Giorgio Caretta

Effects of Spironolactone on Long-term Mortality and Morbidity in Patients With Heart Failure and Mild or No Symptoms

Background:The purpose of this study is to evaluate long-term effects of spironolactone, an affordable and widely used aldosterone receptor blocker, in patients with heart failure (HF) and mild or no symptoms. Methods:The study is a single-blind, placebo-controlled, blinded endpoint, randomized study. Patients with New York Heart Association (NYHA) classes I to II HF and left ventricular ejection fraction < 40% were randomized to spironolactone or placebo in addition to optimal therapy. The primary endpoint was the composite of death from any cause or cardiovascular hospitalization. Results:A total of 130 patients were randomized to spironolactone (n = 65) or placebo (n = 65). Patients on spironolactone had a better event-free survival for cardiovascular death or cardiovascular hospitalizations and for cardiovascular hospitalizations alone. At multivariable analysis, only spironolactone therapy, left ventricular ejection fraction and serum creatinine levels had an independent prognostic value for the combined endpoint, whereas only spironolactone therapy and serum creatinine levels had an independent prognostic value for cardiovascular hospitalizations alone. Conclusions:Administration of spironolactone reduced the composite of death and cardiovascular hospitalization in patients with NYHA classes I to II HF. These results suggest that spironolactone could be beneficial when administered on top of optimal therapy among patients with HF and mild or no symptoms.

The effect of aldosterone-antagonist therapy on aortic elastic properties in patients with nonischemic dilated cardiomyopathy

Background Many studies proved the prognostic importance of aortic stiffness as an independent predictor of cardiovascular morbidity and all-cause mortality. The decrease of arterial compliance has a high prevalence in patients with heart failure and affects both hemodynamics and prognosis. Aortic stiffness is partially caused by excessive activation of the renin–angiotensin–aldosterone system. Spironolactone, a mineralcorticoid receptor antagonist (MRA), has been shown to decrease aortic stiffness and fibrosis in experimental models. However, there are few studies that describe the effects of MRA on aortic stiffness in patients with nonischemic dilated cardiomyopathy. Aims To evaluate the effect of spironolactone on aortic stiffness in patients with nonischemic dilated cardiomyopathy. Materials and methods We randomized (1 : 1) 102 patients with nonischemic dilated cardiomyopathy with New York Heart Association class I–II to receive spironolactone 25 mg/day (up to 100 mg/day) or placebo, in addition to recommended therapy. Aortic stiffness index, aortic strain, aortic distensibility and aortic dimensions were assessed at baseline and after 6 months. All measures were obtained with echocardiography M-mode at 3 cm above the aortic valve on parasternal long axis view and simultaneous brachial arterial pressure with sphygmomanometer. Results Ascending aorta diameters, aortic stiffness index, aortic distensibility and aortic strain were similar at randomization in the two groups. After 6 months of therapy in the treated group, we found a reduction of aortic stiffness index (7.2 ± 3.5 versus 9.6 ± 4.8 mmHg−1; P = 0.03) and an increase of aortic distensibility (3.77 ± 1.0 versus 2.92 ± 0.55 mmHg−1; P = 0.01) and systolic aortic strain (10.0 ± 5.0 versus 8.0% ± 2.1%; P = 0.01). There were no difference in systolic arterial pressure, diastolic arterial pressure and differential pressure in the two groups. Conclusion Therapy with spironolactone is effective in reducing aortic stiffness in patients with nonischemic dilated cardiomyopathy. This effect could improve hemodynamics supporting the use of MRAs in patients with low New York Heart Association class (I–II).

Mineralocorticoid receptor antagonist in heart failure: Past, present and future perspectives

Aldosterone is involved in various deleterious effects on the cardiovascular system, including sodium and fluid retention, myocardial fibrosis, vascular stiffening, endothelial dysfunction, catecholamine release and stimulation of cardiac arrhythmias. Therefore, aldosterone receptor blockade may have several potential benefits in patients with cardiovascular disease. Mineralocorticoid receptor antagonists (MRAs) have been shown to prevent many of the maladaptive effects of aldosterone, in particular among patients with heart failure (HF). Randomized controlled trials have demonstrated efficacy of MRA in heart failure with reduced ejection fraction, both in patients with NYHA functional classes III and IV and in asymptomatic and mildly symptomatic patients (NYHA classes I and II). Recent data in patients with heart failure with preserved ejection fraction are encouraging. MRA could also have anti-arrhythmic effects on atrial and ventricular arrhythmias and may be helpful in patient ischemic heart disease through prevention of myocardial fibrosis and vascular damage. This article aims to discuss the pathophysiological effects of aldosterone in patients with cardiovascular disease and to review the current data that support the use of MRA in heart failure.

