/-0.03 versus 0.77+/-0.02 pmol l(-1) citrulline min(-1)mg protein(-1), respectively) and in cardiac myocytes (17.64+/-0.94 versus 11.30+/-0.59 AU microg(-1) protein and 0.93+/-0.02 versus 0.62+/-0.03 pmol l(-1) citrulline min(-1)mg protein(-1), respectively). On the basis of the eNOS protein expression in the rat aorta, the other ACE inhibitors had similar, but lower effects. Indeed, the rank of potency - based both on eNOS protein expression and activity - was perindopril>trandolapril approximately quinapril approximately ramipril approximately enalapril (P<0.05 perindopril versus trandolapril and ramipril and P<0.01 perindopril versus enalapril, respectively). Levels of circulating nitrite/nitrate, the end-metabolites of nitric oxide, were also significantly affected by ACE inhibition, with the same order of potency. Our findings provide further evidence in favor of differential effects associated with ACE inhibitor therapy and suggest that the clinical benefits associated with these drugs may not solely reflect a class effect extending their benefit beyond blood pressure-lowering effect.

Tissue Doppler deformation imaging identifies myocardial stunning occurring during the Tako-Tsubo syndrome. Case report in a Caucasian patient.

Only a few reports are available on the Tako-Tsubo syndrome in Caucasian patients. The aetiology remains unknown but several pathophysiological mechanisms have been proposed so far. We believe that this condition is not so rare in Caucasian patients because many diagnoses may be missed or misinterpreted. Tissue Doppler evaluation identifies myocardial reversible dysfunction, putatively stunning, at the onset of cardiomyopathy. This can help in diagnosis, prognosis and in choosing the best time for coronary angiography.

Heart rate reduction by pharmacological If current inhibition.

Heart rate reduction is becoming a new strategy to treat coronary patients. The development of heart-rate-lowering drugs, with a more specific activity than Beta-blockers, coincides with the detection of the sinoatrial pacemaker I(f) current. The first selective I(f) inhibitor that has been approved for clinical use is ivabradine. Ivabradine has been shown to reduce heart rate, preserve myocardial contractility, increase diastolic filling and maintain both small and large coronary artery vasodilation, whatever the level of exercise, thus ensuring adequate endocardial blood perfusion during exercise. Furthermore ivabradine decreases myocardial oxygen consumption and improves myocardial energetics, protecting the myocardium during acute ischemic conditions and showing favorable antiremodelling properties in patients with chronic ischemic disease.

Specific properties and effect of perindopril in controlling the renin-angiotensin system.

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Its efficacy, safety, and tolerability are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) and Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), have shown that antihypertensive treatment with perindopril reduces and prevents cardiovascular disease in a large range of patients with vascular diseases, whether or not they are hypertensive. Thus, the outcomes of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the clinical evidence on efficacy and tolerability that has been gathered, perindopril fulfils the criteria of the latest guidelines for hypertension and cardiovascular disease management and should therefore be considered as a first-line antihypertensive agent, forming a consistent part of the comprehensive strategy against hypertension and related cardiovascular complications.

Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review.

Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.

Oxidative stress during myocardial ischaemia and heart failure.

Oxidative stress is a condition in which oxidant metabolites exert their toxic effect because of an increased production or an altered cellular mechanism of protection. The heart needs oxygen avidly and, although it has powerful defence mechanisms, it is susceptible to oxidative stress, which occurs, for instance, during post-ischaemic reperfusion. Ischaemia causes alterations in the defence mechanisms against oxygen free radicals, mainly a reduction in the activity of mitochondrial superoxide dismutase and a depauperation of tissue content of reduced glutathione. At the same time, production of oxygen free radicals increases in the mitochondria and leukocytes and toxic oxygen metabolite production is exacerbated by re-admission of oxygen during reperfusion. Oxidative stress, in turn, causes oxidation of thiol groups and lipid peroxidation leading first to reversible damage, and eventually to necrosis. In man, there is evidence of oxidative stress (determined by release of oxidised glutathione in the coronary sinus) during surgical reperfusion of the whole heart, or after thrombolysis, and it is related to transient left ventricular dysfunction or stunning. Data on oxidative stress in the failing heart are scant. It is not clear whether the defence mechanisms of the myocyte are altered or whether the production of oxygen free radicals is increased, or both. Recent data have shown a close link between oxidative stress and apoptosis. Relevant to heart failure is the finding that tumour necrosis factor, which is found increased in failing patients, induces a rapid rise in intracellular reactive oxygen intermediates and apoptosis. This series of events is not confined to the myocytes, but occurs also at the level of endothelium, where tumour necrosis factor causes expression of inducible nitric oxide synthase, production of the reactive radical nitric oxide, oxidative stress and apoptosis. It is therefore, possible that the immunological response to heart failure results in endothelial and myocyte dysfunction through oxidative stress mediated apoptosis. Clarification of these mechanisms may lead to novel therapeutic strategies.

