Search

Sacubritil ∗ valsartan (Entresto, Novartis, still commonly referred to as LCZ696) is a combination drug described as a new class of dual-acting angiotensin receptor–neprilysin inhibitor (ARNi). This combination drug has been successfully studied in patients with heart failure with both preserved (HFpEF) and reduced ejection fraction (HFrEF). In this review, the evidences in patients with HFpEF and HFrEF are summarized, including the results of more recent studies. [ABSTRACT FROM AUTHOR]

In heart failure, in addition to the renin–angiotensin–aldosterone system and sympathetic nervous system, the natriuretic peptide (NP) system plays a fundamental role among compensating mechanisms. The NPs undergo rapid enzymatic degradation that limits their vasorelaxant, natriuretic, and diuretic actions. Degradation of NPs is partially due to the action of neprilysin, which is a membrane-bound endopeptidase found in many tissues. This article summarizes recent findings on a new natriuretic peptide-enhancing drug and their implication for future pharmacological treatment of patients suffering from heart failure with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Abstract: Background: Atrial fibrillation (AF) is associated with a high risk of stroke and other thrombo-embolic events and their prevention relies on antithrombotic therapy, at present mainly with vitamin K antagonists (VKA). The aim of this study was to provide an overall picture on the extent to which current recommendations on oral anticoagulation (OAC) therapy with VKA in AF correspond to actually prescribed OAC in an unselected, real world, population of consecutive patients with AF in Italy. Secondary objective was to assess the rate of “optimal” anticoagulation. Methods: Sixty-three cardiology units located in different geographic areas of Italy enrolled a total of 2046 outpatients with nonvalvular AF (54% males and 46% females, age 73.3±10.2years). Results: OAC with VKAs was prescribed in 1394 (68%) of patients and was progressively more frequent on going from paroxysmal (46%) to persistent (71%) and permanent AF (78%)(P<0.001). A high prescription rate (88%) occurred in patients with CHA2DS2-VASc >2. In patients with CHA2DS2-VASc=0 and HAS-BLED<3, still 59% were on OAC, whereas in 33% of patients with CHA2DS2-VASc ≥2 and HAS-BLED<3, OAC therapy was not prescribed. In patients with CHA2DS2-VASc ≥2 and HAS-BLED>3, the preference was towards OAC prescription. 66% of patients were at target for INR. Conclusions: The ISPAF study shows that in an Italian population of real world patients with AF adherence to current guidelines on OAC therapy based on stroke-risk scoring system is rather high, although rate of prescription should be increased. However, contrary to recommendations, in a high proportion of low-risk patients OAC therapy is still prescribed, and this might expose patients to unjustified risks. [Copyright &y& Elsevier]

Abstract: Aim: Patients with heart failure (HF) have reduced exercise capacity. The beneficial effect of beta-blocker on prognosis is not matched by an impact on exercise capacity and quality of life. We performed a randomised open blinded endpoint study to assess the effect of heart rate reduction with carvedilol, ivabradine, and their combination on exercise capacity in HF patients receiving maximal dose of ACE inhibitor. Methods and results: After a run-in phase patients were randomly allocated to 3 groups: carvedilol up to 25mg bid (n=38); ivabradine up to 7.5mg bid (n=41); and carvedilol/ivabradine up to 12.5/7.5mg bid (n=42). The maximal dose of study treatment was more frequently tolerated in patients receiving ivabradine (36/41) than in those receiving carvedilol (18/38) or combination therapy (32/42) (P <0.01 ivabradine versus carvedilol). Heart rate was reduced in all three groups, but to a greater extent by the combination. The distance walked on the 6-min walking test and the exercise time on MVO2 test significantly improved in the ivabradine and combination groups (both P <0.01 versus baseline), as did peak VO2 and VAT (P <0.01 for ivabradine and P <0.03 for combination versus carvedilol, respectively). No changes in these parameters were found with carvedilol. The patients receiving ivabradine or the combination had better quality of life (P <0.01 versus baseline for ivabradine and P< 0.02 for combination), versus no change with carvedilol. Conclusion: Ivabradine alone or in combination with carvedilol is more effective than carvedilol alone at improving exercise tolerance and quality of life in HF patients. [Copyright &y& Elsevier]

Abstract: Purpose: To assess if Hydrotherapy (HT) added to endurance training (ET) is more effective than ET alone in order to improve exercise tolerance of elderly male patients with chronic heart failure (CHF). Methods: Twenty-one male CHF patients, age 68+/−7 (mean+/−DS) years; ejection fraction 32+/−9. NYHA II–III were enrolled. Eleven pts were randomized to combined training (CT) group performing HT+ET and 10 patients to ET group (ET only). At baseline and after 24weeks all patients underwent: 6-minute walking test (6MWT), assessment of quadriceps maximal voluntary contraction (MVC) and peak torque (PT), blood pressure and heart rate (HR), echocardiography and non-invasive hemodynamic evaluation. HT was performed 3 times/week in upright position at up to the xyphoid process at a temperature of 31°C. ET was performed 3 times/week. Results: Exercise was well tolerated. No patients had adverse events. Distance at 6MWT improved in both groups (CT group: 150+/−32m; ET group:105+/−28m) with significant intergroup differences (p 0.001). On land diastolic BP and HR significantly decreased in the CT group while remained unchanged in the ET group (−11mmHg+/−2, p 0.04; e — 12bpm, p 0.03; respectively) CO and SV had a relative despite no significant increase in CT group TPR on land significantly decreased in CT group (−23+/−3mmHg/l/m; p 0.01) while remained unchanged in ET group. Patients of CT group had no significant higher increase of both MVC and PT than ET group. Conclusions: CT training, significantly improves exercise tolerance and hemodynamic profile of patients with CHF. [Copyright &y& Elsevier]

