Glucose Metabolism Abnormalities in Heart Failure Patients: Insights and Prognostic Relevance.

Heart failure is a clinical syndrome characterized by left ventricular dysfunction and/or elevated intracardiac pressures, with a prevalence of about 1% to 2% in the general population. In the last decades, many metabolic disorders have been studied as linked with heart failure. Diabetes mellitus and insulin resistance are strictly related to heart failure, with a bidirectional link, where each can influence the other. The aim of this article is to report the role of glucose metabolism abnormalities in the development of heart failure, defining the epidemiology and assessing pathophysiology and prognosis of heart failure related to glucose metabolism disorders.

A New Sustained-release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer.

PURPOSE: This clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. METHODS: A Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28-168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. FINDINGS: All 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28-168 in 96.8% (95% CI, 92.5%-98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively. IMPLICATIONS: Leuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

Effects of novel oral anticoagulants on left atrial and left atrial appendage thrombi: an appraisal.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and predisposes to an increased risk of thromboembolic events. Patients affected by AF exhibit an increased risk of stroke compared with those in sinus rhythm, with the most common location of thrombi in the left atrial appendage. Until 2009, warfarin and other vitamin K antagonists were the only class of oral anticoagulants available. More recently, dabigatran, rivaroxaban, apixaban, and edoxaban have been approved by regulatory authorities for prevention of stroke in patients with non-valvular AF. Few data are available about the efficacy of novel oral anticoagulants for the treatment of left atrial and left atrial appendage thrombosis. Aim of this review is to summarize available evidence regarding the effectiveness of novel oral anticoagulants on left atrial appendage thrombosis.

Efficacy and safety of prolonged dual antiplatelet therapy: a meta-analysis of 15 randomized trials enrolling 85 265 patients.

AIMS: The optimal duration of dual antiplatelet therapy (DAPT) in patients with ischaemic cardiovascular (CV) disease is still debated. Previous meta-analyses reported conflicting results about prolonged DAPT on mortality and major CV events. Aim of this study was to assess the effects of prolonged vs. no/short-term DAPT on myocardial infarction (MI), stroke, bleeding, and mortality. METHODS AND RESULTS: Trial inclusion criteria were: randomization to prolonged duration vs. no/short DAPT; reporting of at least one outcome among overall and CV death, MI, stroke, major non-fatal, fatal, and intracranial bleeding. Fifteen randomized studies including 85 265 patients were included. Prolonged DAPT, compared with no or short DAPT, significantly reduced MI (RR: 0.785, 95% CI: 0.729-0.845, P < 0.001) and stroke (RR: 0.851, 95% CI: 0.754-0.959, P = 0.008), but had no effect on overall (RR: 0.989, 95% CI: 0.921-1.061, P = 0.751) or CV (RR: 0.951, 95% CI: 0.872-1.037, P = 0.258) mortality. Prolonged DAPT significantly increased major non-fatal (RR: 1.690, CI: 1.322-2.159, P < 0.001), but not intracranial or fatal bleeding (RR: 1.236, CI: 0.899-1.698, P = 0.192, RR: 1.069, CI: 0.760-1.503, P = 0.703; respectively). The effects of DAPT were similar to those reported in the overall analysis in patients with stable CV disease, whereas in those with unstable CV disease only the significant reduction of stroke was not confirmed. Dual antiplatelet therapy prolonged beyond 1 year significantly reduced MI but not stroke, all-cause, or CV death. It significantly increased the risk of major non-fatal bleeding, with no difference in intracranial and fatal bleeding. CONCLUSION: Prolonged DAPT significantly reduced ischaemic CV events but not mortality. Even if a significant increase of major non-fatal bleeding was detected, no increased risks of intracranial and fatal bleeding were observed.

Sleep-disordered breathing, impaired cardiac adrenergic innervation and prognosis in heart failure.