Preliminary observations on the effects of acute infusion of growth hormone on coronary vasculature and on myocardial function and energetics of an isolated and blood-perfused heart.

Recent studies have shown that growth hormone (GH) deficiency may deteriorate post-ischemic myocardial reperfusion damage. Furthermore, GH has been reported to be a promising therapeutic option in the treatment of chronic myocardial dysfunction. However, the exact mechanisms of action of GH on the cardiovascular system, particularly in the acute setting, are still unclear. The aim of our study consisted of monitoring the acute effects of GH infusion on isolated blood-perfused rabbit heart according to dose-response pattern and during ischemic conditions to test its anti-ischemic property. Seven blood-donors perfused isolated hearts were used as experimental model. The mechanical and metabolic data of the isolated organs were continuously monitored. Under aerobic conditions, dose-response curves were initially tested after intracoronary infusion of GH at increasing dosages (1, 2, 3 mg/l). After a stabilization period, the effects of GH infusion (5 mg/kg) administered 30 minutes prior to acute global myocardial ischemia (30 minutes) were also investigated. At the doses tested, GH did not induce any changes either in the developed or in the diastolic pressures of the isolated organ. However, transient reduction of the coronary perfusion pressure was observed at the dosage of 3 mg/l. During the ischemia/reperfusion study, at the dosages used in this study, GH did not modify either the degree of stunning in the early reperfusion or the recovery of the developed pressure at the end of reperfusion. In addition, GH did not prevent either the increase of diastolic pressure during ischemia or the release of lactate and CPK during reperfusion. Tissue content of high-energy phosphates was also not changed by GH infusion. In our experimental model, acute GH infusion did not reduce the ischemic/reperfusion damage of the myocardium. However, GH transiently induced coronary vasodilation without modifying the myocardial contractility. Acute effects of GH appear, therefore, to predominantly relate to vascular dilation suggesting that the effects on myocardial contractility may require long-lasting intake being likely linked to enhancement of specific protein synthesis or gene expression of cardiac myocytes.

Revascularization of hibernating myocardium: rate of metabolic and functional recovery and occurrence of oxidative stress.

BACKGROUND: Left ventricular (LV) dysfunction due to coronary artery disease (CAD) may improve after revascularization in patients with hibernating myocardium (HM). METHODS AND RESULTS: We compared the rate of metabolic (arterial-great cardiac vein differences of lactate, glucose and pyruvate) and functional (intra-operative transesophageal and epicardial echocardiography) recovery and occurrence of oxidative stress (myocardial release of oxidized glutathione (GSSG)) early after surgical revascularization, in patients with CAD, LV dysfunction and HM (n=16) vs those with preserved LV function (n=15). By comparing the two groups, we observed that, after de-clamping, in patients with HM (a) the kinetic of lactate production was converted to extraction (P<0.01 at 1, 5, 10 and 20 min after revascularization), (b) myocardial extraction of pyruvate increased (P<0.01 during the first 5 min after revascularization), (c) GSSG release was less and of shorter duration (P<0.01 at all times), (d) segmental wall motion score improved from 2.4+/-0.3 to 1.7+/-0.5 (P<0.01) as did the thickening of the akinetic territories corresponding to the antero-distal septum and to the distal anterior wall regions (to 36+/-23%, and to 36+/-13%, respectively). There was a correlation between the rate of recovery of metabolic and functional indices. CONCLUSIONS: The contractile and metabolic recovery of HM is more rapid than that of non-HM, and it is not accompanied by oxidative stress.

Transperitoneal approach for pericardial drainage.

A variety of surgical approaches for pericardial drainage have been proposed. The choice of the best approach can be, therefore, oriented depending on the cause of the pericardial effusion. Recently a different approach, for neoplastic or post-traumatic pericardial effusion, has been proposed, in order to create a peritoneal-pericardial window avoiding the insertion of a tube. We report a case of late postoperative cardiac tamponade in a patient with a previous coronary surgery in which, due to extensive adhesion of the anterior wall a modified transperitoneal approach to the pericardium, was used.