Objectives: The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure (CHF). Background: Patients with CHF show decreased exercise capacity and insulin sensitivity. Testosterone supplementation improves these variables in men with CHF. No study has evaluated the effects of testosterone supplementation on female patients with CHF. Methods: Thirty-six elderly female patients with stable CHF, (ejection fraction 32.9 ± 6) were randomly assigned (2:1 ratio) to receive testosterone transdermal patch (T group, n = 24) or placebo (P group, n = 12), both on top of optimal medical therapy. At baseline and after 6 months, patients underwent 6-min walking test (6MWT), cardiopulmonary exercise test, echocardiogram, quadriceps maximal isometric voluntary contraction, dynamic quadriceps isokinetic strength (peak torque), and insulin resistance assessment by homeostasis model. Results: Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group, whereas they were unchanged in the P group (p < 0.05 for all comparisons). The homeostasis model was significantly reduced in the T group in comparison with the P group (−16.5% vs. +5%, respectively; p < 0.05). Maximal voluntary contraction and peak torque increased significantly in the T group but did not change in the P group. Increase in distance walked at 6MWT was related to the increase in free testosterone levels (r = 0.593, p = 0.01). No significant changes in echocardiographic parameters were observed in either group. No side effects requiring discontinuation of T were detected. Conclusions: Testosterone supplementation improves functional capacity, insulin resistance, and muscle strength in women with advanced CHF. Testosterone seems to be an effective and safe therapy for elderly women with CHF. [ABSTRACT FROM AUTHOR]

Recent evidence would indicate that high serum uric acid (SUA) levels can be a significant and independent risk factor for hypertension and cardiovascular diseases, such as ischemic heart disease and heart failure. In the last few years an independent risk relationship between hyperuricemia, cardiovascular disease and mortality has also been reported. Hyperuricemia has been shown as an independent risk factor for acute myocardial infarction and an independent and conjoint association of either gout and SUA with total and cardiovascular mortality has been reported, with mortality impact in gout patients increasing with rising SUA concentrations, even for SUA levels in the normal to high range. These findings prompted a growing research interest on the possible benefits of uric acid lowering drugs in cardiovascular diseases. Indeed, clinical studies have reported on the beneficial effects of uric acid lowering drugs, in particular of xanthine oxidase inhibitors, in hypertension, ischemic heart disease and heart failure. Two main mechanisms have been claimed to explain the dangerous effects of hyperuricemia and, as a consequence, the benefits of uric acid lowering therapy: endothelial dysfunction and systemic inflammation. This brief review aims to summarize current evidence from human studies on the role of acid uric lowering therapy in cardiovascular diseases for practical and clinical purposes. The possible mechanisms underlying the benefits of acid uric lowering therapy are also addressed. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity, ventilatory efficiency, muscle strength, insulin resistance, and baroreflex sensitivity (BRS) in elderly patients with chronic heart failure (CHF). Background: CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure. Methods: Seventy elderly patients with stable CHF—median age 70 years, ejection fraction 31.8 ± 7%—were randomly assigned to receive testosterone (n = 35, intramuscular injection every 6 weeks) or placebo (n = 35), both on top of optimal medical therapy. At baseline and at the end of the study, all patients underwent echocardiogram, cardiopulmonary exercise test, 6-min walk test (6MWT), quadriceps maximal voluntary contraction (MVC), and isokinetic strength (peak torque) and BRS assessment (sequences technique). Results: Baseline peak oxygen consumption (VO2) and quadriceps isometric strength showed a direct relation with serum testosterone concentration. Peak VO2 significantly improved in testosterone but was unchanged in placebo. Insulin sensitivity was significantly improved in testosterone. The MVC and peak torque significantly increased in testosterone but not in placebo. The BRS significantly improved in testosterone but not in placebo. Increase in testosterone levels was significantly related to improvement in peak VO2 and MVC. There were no significant changes in left ventricular function either in testosterone or placebo. Conclusions: These results suggest that long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and BRS in men with moderately severe CHF. Testosterone benefits seem to be mediated by metabolic and peripheral effects. [Copyright &y& Elsevier]

Abstract: Aims: To evaluate whether metabolic syndrome MS has a gender dependent effect on the recovery of functional capacity in patients (pts) with coronary heart disease (CHD) undergoing a cardiac rehabilitation program. Methods and Results: We studied 286 CHD patients, age 66.2±10.6 (median±SD); M/F 187/99. Patients were divided into two groups according to the presence (MS, 48%) or not (nMS, 52%) of MS. MS was present in 48% of patients. Functional capacity was assessed by the distance walked at six minute walking test (6MWT), and by a maximal exercise test. Compared to patients without MS, those with MS walked a lower distance at 6MWT (438±110 vs 408±123 m; p <0.05), had a lower maximal exercise capacity (7.6±1.8 vs 9.3±1.2 MET; p <0.05) and a lower heart rate recovery (HRR) (16±9 vs 22±8; p <0.05). Male patients with or without MS had a similar degree of functional recovery (51%) while women with MS had a significantly lower recovery than nMS (20% vs 40%). In a multivariate logistic regression model, including body mass index, age, gender hypertension, ejection fraction and diabetes, MS predicted a reduced performance at 6MWT in the overall population (OR 1.4, 95% CI 1.7 to 2.4) and in women (OR 1.31; 95% CI 1.20–1.62), while it was not predictive in males. Conclusions: CAD patients with MS have lower functional recovery and HRR than nMS. However MS is an independent predictor of lower exercise capacity only in female gender. [Copyright &y& Elsevier]