OBJECTIVE: Unfavourable effects of sleep-disordered breathing (SDB) in heart failure (HF) are mainly mediated by impaired sympathetic activity. Few data are available on SDB and cardiac adrenergic impairment evaluated at myocardial level. The aim of the study was to assess the relationship between SDB, cardiac sympathetic innervation assessed by 123I-metaiodobenzylguanidine (123I-MIBG) imaging and prognosis in HF. METHODS: Observational, prospective study enrolling patients with HF and reduced systolic function. Patients underwent nocturnal cardiorespiratory monitoring to assess SDB presence by apnoea/hypopnoea index (AHI), and 123I-MIBG imaging to calculate heart-to-mediastinum (H/M) ratios and washout rate. Patients were prospectively followed for 29±18 months for the combined endpoint of cardiovascular death and HF hospitalisation. RESULTS: Ninety-four patients (66.1±9.8 years; left ventricular ejection fraction 32±7%) were enrolled; 72 (77%) showed SDB and, compared with non-SDB, significantly reduced early (1.67±0.22 vs 1.77±0.13; p=0.019) and late H/M ratios (1.50±0.22 vs 1.61±0.23; p=0.038). Dividing patients into two groups according to SDB severity, patients with a moderate-severe disturbance (AHI >15; n=43) showed significantly worse survival for the composite study outcome (log-rank test, p=0.001) with respect to patients with mild or no disorder (AHI ≤15; n=51). Adding SDB variables to the already known prognostic role of 123I-MIBG imaging, we observed a worse survival in patients with both SDB and H/M impairment. CONCLUSIONS: Patients with systolic HF and SDB show more impaired cardiac adrenergic innervation assessed by 123I-MIBG imaging, and more adverse prognosis compared with HF patients without SDB.

Ischemic cardiovascular involvement in psoriasis: a systematic review.

Epidemiologic studies demonstrate that psoriasis is associated with shorter life expectancy, most frequently attributable to cardiovascular (CV) events. Although increased prevalence and incidence of CV risk factors for atherosclerosis have been reported in psoriatic patients, psoriasis likely plays an independent role in the increased cardiovascular risk, presumably linked to the chronic systemic inflammatory state. Consistently, preliminary investigations suggest that anti-inflammatory therapies may improve early subclinical vascular alterations and reduce cardiovascular morbidity and mortality. This review will focus on ischemic CV involvement in psoriatic patients, summarizing the prevalence and incidence of CV risk factors and CV events, as well as evidence on mechanisms of premature atherosclerosis and on effects of systemic anti-inflammatory therapies on CV risk profile. We performed a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and evaluated the quality of studies comparing drug treatments using Detsky score. Our review documented that psoriatic patients are at increased CV risk, related to raised prevalence and incidence of CV risk factor and to inflammatory status. However, available literature lacks of studies that establish appropriate targets for CV risk factors and assess the clinical value of screening for subclinical organ damage and the impact of disease-modifying therapies on CV risk profile in psoriatic patients. Awareness of raised CV risk in psoriatic patients should foster further research aimed at elucidating these aspects.

Prevalence and severity of asymptomatic coronary and carotid artery disease in patients with abdominal aortic aneurysm.

We evaluated the prevalence and severity of occult coronary artery disease (CAD) and cerebrovascular disease (CeVD) in patients with abdominal aortic aneurysm (AAA). We studied 100 consecutive patients with no history of CAD, normal electrocardiogram, normal systolic function, and no angina or dyspnea. All patients underwent carotid Doppler study and invasive coronary angiography. Significant CAD was observed in 61% of patients. In all, 51% of patients with significant CAD showed either left main (n = 7), 3-vessel (n = 17), or proximal left anterior descending (n = 7) CAD, corresponding to 31% of the total cohort. Cerebrovascular disease was detected in 53% of patients, and in 38% of them was significant (peak systolic flow velocity ≥125 <230 cm/s). In 36% of patients with CeVD either left main (n = 5), 3-vessel (n = 11), or proximal left anterior descending (n = 3) CAD was observed. Severe asymptomatic CAD is prevalent in AAA, and 31% of patients fulfill indications for coronary revascularization.

Reduction of C-reactive protein is not associated with reduced cardiovascular risk and mortality in patients treated with statins. A meta-analysis of 22 randomized trials.

BACKGROUND: The association between C-reactive protein (CRP) levels and risk of cardiovascular (CV) events has been reported in several studies. However, it is unclear whether a reduction in CRP is associated with a reduction in risk of clinical events. Therefore we sought to investigate, in a meta-regression analysis of randomized studies enrolling patients treated by statins, whether changes in CRP are associated with changes in risk of CV events or overall survival. METHODS: Randomized trials enrolling patients treated by statins, reporting CRP at baseline and at end of follow-up, CV events [myocardial infarction (MI) and stroke], CV and all-cause mortality were selected. RESULTS: Twenty-two trials enrolling 54,213 participants were included in the analysis. Meta-analysis showed that active treatment significantly reduced risk of all-cause death by 8%, myocardial infarction by 11%, stroke by 10.3% and the composite outcome (including CV death, MI and stroke) by 8%, whereas risks of CV mortality was not significantly reduced. Meta-regression analysis revealed that reduction in CRP levels was significantly associated only with the reduction of MI, whereas no relationship was identified between changes in CRP and risk of stroke, CV and all-cause mortality, and the composite outcome. CONCLUSIONS: These findings demonstrate that statin-induced changes in CRP do not correlate with major CV events apart from the risk of MI nor with overall survival in high-risk patients. These data suggest that although CRP may be a surrogate marker for coronary risk, it should not be used for predicting the effectiveness of statin therapy.