Diagnosis of Cor Triatriatum Sinister in Patient with Pulmonary Edema and Severe Pulmonary Arterial Hypertension: Assessment by Three‐Dimensional Transesophageal Echocardiography

(Echocardiography 2011;28:E198‐E201)

Multiorgan paradoxical embolism consequent to acute pulmonary thromboembolism with patent foramen ovale: a case report

Paradoxical embolism is defined as a systemic arterial embolism requiring the passage of a venous thrombus into the arterial circulatory system through a right-to-left shunt. It is a relatively rare phenomenon, representing about 2% of all cases of arterial embolism. We report a case of a 79-years-old woman admitted to hospital because of dyspnea and lower left limb pain. CT scan revealed multiple thrombi to kidney, lower limb and superior mesenteric artery during acute pulmonary embolism. Echocardiogram documented a patent foramen ovale with a right-to-left shunt. The patient was treated with thrombolytic therapy and heparin with progressive improvement of symptoms and resolution of pulmonary embolism and peripheral thrombosis. Patent foramen ovale closure was not performed because a life-long anticoagulation therapy was necessary, a tunnel-type patent foramen ovale may increases difficulty in realizing device implantation and there are no clear evidence-based guidelines to date addressing treatment in presence of a patent foramen ovale.

Galectin-3 predicts left ventricular remodelling after anterior-wall myocardial infarction treated by primary percutaneous coronary intervention

Objectives Despite modern reperfusion therapies, left ventricular remodelling (LVR) occurs frequently after an ST-elevated myocardial infarction (STEMI) and represents a strong predictor of mortality and heart failure. Galectin-3 (Gal-3), a novel biomarker involved in inflammation, tissue repair and fibrogenesis, might be a valuable predictor of LVR. Methods We enrolled consecutively admitted patients with a first anterior STEMI and left anterior descending artery occlusion treated by primary percutaneous coronary intervention (pPCI). Gal-3, N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography and cardiovascular events were evaluated 48 hours after admission, at 1 and 6 months. LVR was defined as a ≥15% increase in LV end-systolic volume. Results We recruited 103 patients (28% women, aged 64.6±12 years, LV ejection fraction 47±11%). Median baseline Gal-3 and NT-proBNP levels were 13.2 ng/mL (10.8–17.1 ng/mL) and 2132 pg/mL (1019–4860 pg/mL) respectively. During 6 months of follow-up, 4 patients dropped out, 7 died and 26 (28.3%) of the 92 survivors developed LVR (LVR+). LVR+ patients had higher Gal-3 levels at baseline, 1 and 6 months than LVR− (p<0.0001). By univariable logistic regression, age, female gender, higher baseline Gal-3 and NT-proBNP, smaller LV end-diastolic volume (LVEDV) were associated to an increased risk of LVR. By multivariable analysis, only LVEDV (OR 0.96, 95% CI 0.93 to 0.99/1 mL change) and Gal-3 levels (OR 1.22, 95% CI 1.06 to 1.42/1 ng/mL change) independently predicted LVR (C-statistics 0.84, 95% CI 0.75 to 0.93). Conclusion Gal-3 serum levels measured during hospitalisation could be clinically useful in predicting LVR among patients admitted with anterior STEMI treated by pPCI.

Biological drugs: classic adverse effects and new clinical evidences.

The last 20 years was characterized by great improvements in the efficacy and tolerability of anticancer therapies. Most of these changes are related to the introduction of targeted drugs, which presents a better activity on the biology of cancer and less toxicity. Nevertheless, the initial enthusiasm was cooled by the emerging evidences of cardiac side effects. The aim of this review is to describe the actual knowledge about the possible cardiotoxicity of targeted drugs. The most important need is the detection of early cardiotoxicity and the evidence of subtle myocardial dysfunction that allows to begin a protective therapy. In our review we analyzed the non invasive imaging techniques to early predict myocardial dysfunction. Echocardiography seems to be the ideal method for her availability, safety and clinical usefulness, in particular the new echocardiographic techniques like speckle tracking.