Eplerenone is a selective mineralocorticoid receptor antagonist that has been recently included in the treatment of patients with chronic heart failure (CHF) and reduced systolic function. This brief review aims to summarize current evidence on the role of eplerenone in the therapy of patients with CHF. In the EPHESUS trial, 6632 post-myocardial infarction patients with ejection fraction (EF) < 40% and clinical HF signs were randomized to eplerenone or placebo added to standard therapy 3 to 14 days after the event. After a 16 month follow-up period, eplerenone given early (< 7 days) reduced the primary endpoints of all-cause mortality by 15% and cardiovascular death or cardiovascular hospitalization by 13%. In the subsequent EMPHASIS-HF trial, the efficacy and tolerability of eplerenone were tested in patients with mild CHF (NYHA functional class II) and EF ≤ 30% or between 30 and 35% with QRS duration > 130 ms. After a median follow-up of 21 months eplerenone significantly reduced (by 37%) the primary composite outcome of risk of death from CV causes and first hospitalization for HF. Based on the above findings, the addition of eplerenone to standard therapy, at doses to be titrated from 25 to 50 mg per day, is currently recommended in CHF patients with functional classes II to IV closely resembling those enrolled in these large clinical trials, with adequate monitoring for side effects (mainly hyperkalemia and renal failure). Whether the same beneficial effects of eplerenone extend to CHF patients with mild symptoms and no additional risk factors are unknown. [ABSTRACT FROM AUTHOR]

Abstract: The modulation of cardiac metabolism with Trimetazidine is very important for the control of myocardial ischemia and for the preservation of left ventricular function. The optimization of cardiac metabolism should also include improvement of cardiac insulin resistance with insulin sensitizer agents and the optimization of Kreb’s Cycle with essential amino acids. Regarding new drugs that may act inhibiting free fatty acid oxidation we have to underline that to date it is not clear whether Ranolazine has an effect on cardiac metabolism. We agree instead that metabolic agents like Dichloroacetate, Perhexiline and Etomoxir have an antiischemic effect, while their administration requires adjustment of dose and careful monitoring of side effects. [Copyright &y& Elsevier]

During the COVID-19 pandemic, reductions in heart failure (HF) hospitalizations have been widely reported, and there is an urgent need to understand how HF care has been reorganized in countries with different infection levels, vaccination rates and healthcare services. The OPTIMIZE Heart Failure Care program has a global network of investigators in 42 countries, with first-hand experience of the impact of the pandemic on HF management in different care settings. The national coordinators were surveyed to assess: 1) the challenges of the COVID-19 pandemic for continuity of HF care, from both a hospital and patient perspective; 2) the organizational changes enacted to ensure continued HF care; and 3) lessons learned for the future of HF care. Contributions were obtained from 37 national coordinators in 29 countries. We summarize their input, highlighting the issues raised and using the example of three very different settings (Italy, Brazil, and Taiwan) to illustrate the similarities and differences across the OPTIMIZE program. [Display omitted] • The COVID-19 pandemic has resulted in reductions in heart failure hospitalizations. • The OPTIMIZE Heart Failure Care program has a global network in 42 countries. • Input was obtained from 37 OPTIMIZE Heart Failure Care coordinators in 29 countries. • Organizational changes were reported to help ensure continuity of HF care. • The OPTIMIZE program helped focus on key guideline-based treatment recommendations. [ABSTRACT FROM AUTHOR]

To date, the complex pathological interactions between renal and cardiovascular systems represent a real global epidemic in both developed and developing countries. In this context, renovascular hypertension (RVH) remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation. Adult male Wistar rats underwent unilateral renal artery ligation and treatment with deoxycorticosterone acetate (DOCA) (20 mg/kg, s.c.), twice a week for a period of 4 weeks, and 1% sodium chloride (NaCl) water (n = 10). A subgroup of hypertensive rats received BPF (100 mg/kg/day for 28 consecutive days, n = 10) by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (that served as control, n = 8). Unilateral renal artery ligation followed by treatment with DOCA and 1% NaCl water resulted in a significant increase in mean arterial blood pressure (MAP; p< 0.05. vs CTRL) which strongly increased the resistive index (RI; p<0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p<0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion when compared to CTRL group, as shown by the increased time-to-peak (T2P; p<0.05) and the decreased whole peak capacity (Pk; p<0.01) in displacement and strain rate (p<0.05, respectively) in longitudinal motion. Consequently, the hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) when compared to CTRL group (p<0.05 in displacement and p <0.01 in strain rate). Furthermore, a significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p< 0.05 for IL-12(40), p< 0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p< 0.001) was observed compared to CTRL group. Interestingly, this pathological condition is prevented by BPF treatment. In particular, BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats (p< 0.05) and exerts a protective effect on the volume of the contralateral kidney (p <0.01). Moreover, BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p <0.01) and reducing the T2P in strain rate motion (p<0.05). These latter effects significantly improve MOWD (p <0.05) preventing the overt dyssynchrony in cardiac wall motion. Finally, the reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of some pro-inflammatory cytokines and chemokines (p<0.05 for KC and IL-12(40), p<0.01 for GM-CSF, IL-13, and TNF- α) restoring physiological levels of renal neutrophil gelatinase-associated lipocalin (NGAL, p<0.05) protein of the tethered kidney. In conclusion, the present results show, for the first time, that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage. Overall, these data point to a potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome. • BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats. • The treatment promotes a renovascular protection preventing inflammation. • MRI showed the protective effect of BPF on the volume of the contralateral kidney. • The speckle-tracking analysis showedthat BPF improves cardiac tissue strain dysfunction. • Further molecular studies could suggest BPF as a supplementation for the treatment of hypertension associated with renal or cardiovascular events. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) occurs frequently soon after coronary artery bypass grafting (CABG) and often results in increased mortality and morbidity, particularly in patients with heart failure. New-onset AF is also a common event in the early period after discharge from a cardiac surgery clinic. Current guidelines recommend β blockers as first-line medication for the prevention of AF after CABG. In this prospective study, we investigated the effectiveness of the highly selective β1 receptor antagonist bisoprolol compared to the less selective β blocker carvedilol in preventing postdischarge AF after CABG in patients with decreased left ventricular function. Three hundred twenty patients (231 men, 89 women, mean age 66 ± 10 years) with ejection fraction <40% who underwent CABG and were then referred to an in-hospital cardiac rehabilitation program were randomized to receive bisoprolol (n = 160) or carvedilol (n = 160) starting 4 to 5 days after surgery. Bisoprolol was started at 1.25 mg 1 time/day and carvedilol was started 3.125 mg 2 times/day. All patients underwent continuous telemetric electrocardiographic monitoring for 5 days after entry in the study and thereafter 2 times/day routinely up to hospital discharge. During follow-up, 23 patients (14.6%) in the bisoprolol group and 37 patients (23%) in the carvedilol group developed AF (relative risk 0.6, confidence interval 0.4 to 0.9, p = 0.032). Twenty-six percent of all AF episodes were asymptomatic. At the 4-week outpatient visit, those in the bisoprolol group showed a significantly greater decrease in heart rate, being in sinus rhythm or AF (−15.6 ± 3 vs −9.4 ± 3 beats/min, p = 0.021), whereas changes in systolic and diastolic blood pressures did not differ significantly. In conclusion, bisoprolol is more effective than carvedilol in decreasing the incidence of postdischarge AF after CABG in patients with decreased left ventricular function. [ABSTRACT FROM AUTHOR]