Ischemic heart disease in systemic inflammatory diseases. An appraisal.

Systemic inflammatory diseases are inflammatory syndromes that are associated with increased cardiovascular morbidity and mortality. The link between inflammatory and cardiovascular diseases can be attributed to coexistence of classical risk factors and of inflammatory mechanisms activated in systemic inflammatory diseases and involving the immune system. Yet, clinical implications of these findings are not entirely clear and deeper knowledge and awareness of cardiac involvement in inflammatory diseases are necessary. The aims of this review are to summarize cardiac involvement in systemic inflammatory diseases and to identify areas where evidence is currently lacking that deserve further investigation in the future.

[Cardiovascular risk in systemic inflammatory diseases]. / Il rischio cardiovascolare nelle patologie infiammatorie sistemiche.

Systemic inflammatory diseases are associated with increased cardiovascular morbidity and mortality. The link between inflammatory and cardiovascular diseases can be attributed to the coexistence of classical risk factors and inflammatory mechanisms activated during systemic inflammatory diseases involving the immune system. Unfavorable metabolic effects of anti-inflammatory drugs can also contribute to increase cardiovascular risk. Yet, clinical implications of these findings are not entirely clear, and deeper knowledge and awareness of cardiac involvement in inflammatory diseases are necessary. The aim of this review is to summarize cardiac involvement in systemic inflammatory diseases and to identify aspects where evidence is currently lacking that would deserve further investigation in the future.

Prevalence and severity of asymptomatic coronary and carotid artery disease in patients with lower limbs arterial disease.

OBJECTIVES: Lower limbs arterial disease (LLAD) portends high risk of cardiovascular events. Yet, the prevalence of significant occult coronary artery (CAD) and cerebrovascular (CVD) disease in patients without CAD and CVD has not been widely investigated. The purpose of this study was to evaluate the prevalence and severity of CAD and CVD in patients with LLAD of the lower extremities. METHODS: From January 2008 through December 2011 we studied 200 consecutive patients admitted for symptomatic LLAD, with normal global and regional systolic function, no symptoms of angina or dyspnea. During hospital admission all patients underwent carotid Doppler study and invasive angiography. RESULTS: Significant CAD was observed in 110 of 200 (55%) patients. Fifty-eight (53%) patients with significant CAD showed either left main (n = 7), 3 vessels (n = 35) or proximal left anterior descending (n = 16) CAD, corresponding to 29% of total cohort. CVD was detected in 86(43%) patients (69% with concomitant CAD), including 30(35%) with severe and 15(17%) with significant disease. In thirty-two (37%) patients with CVD either left main (n = 4), 3 vessels (n = 18) or proximal left anterior descending (n = 10) CAD was observed. The percent of patients with left main, 3 vessel or proximal left anterior descending stenosis among those with CVD was significantly higher (37%; p = 0.03) compared to those without CVD. CONCLUSIONS: Severe asymptomatic CAD and CVD are quite prevalent in LLAD, and 29% of patients fulfill indications for coronary revascularization. Cost-effective strategies to detect occult CAD or CVD in LLAD patients need to be investigated in large multicenter studies.

Cardiovascular involvement in patients affected by acromegaly: an appraisal.

Cardiovascular complications are frequent in acromegalic patients. Several studies reported increased prevalence of traditional cardiovascular risk factors and early development of endothelial dysfunction and of structural vascular alterations, with subsequent increased risk of coronary artery disease. Furthermore, chronic exposure to high levels of GH and IGF-I leads to the development of the so called "acromegalic cardiomyopathy", characterized by concentric biventricular hypertrophy, diastolic dysfunction and, additionally, by progressive impairment of systolic performance leading to overt heart failure. Cardiac valvulopathies and arrhythmias have also been documented and may concur to the deterioration of cardiac function. Together with strict control of cardiovascular risk factors, early control of GH and IGF-I excess, by surgical or pharmacological therapy, has been reported to ameliorate cardiac and metabolic abnormalities, leading to a significant reduction of left ventricular hypertrophy and to a consistent improvement of cardiac performance.

