na Valenti

Natriuretic peptides: An update on bioactivity, potential therapeutic use, and implication in cardiovascular diseases

The natriuretic peptide system includes three known peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They contribute to the regulation of cardiovascular homeostasis through diuretic, natriuretic, and vasodilatory properties. Among them, ANP has received particular attention because of its effects on blood pressure regulation and cardiac function. Although the potential for its therapeutic application in the treatment of hypertension and heart failure has been evaluated in several experimental and clinical investigations, no pharmacological approach directly targeted at modulation of ANP levels has ever reached the stage of being incorporated into clinical practice. Recently, ANP has also received attention as being a possible cardiovascular risk factor, particularly in the context of hypertension, stroke, obesity, and metabolic syndrome. Abnormalities in either peptide levels or peptide structure are thought to underlie its implied role in mediating cardiovascular diseases. Meanwhile, BNP has emerged as a relevant marker of left ventricular (LV) dysfunction and as a useful predictor of future outcome in patients with heart failure. This review deals with the major relevant findings related to the cardiovascular and metabolic effects of natriuretic peptides, to their potential therapeutic use, and to their role in mediating cardiovascular diseases.

Myocardial Salvage by CMR Correlates With LV Remodeling and Early ST-Segment Resolution in Acute Myocardial Infarction

OBJECTIVES The purpose of this study was to assess the association of myocardial salvage by cardiac magnetic resonance (CMR) with left ventricular (LV) remodeling and early ST-segment resolution in patients with acute myocardial infarction (MI). BACKGROUND Experimental studies revealed that MI size is strongly influenced by the extent of the area at risk (AAR), limiting its accuracy as a marker of reperfusion treatment efficacy in acute MI studies. Hence, an index correcting MI size for AAR extent is warranted. T2-weighted CMR and delayed-enhancement CMR, respectively, enable the determination of AAR and MI size, and the myocardial salvage index (MSI) is calculated by correcting MI size for AAR extent. Nevertheless, the clinical value of CMR-derived MSI has not been evaluated yet. METHODS In a prospective cohort of 137 consecutive patients with acutely reperfused ST-segment elevation MI, CMR was performed at 1 week and 4 months. T2-weighted CMR was used to quantify AAR, whereas MI size was detected by delayed-enhancement imaging. MSI was defined as AAR extent minus MI size divided by AAR extent. Adverse LV remodeling was defined as an increase in LV end-systolic volume of >or=15%. The degree of ST-segment resolution 1 h after reperfusion was also calculated. RESULTS AAR extent was consistently larger than MI size (32+/-15% of LV vs. 18+/-13% of LV, p<0.0001), yielding an MSI of 0.46+/-0.24. MI size was closely related to AAR extent (r=0.81, p<0.0001). After correction for the main baseline characteristics by multivariate analyses, MSI was a major and independent determinant of adverse LV remodeling (odds ratio: 0.64; 95% confidence interval: 0.49 to 0.84, p=0.001) and was independently associated with early ST-segment resolution (B coefficient=0.61, p<0.0001). CONCLUSIONS In patients with reperfused ST-segment elevation MI, CMR-derived MSI is independently associated with adverse LV remodeling and early ST-segment resolution, opening new perspectives on its use in studies testing novel reperfusion strategies.

Association of renal damage with cardiovascular diseases is independent of individual cardiovascular risk profile in hypertension: Data from the Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease study