Drospirenone (DRSP) is an antialdosterone agent with progestogenic and antiandrogenic effects. This compound, has been recently used in combination with 17β-estradiol (E2) as hormonal therapy in postmenopausal women and has been shown to exert a significant antihypertensive effect in hypertensive post-menopausal women. Aim of the present study was to compare the effect of DRSP/E2 with those of Tibolone (T) on endothelial function, arterial stiffness, and lipid profile of early postmenopausal women naïve on post-menopausal hormonal therapy. Twenty-four women met the inclusion criteria and entered the study. Women were randomized to receive either DRSP/E2 or T for 6 months. Blood pressure and heart rate were similar in both groups at baseline and at the end of the study. Compared to baseline, endothelial function assessed by Reactive Hyperemia (RH) significantly improved in women receiving E2/DRSP, whereas no significant differences between baseline and follow up were detected in women receiving Tibolone. Women receiving E2/DRSP showed a significant decrease in pulse wave velocity and Augmentation Index compared to baseline while no changes were observed in women receiving Tibolone. The capacity of sera to trigger endothelial cells apoptosis in vitro measured by cell death assay was significantly reduced by E/DRSP but not by T (HFA-E 70 ± 5,6% vs HFD-E 41 ± 4,5%, p < 0,001). In conclusion, the present study shows that the association of Estradiol and Drospirenone as hormonal replacement therapy significantly improves vascular parameters and the composition of sera relevant for vascular protection in early post-menopausal normotensive women. These effects are not shared by Tibolone. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor antagonists have been shown to have favourable safety and cost-effectiveness profiles across a broad range of clinical indications, including heart failure, primary aldosteronism and resistant hypertension. The clinical biology of the first aldosterone blocker, i.e. spironolactone, and its effects in several organ systems has been well elucidated from multiple studies. The range of adverse effects experienced with spironolactone has led to its modification and the consequent synthesis of eplerenone. Scientific evidence accumulated so far supports the role of eplerenone as first-choice drug in heart failure, with lower prevalence rates of sex-related adverse effects associated with eplerenone as compared to spironolactone. In Europe, eplerenone is currently marketed only in some countries and only with the indication of heart failure, whereas its clinical efficacy and safety in mild to moderate hypertension is said to be uncertain. A review of available scientific evidence, however, discloses that 11 randomized clinical trials assessing eplerenone in > 3500 hypertensives have been reported so far. The results of these studies clearly show that eplerenone is an effective antihypertensive agent when used alone or in combination with other medications. In doses ranging from 25 to 100 mg daily, eplerenone monotherapy results in a dose-dependent reduction in clinic blood pressure. As compared to placebo, eplerenone reduces significantly blood pressure from baseline. In general, 100 mg daily eplerenone has a blood pressure lowering that is 50 to 75% that of spironolactone. Eplerenone results in a greater reduction in blood pressure as compared with losartan, and comparison between eplerenone and amlodipine shows that both treatments decrease systolic blood pressure to a similar extent but eplerenone is better tolerated. In conclusion, there is now evidence that eplerenone can play an important role in the treatment of mild to moderate arterial hypertension and therefore scientific experts and regulatory authorities should support its wider use in clinical practice worldwide. [ABSTRACT FROM AUTHOR]

Telemedicine is the provision of health care services, through the use of information and communication technology, in situations where the health care professional and the patient, or 2 health care professionals, are not in the same location. It involves the secure transmission of medical data and information, through text, sound, images, or other forms needed for the prevention, diagnosis, treatment, and follow-up of a patient. First data on implementation of telemedicine for the diagnosis and treatment of acute myocardial infarction date from more than 10 years ago. Telemedicine has a potential broad application to the cardiovascular disease continuum and in many branches of cardiology, at least including heart failure, ischemic heart disease and arrhythmias. Telemedicine might have an important role as part of a strategy for the delivery of effective health care for patients with cardiovascular disease. In this document the Working Group on Telecardiology and Informatics of the Italian Society of Cardiology intends to remark some key-points regarding potential benefit achievable with the implementation of telemedicine support in the continuum of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. In recent years, great advances have occurred in our understanding of the pathophysiologic mechanisms underlying the characteristic vascular proliferative lesions, thus allowing the development of several specific drugs. Nevertheless, PAH still presents a high mortality; therefore, early diagnosis and prognostic stratification seem to be of paramount importance in order to choose the best therapeutic strategies. Circulating biomarkers have been proposed as potentially noninvasive and objective parameters for diagnosis, prognosis, and response to therapy. The molecules evaluated to date, including markers of dysfunction and neurohormonal activation, myocardial injury, inflammation and oxidative stress, vascular damage and remodelling, end-organ failure, and gene expression, reflect the complex pathophysiology of PAH. However, not one of these shows all the characteristics of the ideal biomarker; thus, a multiparameter approach is probably desirable. Moreover, future direction could be research of structural proteins specifically expressed in the pathologic tissue that act as disease-specific markers. This report presents an extensive review of circulating biomarkers in PAH and some consideration about potential future direction in this area. [ABSTRACT FROM AUTHOR]