[Clinical applications of MIBG SPECT in chronic heart failure]. / Applicazioni cliniche della SPECT con MIBG nello scompenso cardiaco cronico.

Heart failure is characterized by several abnormalities of sympathetic cardiac activity that can be assessed by 123I metaiodobenzylguanidine single photon emission computed tomography (MIBG SPECT). This technique may be useful in the clinical management of heart failure patients. Abnormal MIBG uptake has been demonstrated to be a predictor of death and arrhythmic events in heart failure patients with a prognostic power incremental to that of conventional risk markers; it may also be useful to identify patients at low risk of arrhythmias despite current guideline indications for an implantable cardioverter-defibrillator (ICD) or patients at high risk for arrhythmias not fulfilling ICD indications. This review will focus on the clinical applications of MIBG SPECT in chronic heart failure, on the basis of the most recent evidence.

[From myocardium to the atherosclerotic plaque: new perspectives in cardiologic imaging]. / Dal miocardio alla placca aterosclerotica: le nuove prospettive dell'imaging in cardiologia.

Molecular imaging is an innovative and promising approach in cardiology for functional characterization of atherosclerosis. Nuclear, ultrasound and magnetic resonance imaging have been used for assessment of atherosclerosis of large and small arteries in several clinical and experimental studies. Positron Emission Tomography with fluorodeoxyglucose can measure metabolic activity and vulnerability of atherosclerotic plaques, identifying individuals at risk of future cardiovascular events. Magnetic resonance imaging can quantify carotid artery inflammation using iron oxide nanoparticles as contrast agent. In addition, macrophage accumulation of iron particles in atherosclerotic plaques may allow monitoring of inflammation during drug therapy, whereas contrast-enhanced ultrasound imaging may detect plaque neovascularization. Currently, technical factors, including cardiac and diaphragmatic motion and small size of coronary vessels, limit routine application of these techniques for coronary imaging. Purpose of this review is to describe state of the art and potential areas of clinical applications of molecular imaging of atherosclerosis.

Assessment of cardiac sympathetic activity by MIBG imaging in patients with heart failure: a clinical appraisal.

Cardiac sympathetic activity can be assessed by (123)I-labelled meta-iodobenzylguanidine (MIBG) scintigraphy. Abnormalities of sympathetic cardiac activity have been shown in patients with heart failure, resulting in reduced MIBG uptake. Abnormal MIBG uptake predicts cardiac death, arrhythmias and all-cause mortality in patients with heart failure with a prognostic power incremental to that of conventional risk markers, and may identify patients at low risk of arrhythmias despite current guideline indications for implantable cardioverter defibrillator or patients at high risk for arrhythmias not fulfilling implantable cardioverter defibrillator indications. Prospective outcome studies are needed to assess whether MIBG imaging will have an impact on the mortality and morbidity of patients with heart failure.

N-terminal pro-b-type natriuretic peptide and left atrial function in patients with congestive heart failure and severely reduced ejection fraction.

AIMS: Amino-terminal portion of pro-B-type natriuretic peptide (NT-pro-BNP) is a valuable diagnostic and prognostic marker in congestive heart failure (CHF). In CHF patients, elevation of natriuretic peptide levels correlate with decreased left ventricular (LV) ejection fraction (EF) and increased left atrial (LA) volumes, but a correlation with LA function that is a determinant of haemodynamic and clinical status in CHF with independent prognostic value has never been investigated. Aim of this study was to evaluate the relationship between cardiac neurohormonal activation and LA function in patients with CHF due to dilated cardiomyopathy. METHODS AND RESULTS: One hundred and one patients (86% males; mean age, 64 ± 11 years) with dilated ischaemic or non-ischaemic cardiomyopathy, LV EF ≤45% (mean LV EF, 33 ± 8%), and New York Heart Association class II-IV underwent transthoracic echocardiography to evaluate LA fractional active and total emptying from M- and B-Mode images, and, on the same day, venous blood sample collection to dose NT-pro-BNP. By univariate analyses, NT-pro-BNP significantly correlated to age, LA dimensions, LA function indexes, EF, and functional class. At multivariate analysis, LV EF and M- or B-Mode indexes of LA function were the only independent predictors of NT-pro-BNP values. A NT-pro-BNP cut-off of 1480 pg/mL identified LA dysfunction with 89% specificity and 54% sensitivity. CONCLUSION: In CHF patients with severely impaired systolic function, NT-pro-BNP levels reflect LA and LV dysfunction. These data should prompt studies to investigate the relationship between changes of LA function and NT-pro-BNP levels and their clinical value as prognostic and therapeutic targets in CHF.