[An older female patient with refractory anemia and hemochromatosis]. / Eine ältere Patientin mit refraktärer Anämie und Hämochromatose.

CASE HISTORY AND CLINICAL FINDINGS: A 69-year-old woman was admitted because of a normocytic anemia. One year before an acute B19 parvovirus infection had been diagnosed, but the anemia was attributed to intestinal bleeding caused by a dysplastic colonic polyp. However, anemia persisted despite polypectomy. There was an excessive elevation of serum ferritin. ADDITIONAL EXAMINATIONS: A bone marrow biopsy and aspirate led to the diagnosis of a myelodysplastic syndrome (pure sideroblastic anemia). Ultrasound demonstrated advanced fibrosis of the liver. Fibrosis in association with severe parenchymatous siderosis was also demonstrated by histology. Analysis of the hemochromatosis gene (B-HFE, nt 845, G/A) was negative. DIAGNOSIS, THERAPY AND CLINICAL COURSE: The patient had secondary hemochromatosis due to a myelodysplastic syndrome. An acute infection with parvovirus B19 had been noted at the time of the first admission, one year before MDS was diagnosed. At that time, hemochromatosis had already caused fibrosis of the liver. However, complete regression of organ siderosis was achieved by deferoxamine administration. The myelodysplastic syndrome itself did not show any progression even 7 years after the diagnosis was established. CONCLUSION: Our case demonstrates the uncommon association between sideroblastic anemia and secondary hemochromatosis. Acute parvovirus infection may induce severe anemia in myelodysplastic syndromes. In acute B19 parvovirus infections an underlying hematologic disease should be excluded.

Chromogranin A in heart failure; a novel neurohumoral factor and a predictor for mortality.

BACKGROUND: In chronic heart failure, several hormonal systems are activated with diagnostic and prognostic implications. We tested the hypotheses that serum Chromogranin-A (CgA) -- a 49 kDa acid protein present in the secretor granules of neuroendocrine cells -- is increased in chronic heart failure and that CgA levels are a predictive factor for mortality. METHOD AND RESULTS: In 160 patients with chronic heart failure, we measured serum CgA and other neuroendocrine hormones. The results showed that CgA is increased in chronic heart failure and the increase is related to the clinical severity of the syndrome: CgA levels in New York Heart Failure (NYHA) class II (median 146.9 ng x ml(-1), inter-quartiles 108.3-265.5) were significantly higher (P<0.05) than in class I (median 109.7 ng x ml(-1), inter-quartiles 96.7-137.6), and significantly lower (P<0.05) than in class III (median 279.0 ng x ml(-1), inter-quartiles 203.6-516.1). Class IV patients showed the highest serum levels of CgA (median 545.0 ng. ml(-1), inter-quartiles 231.8-1068.3), being statistically significantly different from class III patients (P<0.001). The association between survival and some recognized variables of prognostic significance, including CgA was also studied. The results showed that ejection fraction, noradrenaline, atrial natriuretic peptide, NYHA class and CgA were significant univariate prognosticators; however, in the multivariate analysis by the Cox proportional-hazard model, CgA and NYHA class were the only independent predictive factors for mortality (P<0.005, RR=1.22, 95% CI=1.06-1.41 and P=0.04, RR=1.58, 95% CI=1.02-2.46, respectively). CONCLUSIONS: CgA is a pro-hormone, precursor of several active fragments likely to exert biological effects in chronic heart failure. CgA serum levels are increased in patients with chronic heart failure and are a predictive factor for mortality.

Long-term results of coronary artery bypass grafting procedure in the presence of left ventricular dysfunction and hibernating myocardium.