Background Although increased pulmonary pressure is caused by changes in the pulmonary vasculature, prognosis in idiopathic pulmonary arterial hypertension (IPAH) is strongly associated with right ventricular (RV) function. The aim of this study was to describe the best RV adaptive remodeling pattern to increased afterload in IPAH. Methods In 60 consecutive patients with IPAH, RV morphologic and functional features were evaluated by echocardiography and cardiac magnetic resonance imaging. To address the question of the best RV adaptation pattern, we divided the study population into two groups by the median value of RV mass/volume ratio (0.46) because this parameter allows the distinction between RV eccentric (≤0.46) and concentric hypertrophy (>0.46). The two groups were compared for RV remodeling and systolic function parameters, World Health Organization class, pulmonary hemodynamics, and 6-minute walk test. Results Despite similar pulmonary vascular resistance, mean pulmonary pressure, and compliance, patients with eccentric hypertrophy had advanced World Health Organization class and worse 6-minute walk test, hemodynamics, RV remodeling, and systolic function parameters compared with patients with concentric hypertrophy. The group with concentric hypertrophy had higher RV to pulmonary arterial coupling compared with the group with eccentric hypertrophy (1.24 ± 0.26 vs 0.83 ± 0.33, p = 0.0001), indicating higher RV efficiency. A significant correlation was found between pulmonary vascular resistance and RV to pulmonary arterial coupling ( r = −0.55, r 2 = 0.31, p = 0.0001), with patients with RV mass/volume ratio > 0.46 at the higher part of the scatterplot, confirming more adequate RV function. Conclusions Concentric hypertrophy might represent a more favorable RV adaptive remodeling pattern to increased afterload in IPAH because it is associated with more suitable systolic function and mechanical efficiency. [ABSTRACT FROM AUTHOR]

Background The ultimate goal of antihypertensive therapy is cardiovascular risk (CVR) reduction. The aim of this study was to compare the efficacy and safety of once-daily fixed combination (ODFC) versus free-drug combination (FDC) of 3antihypertensive agents and statin. Methods The ALL-IN-ONE trial was a 12-week randomized, prospective, multicenter trial. A total of 305 hypertensive patients were randomized 1:1. The “fixed group” was given an ODFC of perindropil 10 mg plus indapamide 2.5 mg plus amlodipine 5 or 10 mg plus atorvastatin 20 mg. The “free group” was given a FDC of the 3antihypertensive agents plus atorvastatin 20 mg. Primary end-points were the differences in clinic BP, cholesterol levels and CVR risk between the 2 groups after treatments. Secondary end-points included intragroup differences in clinic BP. Safety and compliance were also assessed. Results At 12-weeks, the fixed group had lower systolic BP and similar diastolic BP compared to the free group. BP targets at week 12 were more commonly reached with fixed than free combination (89% and 80% respectively, p = 0.048). For cholesterol serum in both groups there was a significant reduction of values. Also CVR reduction was greater in those taking ODF. Safety was not significantly different between the 2 groups. Conversely, compliance was significantly greater in the fixed-group vs. the free-group. Conclusion This randomized trial shows that ODF combination of perindropil, indapamide and amlodipine is as safe as free combination of the 3 drugs, but is associated with a greater efficacy in BP control, compliance and, associated with statin, in cholesterol reduction. A better cardiovascular risk control is achieved with ODF combination than with a free administration. ClinicalTrials.gov ID: NCT02710539 [ABSTRACT FROM AUTHOR]

Background The aim of this pilot study was to evaluate if ranolazine (R) could improve insulin resistance (IR) in obese/overweight non-diabetic patients with coronary heart disease (CHD). Methods The study enrolled 40 patients with already diagnosed CHD, previous revascularization, residual ischemia at ergometric test and IR. Mean age was 62.4 ± 9 years, M/F = 31/9. Patients were randomly assigned to one of the two following groups: group 1 (20 patients) started R at dose of 500 mg/bid; group 2 (20 patients) increased the dose of beta/blockers or calcium-channel blockers without introducing R. IR was defined as having HOMA-IR > 2.5. At baseline and after 12 weeks, all subjects performed an ergometric test and 12 h fasting blood sample collection for determining glucose and insulin levels. Results At 12 weeks follow-up visit HOMA-IR significantly decreased in group 1 (from 3.1 ± 1.7 to 2.3 ± 0.9; p = 0.02) while it remained unchanged in group 2 (from 3.0 ± 1.4 to 2.8 ± 1.2; p = 0.14) (between groups p = 0.009). At 12 weeks follow-up visit patients of both groups obtained a significant increase of ischemic threshold at ergometric test, compared to baseline, (group 1 from 308.4 ± 45 s to 423.9 ± 57 s, p = 0.0004); (group 1 from 315.7 ± 63 s to 441.2 ± 51 s, p = 0.0001); without between groups difference (p = 0.25). Conclusions Our data suggest that starting R, instead of increasing the dose of beta-blockers/calcium-channel blockers, could be a preferable choice in obese/overweight CHD subjects with residual ischemia after revascularization. [ABSTRACT FROM AUTHOR]