Differences between nitrates: role of isosorbide 2-mononitrate.

Introduction Nitrates are used in the treatment of coronary heart disease and heart failure. The major drawback of their therapeutic use is the rapid development of tolerance. Aim of the study To investigate the effect of different nitrates on isolated rabbit hearts and aortic strips and the mechanism responsible for nitrate tolerance, using nitroglycerine (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-moninitrate (2MN). Materials and methods Preparations were stimulated by different spasmogenic agents: KCl, angiotensin II and noradrenaline; nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. In another series of experiments, preparations were preincubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance. Results Nitrates produced the following maximum inhibitions on noradrenaline-induced contraction: NTG 90% (10−6 mol/l), ISDN 60% (10−4 mol/l), 5MN 55% (10−4 mol/l) and 2MN 80% (10−4 mol/l). After incubation a loss of vasodilator effect of nearly 50–60% was observed for all the nitrates considered except 2MN, whose loss of effect was significantly lower (36%). The cyclic guanosine monophosphate (cGMP) levels measured in the preparations were lower in the presence of 2MN than the other compounds. Conclusion These data suggest that 2MN is able to induce a lower cGMP increase and less tolerance induction; since these observations seem to be correlated, the vasodilator effect of 2MN probably also involves mechanisms other than stimulation of guanylate cyclase.

Nitric oxide and cardiovascular risk factors

The endothelium is a dynamic organ with many properties that takes part in the regulation of the principal mechanisms of vascular physiology. Its principal functions include the control of blood-tissue exchange and permeability, the vascular tonus, and the modulation of inflammatory or coagulatory mechanisms. Many vasoactive molecules, produced by the endothelium, are involved in the control of these functions. The most important is nitric oxide (NO), a gaseous molecule electrically neutral with an odd number of electrons that gives the molecule chemically reactive radical properties. Already known in the twentieth century, NO, sometimes considered as a dangerous molecule, recently valued as an important endogenous vasodilator factor. Recently, it was discovered that it is involved in several physiological mechanisms of endothelial protection (Tab. I). In 1992, Science elected it as “molecule of the year”; 6 yrs later three American researchers (Louis Ignarro, Robert Furchgott and Fried Murad) obtained a Nobel Prize for Medicine and Physiology “for their discoveries about NO as signal in the cardiovascular system”. TABLE I EFFECTS OF ENDOTHELIAL NITRIC OXIDE ON THE CARDIOVASCULAR SYSTEM NO is synthesized by endothelial cells from L-argynine and oxygen (Fig. 1). Blood flow and laminar shear stress induce the activation through phosphorilation of NO synthase (NOS), that catalyzes the conversion reaction from L-arginine to citrullin and NO, through two cofactors: calmodulin and pteridin-thetraidrobiopterine (BH4) (Fig. 2). There are at least three isoforms of constitutive NOS: the endothelial form (eNOS), the neuronal form (nNOS) and the inducible form (iNOS); eNOS, the calcium-dependent form of the enzyme, is in many cellular types and it is responsible for NO production in healthy blood vessels. nNOS is a special type of eNOS, expressed in the central nervous system. iNOS, a form induced by immunological stimuli (1), is expressed in the myocytes, in the macrophages and in the endothelial cells. NOS are formed by two distinct catalytic subunits, as terminal C-reductase and terminal N-oxygenase domain. In the presence of sufficient amounts of BH4, these domains work together and synthesize NO. Otherwise in case of increased oxidative stress they cause the production of peroxynitrites. The NO produced induces guanilate cyclase to the synthesis of cGMP from cGTP. The last molecule causes cellular hyperpolarization due to the activation of the potassium canals. These reactions cause the inhibition of the entrance of calcium and, in this way, the vasodilatation in the cardiovascular system (Tab. I). Fig. 1 Fig. 2 1 ENDOTHELIAL DYSFUNCTION AND NO Normal vascular tonus depends on the equilibrium between the vasoconstrictor and vasodilator molecules released from the endothelium. In healthy endothelium, the balance is shifted towards vasodilatation due to NO (Tab. II). Endothelial dysfunction is synonymous with the insufficiency of endothelium dependent vasodilatation and results in the failure of vasoactive, anticoagulant and anti-inflammatory effects of healthy endothelium. The most important mechanism for endothelial dysfunction is the reduction in NO availability. The substrate insufficiency such as the reduction in L-arginine in endothelial cells or any defect in the transport of L-arginine into the cell, the existence of NOS inhibitors such as asymmetrical dimethylarginine (ADMA) and G-monomethyl-L-arginine (L-NM-MA), increase in the reactive oxygen molecules, reduction in the diffusion of NO due to intimal thickening, the mutations in the eNOS gene expression, increase in the catabolism of NO, cofactor insufficiency and increase in the vasoconstrictor molecules released from the endothelium are the other mechanisms that must be considered in endothelial dysfunction. Endothelial dysfunction coexists with many disease states in the cardiovascular system and is known as the first stage of atherosclerosis, which is probably the most important disease of the modern age. In the cardiovascular system, other clinical conditions, which are related with endothelial dysfunction are hypertension, are hyperglycemia-insulin resistance, dyslipidemia, menopause, heart failure, variant angina, cardiac syndrome X and hyperhomocysteinemia. TABLE II EFFECTS OF ENDOTHELIAL NITRIC OXIDE ON THE CARDIOVASCULAR SYSTEM NO oppose the atherogenical stimuli preventing vascular structural modifications; it can inhibit the adhesion of platelets and monocytes, the migration of the smooth muscular cells and the endothelial apoptosys. It was demonstrated that NO, for example, inhibits, through S-nytrosation, key-enzymes of the apoptotic chart (Caspases 6, 7, 8) (2). I. Aging Data obtained in humans and in animal experiments indicate that aging alters the endothelial dependent vasodilatation in the big arteries and in the resistance vessels (3). Moreover, aging is associated with a progressive remodeling of the vascular wall, which includes the thickening of the tunica intima and of the tunica media and the increase in its rigidity (4). With advancing old age, smooth muscular cells migrate progressively from the tunica media and accumulate in the intima (5). This fact is associated with a progressive decline in endothelial functionality, which causes a reduced response to the vasodilating factors, consequent to the alteration of the expression and/or the activity of NOS and with an increased formation of free radicals. Aging is associated with an alteration in the equilibrium between vasoconstrictor and vasodilating factors released by the endothelium, or rather with a progressive reduction in NO and endothelial derived hyperpolarizing factor (EDHF) associated with an increase in oxygen free radicals and prostanoids derived from cycle-oxygenase. In addition, it was recently demonstrated that, with aging, there is an inferior proliferation and migration of the endothelial cells from the sites near the atherosclerotic lesion, preventing the preservation of intimal integrity, which is normally favored by a healthy endothelium (6).