Objectives In the past years, several risk charts have been created to increase the accuracy of cardiovascular risk stratification. The most widely used and validated algorithms do not included target organ damage as risk prediction. The aim of the present study was to evaluate whether preclinical renal damage is associated with cardiovascular diseases independently of individual risk profile assessed by risk charts. Methods The study population was that of Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease, a large observational study conducted on hypertensive patients in Italy. The Framingham Risk Score (FRS), Systematic COronary Risk Estimation (SCORE) and Progetto Cuore Risk Score (Progetto Cuore RS) were computed in each eligible patient. Chronic kidney disease was defined by the presence of albuminuria or by a reduction of glomerular filtration rate. Results Study participants were categorized to have low, medium and high risk according to the tertiles of the three charts. Prevalence of total cardiovascular diseases progressively and significantly increased according to the degrees of risk assessed by the three charts, the highest prevalence being in participants with a high-risk profile (both high and medium vs. low risk <0.01 for FRS, SCORE and Progetto Cuore RS). The presence of chronic kidney disease was associated with total cardiovascular diseases, independently of FRS (odds ratio 1.64, 95% confidence interval 1.33–2.02, P < 0.001), SCORE (odds ratio 1.55, 95% confidence interval 1.21–1.98, P < 0.001) and Progetto Cuore RS (odds ratio 1.59, 95% confidence interval 1.22–2.07, P < 0.001). Moreover, inclusion of renal damage in the logistic model significantly increased the accuracy of the FRS (P < 0.05), SCORE (P < 0.01) and Progetto Cuore RS (P < 0.01) to identify patients with overt cardiovascular diseases. Conclusion Identification of patients with preclinical renal damage should be encouraged in the hypertension cardiovascular risk stratification setting in order to achieve a more accurate individual risk computation. The presence of renal damage could improve cardiovascular risk prediction over the widely used risk stratification charts.

A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling

Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.

Prognostic Utility of Coronary Artery Calcium Scoring in Active Smokers: A 15-Year Follow-Up Study