Abstract: Background/objectives: Trimetazidine (TMZ) is a metabolic agent of proven efficacy in improving myocardial ischemia and angina. VASCO, a randomised double-blinded, placebo-controlled trial, assessed anti-anginal efficacy and safety of standard and high dose of modified-release TMZ (70mg/d and 140mg/d) in symptomatic and asymptomatic patients with chronic ischemic heart disease receiving background atenolol 50mg/d on exercise test parameters. The VASCO-angina study assessed the efficacy of the two doses of TMZ on total exercise duration (TED) and time to 1-mm ST segment depression (T1), in symptomatic patients with chronic stable angina receiving background atenolol treatment. Methods and results: In the all cohort of chronic stable angina patients TMZ significantly improved TED compared to baseline and to placebo. Both doses of TMZ significantly increased TED (p=0.0044 and p=0.0338 for TMZ 140mg/d and TMZ 70mg/d, respectively). A greater TED improvement was observed in TMZ 140mg/d than in TMZ 70mg/d, although the difference was not significant. Amongst patients with limiting angina during exercise test, both doses of TMZ significantly improved both T1 and TED. No difference in serious adverse events was noted between TMZ and placebo. Conclusions: The VASCO-angina gives evidence for the efficacy and tolerability of standard and high dose of TMZ in improving effort-induced myocardial ischemia and functional capacity in patients with chronic stable angina receiving background beta-blockers. [Copyright &y& Elsevier]

Abstract: Background: The best format of exercise training in patients with chronic heart failure (CHF) is controversial. We tested the hypothesis that aerobic continuous training (ACT) and aerobic interval training (AIT) induce similar effects on functional capacity, central hemodynamics and metabolic profile in patients with postinfarction CHF provided that the training load is equated by an individually-tailored volume/intensity dose of exercise. Methods: Twenty patients with postinfarction CHF under optimal medical treatment were randomized to ACT or AIT for 12weeks. Exercise training consisted in individualized loads prescribed according to the Training Impulses (TRIMPi) method, which was determined using the individual HR and lactate profiling obtained during a treadmill test at baseline. Results: Peak VO2 increased significantly by 22% with both ACT and AIT, without differences between the two training programs. Changes in anaerobic threshold and VE/VCO2 slope were not significantly different between ACT and AIT. Resting HR significantly decreased with both exercise modes. Resting cardiac output and stroke volume, left ventricular diastolic dimension and ejection fraction did not change from baseline with both exercise modes. Lipid profile and glucose metabolism were not substantially altered by ACT and AIT. Conclusions: ACT and AIT both induce significant improvement in aerobic capacity in patients with postinfarction CHF, without significant differences between the two training modes, provided that patients are trained at the same, individually tailored, dose of exercise. The TRIMPi method might represent a step forward in the individualization of an aerobic training tailored to the patient's clinical and functional status within cardiac rehabilitation programs. [Copyright &y& Elsevier]

Abstract: Background: Heart Rate Variability (HRV) and Baroreflex Sensitivity (BRS) are impaired in patients with Chronic Heart Failure (CHF) and carry negative prognosis. Exercise training improves these parameters. However, the relationship between exercise training with HRV and BRS has been investigated without regard for individual training loads. We tested the hypothesis that in CHF patients changes in HRV and BRS are dose–response related to individual volume/intensity training load (TL). Methods: Twenty patients with stable postinfarction CHF under optimal medical treatment were randomized to either aerobic continuous training (ACT) or aerobic interval training (AIT) for 12weeks. Individualized TL was monitored by the Training Impulses (TRIMPi) method, which was determined using the individual HR and lactate profiling determined during a treadmill test at baseline. HRV (standard deviation of mean R-R interval) and BRS were assessed at rest and 3weeks apart, throughout the study. Results: HRV, BRS and R–R interval increased significantly with training, being very highly correlated to the dose of exercise with a second-order regression model (r 2 ranged from 0.75 to 0.96; P<0.001), resembling a bell-shaped in the ACT, and an asymptotic-shaped curve in the AIT groups, respectively. These changes were accompanied by a significant increase in functional capacity. No significant differences were detected between ACT and AIT in any variable. Conclusions: These results suggest that improvements in HRV and BRS by exercise training in CHF patients are dose related to TL in a non-linear fashion on an individual basis, with optimal results at moderate doses of exercise. [Copyright &y& Elsevier]

Abstract: Objectives: We studied the effect of a short-term (3weeks) exercise training program on the number of circulating CD34/KDR+ endothelial progenitor cells (EPCs) and on serum levels of matrix metalloproteinases (MMPs) in chronic heart failure (CHF) patients as well as on serum capacity to foster colony forming units-endothelial cells (CFU-ECs) in vitro. Methods: Effectiveness of training was assessed by the 6-minute walking test (6MWT). Peripheral blood and serum were obtained from fourteen patients with CHF due to coronary artery disease before and after an inpatient aerobic exercise training program. At admission and at discharge we analysed circulating EPC number and serum levels of MMPs, TIMP-1 and TNF-α. The number and function of CFU-EC colonies were evaluated in cultures performed with serum obtained before and after training. Results: After training, distance walked at 6MWT and number of circulating CD34/KDR+ cells increased (from 154±27 to 233±48m; P <0.0001 and from 5±3 to 9±6 cells/ml P <0.05, respectively). Conversely, serum concentrations of MMP-1 and TIMP-1 decreased significantly (from 11.4±2.4 to 6.3±1.1ng/ml, and from 320.4±41.2 to 167.2±12.6ng/ml, respectively, both P <0.01), while MMP2/TIMP-1 and MMP-9/TIMP-1 ratios increased. Interestingly, we found increased CFU-EC proliferation in cultures performed with serum obtained after training. Conclusions: Considering that both EPCs and MMPs might play a role in vascular remodeling, the increased number of EPCs and MMP activities observed in this study, suggest that the selected short-term exercise training could be a potential therapeutic strategy to rescue cardiac function in CHF patients. [Copyright &y& Elsevier]