[Sleep apnea and heart failure: pathophysiology, diagnosis and therapy]. / Apnee notturne e scompenso cardiaco: fisiopatologia, diagnosi e terapia.

Sleep apnea, defined as a pathologic pause in breathing during sleep >10 s, promotes the progression of chronic heart failure and may be a predictor of poor prognosis. It causes, in fact, several mechanical, hemodynamic, chemical and inflammatory changes that negatively compromise cardiovascular homeostasis of heart failure patients. Sleep apnea is recognized as sleep apnea syndrome when specific symptoms, such as sleepiness and headache during the daytime and snoring, are present and is diagnosed with an overnight test called polysomnography. There are two different forms of sleep apnea, central and obstructive. Breathing is interrupted by the loss of respiratory drive and the lack of respiratory effort in the central form, which affects about 40-60% of heart failure patients. In obstructive sleep apnea, breathing stops when throat muscles relax, despite respiratory effort. This form affects about 3% of the general population, while it is present in at least 30% of heart failure patients. The diagnosis of sleep disorders in heart failure becomes very important to help patients adopting lifestyle changes and starting specific therapies to improve quality of life and retard the progression of chronic heart failure.

[Inflammation and lipids in the coronary pathology. Risk factors, causes or therapeutic target?]. / Infiammazione e lipidi nella patologia coronarica. Fattori di rischio, cause scatenanti o target terapeutici?

The search for new risk markers of cardiovascular (CV) risk is continuous, aimed to improve its estimate. Among them, the measurement of C-reactive protein (CRP) levels seems the most promising one. CV risk evaluation systems as Reynolds score, integrating CPR dosage to classic risk factors, were shown to improve the detection of subjects at higher risk, who deserve a more effective CV prevention. The use of CRP as a guide in primary prevention was tested for the first time in the JUPITER study, a large randomized trial comparing rosuvastatin 20 mg and placebo. Admission criteria were based on the presence of an inflammatory status only (CRP >2 mg/l), aside from CV risk factors (LDL <130 mg/dl). Rosuvastatin 20 mg, compared to placebo, significantly reduced composite primary endpoint (CV mortality, myocardial infarction, ischemic stroke, hospitalization for unstable angina and myocardial revascularization). These results confirmed the continuous relationship between decreased cholesterol level and clinical benefit also in primary prevention. The high prevalence of metabolic syndrome in this study population confirmed the link between this condition and the presence of an inflammatory status, and the high incidence of events occurred in the placebo group suggests an important role of CRP in the detection of subjects at higher CV risk. The greatest reduction of CV events was seen in the subgroup of patient who achieved the "double target" of both decreased lipids and inflammation marker, similarly to PROVE IT-TIMI 22 in secondary prevention. The presence of an inflammatory status may allow the detection of more vulnerable patients, where statin treatment may result in a greater benefit, as both LDL cholesterol and inflammatory status are reduced, and clinical CV events are consequently decreased.

Prognostic role of myocardial single photon emission computed tomography in the elderly.

The increase in average life expectancy will move the burden of coronary artery disease (CAD) to older patients. Myocardial perfusion imaging by single photon emission computed tomography (SPECT) has been extensively validated for diagnosis and prognostic evaluation in large population series. Yet, its use is usually limited in elderly patients in whom, despite increased absolute cardiovascular risk, diagnostic and therapeutic work-up is often underperformed. American College of Cardiology/American Heart Association guidelines recommend exercise ECG testing as the initial noninvasive method for assessment of CAD in patients with a normal or near-normal resting ECG, regardless of age. However, a considerable proportion of elderly patients is unable to reach an adequate workload during the exercise test and the majority of those undergoing for standard exercise treadmill score are classified as intermediate risk. In elderly patients, SPECT imaging may provide valuable diagnostic and prognostic information for clinical management. In particular, normal or near normal SPECT identifies elderly patients at low risk of major adverse cardiac events at the short-term follow-up.