Clinical characteristics and outcomes of Yemeni patients with acute heart failure aged 50 years or younger: Data from Gulf Acute Heart Failure Registry (Gulf CARE)

AIMS There is a shortage of data about acute heart failure (AHF) in the young, including its underlying causes, clinical presentation and outcomes. We aim to describe clinical characteristics, causes and outcomes of AHF in Yemeni patients aged 50years or younger. METHODS AND RESULTS we evaluated Yemeni patients with AHF enrolled in Gulf CARE registry. Patients were divided into two groups: young patients (≤50years) and older patients (>50years). A total of 1536 patients with AHF were enrolled, of whom 635 (41.3%) were 50years old or younger. The mean age for this group was 38.8 (±9.5) years; and 399 (62.8%) were males. Younger patients had a higher prevalence of non-ischemic cardiomyopathy (41% vs 11.1%, p<0.001), primary valvular disease (27.9% vs 3.2%, p<0.001), viral myocarditis (0.8% vs 0, p<0.001). Ischemic heart disease (61.6% vs 25.5%, p<0.001) and hypertensive heart disease (18.3% vs 6.3%, p<0.001) were more frequent in the elderly group. Cardiogenic shock was more frequent among younger patients (13.7% vs 7.0, p<0.001). In-hospital mortality was higher in patient aged ≤50years (12% vs 7.6%, p=0.002) while no difference in all-cause mortality was present at 3months (17.8 vs 14.5, p=0.089) and after 1year (21.9% vs 20.6%, p=0.56). CONCLUSION This analysis of Gulf CARE registry represents the largest report of patients admitted with AHF in Yemen. There were differences among cause of HF and precipitating factors of AHF among younger and elderly patients. Younger patients had higher in-hospital mortality and more severe clinical condition at admission.