Abstract: Background: Arterial hypertension affects endothelial function and arterial stiffness. The angiotensin (AT1) receptor antagonist irbesartan improves endothelial function and arterial stiffness in hypertensive patients. Nebivolol, a beta1-selective beta blocker, reduces systemic vascular resistance and stimulates nitric oxide release thus exerting positive effects on vascular function. However, comparative studies on the vascular effects of third generation beta-blockers and AT1 receptor blockers are lacking. Aim of this randomized, double-blind study was to test the hypothesis of non-inferiority of nebivolol to irbesartan, both in association with hydrochlorothiazide, on endothelial function, arterial stiffness and central hemodynamic parameters in patients with arterial hypertension naïve on therapy. Methods: Sixty-five patients were randomized to receive irbesartan/hydrochlorothiazide (150mg/12.5mgday) or nebivolol/hydrochlorothiazide (5mg/12.5mgday) for 8-weeks. Endothelial function, pulse wave velocity, augmentation index, central and brachial blood pressures were measured at baseline and at the end of the study. Results: Systolic and diastolic central blood pressure, as well as brachial arterial pressure, decreased to a similar extent after both treatments. Similar changes in endothelial function between groups were detected at the end of the study. A significant reduction in pulse wave velocity, central blood pressure, and augmentation index adjusted for heart rate, was found in both the treatment groups at the end of the study, without significant differences between groups. Conclusions: The results of this study confirm the hypothesis of non-inferiority of short-term treatment with nebivolol compared to irbesartan, both in association with hydrochlorothiazide, on endothelial function, arterial stiffness and central hemodynamic parameters in hypertensive patients naïve on therapy. [Copyright &y& Elsevier]

Abstract: Background: The evidence of antiatherogenic and vasodilatatory effects of testosterone (T) suggest a possible role of the lack of this hormone in the development and pathophysiology of coronary artery disease (CAD). Aim of the present study was to evaluate the effects of oral administration of testosterone undecanoate during a period of three months on serum lipid levels and on the occurrence of anginal attacks and daily ischemic episodes in patients with CAD. Methods and results: Eighty seven (87) diabetic male subjects (mean age: 74±7 years) with proven CAD were randomized to a 12 week treatment with either T undecanoate (40 mg administered three daily) or placebo (P) in a double blind protocol. Weekly episodes of angina attacks, number of ischemic episodes daily and total ischemic burden on ambulatory ECG Holter were evaluated at baseline and at the end of the study. Serum total cholesterol and triglyceride concentrations were also measured at the same time points. Compared to P, T significantly reduced the number of anginal attacks/weeks of 34% (p <0.05); the silent ischemic episodes of 26% (p <0.05), and the total ischemic burden of 21% (p <0.05) on ambulatory ECG monitoring. After 12 weeks total cholesterol, plasma triglycerides and HOMA index were significantly reduced in the T group compared to P group. Conclusions: Three months administration of T has beneficial effect on serum cholesterol and triglyceride levels in patients with CAD and reduces the number of anginal attacks, and ischemic episodes. These effect may be related to the metabolic and vasoactive properties of the hormone. Further studies are needed in order to assess the long term relevance of these effects. [Copyright &y& Elsevier]

Abstract: Aims: The aim of our study was to examine the effects of statin therapy (atorvastatin) on post-implant structural changes of bovine pericardial tissue in a subcutaneous animal model. Methods and results: Sixty male C57BL/6 mice underwent subcutaneous dorsal implantation of bovine pericardial fragments. Animals were randomized to treatment with atorvastatin (50 mg/kg) (statin group — SG) or to vehicle (control group — CG). After 1.5 months, all fragments were explanted and submitted to histopathological assessment (semi-quantitative analysis) to elucidate extent of inflammatory infiltrate, signs of tissue injury, or presence of microcalcification. Calcium determination of the implanted pericardial tissue was also performed by inductively coupled plasma mass spectrometry (ICP-MS) assessment. ICP-MS analysis showed that pericardial fragments in SG had significantly (p <0.01) less calcium content than CG (625±142 vs. 962±590 µg/g, respectively). Light microscopy showed marked inflammatory infiltrates and tissue injury of pericardial specimens in CG animals, whereas SG animals maintained a better preserved original pericardial structure. Conclusions: Our findings indicate that atorvastatin significantly attenuates the post-implant structural degeneration of artificial valve bovine pericardial tissue in a subcutaneous animal model. Further observations are mandatory to assess the effects of statins on the implanted bioprosthetic valve tissue in the blood circulation. [Copyright &y& Elsevier]