OBJECTIVE: Long-term left ventricular (LV) performance and patient outcome after coronary artery bypass grafting (CABG) procedure in the presence of depressed LV function and hibernating myocardium (HM) have been poorly determined. Therefore, we prospectively evaluated patients undergoing CABG with severe LV dysfunction and HM to elucidate postoperative prognosis. METHODS: We enrolled 120 consecutive patients undergoing CABG with severe LV dysfunction and HM as assessed by dobutamine echocardiography and by rest-redistribution radionuclide (Thallium-201) study. Mean patient age was 60+/-9 years (range 31-77 years). Mean preoperative LVEF was 28%+/-9 (range 10-40%). All patients underwent echocardiographic study to assess LV recovery of function intraoperatively, prior to hospital discharge, at 3 months, at 1 year, and yearly during the follow-up. Univariate and multivariate analysis were performed to to evaluate predictors of postoperative survival. RESULTS: There were 2 hospital (1.6%) and 15 late (12.5%) deaths, mainly for heart failure, leading to an actuarial survival of 80+/-6% and 60+/-9% at 5 and 8 years, respectively. LVEF significantly improved perioperatively (from 28+/-9% to 40+/-2%, P<0.01). Increase in LVEF, however, was gradually offset over the time (EF of 33+/-9%, 32+/-8%, and 30+/-9% at 3 months, and 12 months, and 8 years after surgery, respectively). Furthermore, patients who experienced limited LV functional recovery perioperatively had a more remarkable decline of LVEF thereafter, and suffered from recurrence of heart failure symptoms (freedom from heart failure 82+/-5% and 60+/-8% at 4 and 8 years respectively). Advanced preoperative NYHA Class, and age were independent risks factors for reduced postoperative survival. Preoperative angina and use of arterial conduits apparently did not influence patient morbidity and mortality at long term. CONCLUSION: CABG procedure in the presence of HM enhances LV recovery of function and has a favourable prognosis. Functional benefit of the left ventricle, however, appears to be time-limited, despite remarkable improvement in patient functional capacity. Advanced preoperative heart failure, minimal perioperative improvement of LVEF, and age account for a poor long-term prognosis.

Beta-adrenergic receptors and intracellular signalling pathway in stunned and non-ischemic regions of pig myocardium.

The beta-adrenergic pathway may have a role in the pathophysiology of ischemic syndromes characterised by reversible left ventricular dysfunction, such as myocardial stunning and other clinical conditions of unstable angina or coronary spasms, or chronic reversible left ventricular dysfunction, which might be a consequence of repeated events of short-term ischemia ("repetitive stunning"). A partial-to-total occlusion of the left anterior descending coronary artery in pigs was used to induce short periods of ischemia (total ischemic time 12 +/- 2 min). Hypokinesis and dyskinesis of the myocardium were considered signs of myocardial dysfunction. We found a maintained function of the beta-adrenergic signalling system. Density and affinity of beta-adrenergic receptors were not different in stunned and non-ischemic regions, nor were cyclic AMP and cyclic GMP intracellular contents and ratio, nor well as the ratio of stimulatory/inhibitory G protein a subunits. Our findings are in agreement with a maintained beta-adrenergic signalling system in the pathophysiology of chronic reversible left ventricular dysfunction.

Role of bradykinin and eNOS in the anti-ischaemic effect of trandolapril.

1. Angiotensin converting enzyme (ACE) inhibitors are under study in ischaemic heart diseases, their mechanism of action being still unknown. 2. The anti-ischaemic effect of trandolapril and the possible involvement of a bradykinin-modulation on endothelial constitutive nitric oxide synthase (eNOS) in exerting this effect, were investigated. 3. Three doses of trandolapril, chronically administered in vivo, were studied in isolated perfused rat hearts subjected to global ischaemia followed by reperfusion. 4. Trandolapril has an anti-ischaemic effect. The dose of 0.3 mg kg(-1) exerted the best effect reducing diastolic pressure increase during ischaemia (from 33.0+/-4.5 to 14.0+/-5.2 mmHg; P<0.05 vs control) and reperfusion (from 86.1+/-9.4 to 22.2+/-4.1 mmHg; P<0.01 vs control), improving functional recovery, counteracting creatine phosphokinase release and ameliorating energy metabolism after reperfusion. 5. Trandolapril down-regulated the baseline developed pressure. 6. Trandolapril increased myocardial bradykinin content (from 31.8+/-6.1 to 54.8+/-7.5 fmol/gww; P<0.05, at baseline) and eNOS expression and activity in aortic endothelium (both P<0.01 vs control) and in cardiac myocytes (from 11.3+/-1.5 to 17.0+/-2.0 mUOD microg protein(-1) and from 0.62+/-0.05 to 0.80+/-0.06 pmol mg prot(-1) min(-1); both P<0.05 vs control). 7. HOE 140 (a bradykinin B(2) receptor antagonist) and NOS inhibitors counteracted the above-reported effects. 8. There was a negative correlation between myocyte's eNOS up-regulation and myocardial contraction down-regulation. 9. Our findings suggest that the down-regulation exerted by trandolapril on baseline cardiac contractility, through a bradykinin-mediated increase in NO production, plays a crucial role in the anti-ischaemic effect of trandolapril by reducing energy breakdown during ischaemia.