Objectives: This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity, ventilatory efficiency, muscle strength, insulin resistance, and baroreflex sensitivity (BRS) in elderly patients with chronic heart failure (CHF). Background: CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure. Methods: Seventy elderly patients with stable CHF-median age 70 years, ejection fraction 31.8 +/- 7%-were randomly assigned to receive testosterone (n = 35, intramuscular injection every 6 weeks) or placebo (n = 35), both on top of optimal medical therapy. At baseline and at the end of the study, all patients underwent echocardiogram, cardiopulmonary exercise test, 6-min walk test (6MWT), quadriceps maximal voluntary contraction (MVC), and isokinetic strength (peak torque) and BRS assessment (sequences technique). Results: Baseline peak oxygen consumption (VO(2)) and quadriceps isometric strength showed a direct relation with serum testosterone concentration. Peak VO(2) significantly improved in testosterone but was unchanged in placebo. Insulin sensitivity was significantly improved in testosterone. The MVC and peak torque significantly increased in testosterone but not in placebo. The BRS significantly improved in testosterone but not in placebo. Increase in testosterone levels was significantly related to improvement in peak VO(2) and MVC. There were no significant changes in left ventricular function either in testosterone or placebo. Conclusions: These results suggest that long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and BRS in men with moderately severe CHF. Testosterone benefits seem to be mediated by metabolic and peripheral effects. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Free fatty acid inhibition with trimetazidine (TMZ) improves myocardial metabolism and myocardial ischemia in patients with coronary artery disease (CAD). Because of its effect on myocardial glucose utilization TMZ may represent a therapeutic option in diabetic patients with CAD. Aim of the present study was to evaluate whether the metabolic effect of TMZ may improve episodes of myocardial ischemia in diabetic patients with CAD. Research design and methods: We assessed the effect of TMZ on 24 h ambulatory ECG monitoring (AEM) in 30 patients (22 males and 8 females, mean (SE) age 67±6.5 years) with NIDDM and ischemic cardiomyopathy. Patients were randomized to receive on top of standard therapy either TMZ (20 mg, tds) or placebo (tds) and were evaluated at baseline and after 6 months. Results: Patients randomized to TMZ or placebo were comparable regarding demographic data, distribution of CAD, and glicated haemoglobin levels. TMZ significantly reduced the number of episodes of transient myocardial ischemia (−24% compared to baseline, p <0.01; −27% compared to placebo, p <0.01), and Total Ischemic Burden (−28% compared to baseline, p <0.01; −29% compared to placebo, p <0.01). TMZ also significantly reduced the number of silent episodes of myocardial ischemia (−42% compared to baseline and −39% compared to placebo, p <0.01) and the time of silent myocardial ischemia/24 h (−37% compared to baseline and −35% compared to placebo, p <0.01). No significant changes in heart rate were detected between baseline, placebo and TMZ evaluations. Conclusions: TMZ is effective in reducing silent and symptomatic episodes of transient myocardial ischemia in diabetic patients with CAD on standard anti-anginal therapy. [Copyright &y& Elsevier]

Background: Atrial fibrillation (AF) is the most common sustained cardiac tachyarrhythmia and is often an occasional diagnosis in the absence of known cardiac disease. The aim of this study is to describe an Italian patient population with AF followed by their General Practitioners (GPs) using a telecardiology service. Methods: A total of 655 Italian GPs were equipped with a portable electrocardiographer. The ECG tracing of all consecutive patients (7516) received between January and September 2001 was included into the study. Results: AF was detected in 719 patients (9.%) (77±12 years). In 448 patients, it was a known chronic condition, while in 271 patients, it was a new diagnosis. In the chronic AF, the principal reason for the teleconsultation was a routine control by the GPs, but an uncontrolled cardiac rate was present in 29% of the cases, while an antiplatelet or anticoagulation therapy was administered in only 46.2% cases. The teleconsultation alone provided a solution to the GPs'' requests in 348 patients (77.6%) (154 cases (34.5%) required no further action while 194 patients (43.5%) needed therapy adjustments only), while 47 patients (10.5%) required hospitalization and 51 patients needed further diagnostic tests. In 271 cases, a first evidence of atrial fibrillation was recorded: in 259 patients, GPs requested a teleconsultation in the presence of symptoms (mainly palpitation, dyspnoea and fatigue) and in 12 for routine control; in this case, 121 patients (46.9%) needed Emergency Department (ED) admission, 113 patients (39.1%) needed therapy adjustments and, for 19 patients (7.5%), further diagnostic tests were prescribed. Conclusion: In Italy, many patients, in particular the elderly, with AF are followed by their GPs on a routine basis; a telecardiology service may provide a useful tool in the home management of chronic AF and in the first detection of new cases of AF. [Copyright &y& Elsevier]

A large proportion of patients who have erectile dysfunction also have coronary artery disease (CAD). In these patients, nitrate therapy is a contraindication to the use of sildenafil. To assess whether the metabolic anti-ischemic agent, trimetazidine, is effective in controlling episodes of myocardial ischemia during sexual activity in patients who have CAD and use long-term nitrate therapy, we studied 38 men (57 ± 6 years of age) who had proved CAD. Patients underwent 24-hour ambulatory electrocardiographic monitoring at baseline, after 1 week of oral nitrate therapy (20 mg 3 times a day), and after 1 week of trimetazidine (20 mg 3 times a day). Patients were asked to engage in ≥1 session of sexual intercourse during each session of ambulatory electrocardiographic monitoring. They were instructed to take sildenafil (100 mg) 1 hour before sexual intercourse performed at baseline and during therapy with trimetazidine and sildenafil or placebo (blinded) during therapy with nitrates. A decrease in total ischemic burden was observed with nitrates and trimetazidine compared with baseline (−3 ± 1.2 episodes/patient/24 hours vs −5 ± 1.3 episodes/patient/24 hours and −6 ± 5 min/patient/24 hours vs −8 ± 3 min/patient/24 hours, p &#60;0.01 for nitrates and trimetazidine vs baseline). Trimetazidine plus sildenafil was more effective in controlling episodes of myocardial ischemia during sexual activity than nitrates alone (−45 ± 11% vs −18 ± 7%, p &#60;0.04). In conclusion, in patients who have CAD, combination therapy with sildenafil and trimetazidine is more effective than nitrate therapy in the control of ischemic episodes during sexual activity, suggesting that long-term nitrate therapy may be safely switched to trimetazidine therapy when therapy for erectile dysfunction is required. [Copyright &y& Elsevier]

The heart rate regulation problem is addressed for the well-known second order nonlinear model of the human heart rate response during treadmill/cycle-ergometer exercises. The mainly restrictive stability & global attractivity constraint in the literature, being constituted by an inequality involving four constant parameters of such a nonlinear model, is definitely removed. Nonlinear analytical arguments and design steps are innovatively presented to achieve heart rate regulation when model parameters satisfy the so-called 'instability constraint', with just stability & local attractivity properties being involved. Experimental results are included to illustrate all the theoretical derivations. [ABSTRACT FROM AUTHOR]