Coronary artery calcium (CAC) is a frequent finding in smokers, and it is a marker of accelerated atherosclerosis in this population.1 Prior research has demonstrated a higher rate of five to ten year estimated all-cause mortality in smokers with CAC as compared to smokers without CAC.2,3 However, previous studies have produced limited insight regarding the long-term efficacy of CAC for risk stratification in smokers. This study therefore sought to examine the association between smoking, CAC, and all-cause mortality over a 15-year period. The study population was a cohort of 4,143 consecutive asymptomatic patients aged 55 and older (mean 63.2±6.6 years, range 55–99) without known coronary artery disease (CAD) who had been referred by their physician for CAC testing between 1991 and 2004. All study participants completed a baseline questionnaire of demographic characteristics and baseline cardiovascular risk factors. Cigarette smoking was considered present if a subject was an active smoker at the time of CAC scanning. CAC measurement was performed by electron beam computed tomography (EBCT) at three different centers in the United States using standard methods as previously described.3 Each calcified lesion was scored using the method developed by Agatston et al.4 All individuals provided informed consent for a pre-test interview, CAC testing, and follow-up. The study received approval from the appropriate Human Investigations Committee and conforms to the 1975 Declaration of Helsinki. The primary endpoint was all-cause mortality. Individuals masked to baseline data ascertained mortality status using the Social Security Death Index with 100% mortality ascertainment among study participants. For statistical analyses, the chi-square test was employed for comparison of categorical variables. Between-group comparisons for continuous variables were computed using an independent samples t-test or Mann-Whitney U test as appropriate. A Kaplan-Meier survival curve with log-rank test compared survival rates for smokers versus nonsmokers, according to the presence and severity of CAC. Cox proportional hazard regression reporting hazard ratios (HR) with 95% confidence intervals (95% CI) were used to estimate all-cause mortality adjusting for age, sex, diabetes, hypertension, dyslipidemia, and family history of premature CAD. All Cox models were stratified according to smoking status as well as the presence or absence (Model 1) or severity (Model 2) of CAC. As there was no significant interaction effect between sex and CAC, analyses stratified by sex were not performed. Assumption of proportional hazards was evaluated using Schoenfeld residuals. Statistical analyses were performed using SAS version 9.3 software (SAS Institute Inc., Cary, NC). A two-tailed p-value <0.05 was considered statistically significant. The patients were followed on average for 14.5 years (interquartile range 13.5–15.3). At the time of CAC assessment, 39% were self-reported active smokers. Of 553 deaths that occurred, 270 (16.6%) and 283 (11.3%) were smokers and nonsmokers at the time of CAC scan, respectively. Smokers were more prone to a family history of premature CAD (70.7% vs 65.3%, p<0.001) and diabetes (10.4% vs 8.5%, p=0.04) as compared with nonsmokers (Table 1). Smokers had higher median CAC scores (19 vs 3, interquartile range 0–195, p<0.001) and increased CAC severity (p<0.001 for trend), while nonsmokers were more likely to have a CAC of 0 than smokers (47.8 vs. 38.7%, p<0.001). Table 1 Clinical Characteristics of Subjects Irrespective of smoking status, higher CAC severity was associated with heightened mortality risk over the course of this study (p<0.001 by log-rank) (Figure). In multivariable Cox hazard regression models, smokers with a CAC of zero had a nearly two-fold (HR 1.73, 95% CI = 1.20–2.50, p=0.003) increased risk of mortality (Table 2, Model 1). In the presence of any CAC, the adjusted risk of mortality was more than three-fold (HR 3.07, 95% CI = 2.32–4.07, p<0.001) higher in nonsmokers, while the adjusted risk of mortality was almost five-fold (HR 4.67, 95% CI = 3.52–6.20, p<0.001) higher among smokers. Similar findings were observed in patients without additional cardiac risk factors (e.g. hypertension, diabetes, dyslipidemia, family history of premature CAD). In both smokers and nonsmokers, the adjusted risk of death appeared to increase incrementally according to the severity of CAC (Table 2, Model 2). Figure Cumulative survival among non-smokers and smokers stratified by CAC score Table 2 Risk of all-cause death among non-smokers and smokers according to the presence and severity of coronary artery calcium Overall, we found that across nearly 15 years of follow-up, the presence of CAC remained strongly predictive of all-cause mortality in this cohort of older smokers, even in the absence of other cardiac risk factors. Our findings are consistent with prior studies of shorter duration demonstrating increased mortality in smokers with CAC.2,3 Furthermore, in contrast to the general population for which the absence of CAC (CAC=0) is associated with an excellent prognosis,5 in our study smokers with a CAC=0 remained at an elevated risk of death. As such, for smokers a CAC=0 should not be considered a “negative risk factor.”3 Our study was limited by its observational design. Prior smoking history and smoking intensity as measured by pack years were not obtained. Data were unavailable regarding cause-specific mortality, cardiovascular events, post-test changes in risk factors, downstream pharmacological therapy or smoking cessation. Future long-term prospective cohort studies are needed to address these limitations. However, this is the largest cohort of consecutive patients undergoing CAC screening for which outcome data are available. Our findings are timely in that many smokers aged 55–80 are poised to undergo annual lung cancer screening by low dose computed tomography (CT).6–8 There is a high correlation between CAC discovered by CT and ECG-gated CAC screening protocols.9 This study proposes a potential benefit in highlighting the presence of any CAC detected by CT, rather than considering it as an “incidental” finding. While further research regarding CAC in lung cancer screening cohorts is clearly needed, our findings indicate that smokers with CAC detected by CT are at elevated risk and warrant early and aggressive cardiac risk factor reduction.

Comparative safety and effectiveness of coronary computed tomography: Systematic review and meta-analysis including 11 randomized controlled trials and 19,957 patients

BACKGROUND/OBJECTIVES The clinical approach to suspected or established coronary artery disease (CAD) has been revolutionized in the last few decades by coronary computed tomography (coroCT). Yet, uncertainty persists on its comparative diagnostic and clinical effectiveness. We conducted a systematic review on randomized controlled trials (RCTs) of coroCT. METHODS We searched RCTs in PubMed and The Cochrane Library, extracting as outcomes of interest long-term rates of death, myocardial infarction, revascularization, and invasive coronary angiography. Effects were estimated with risk ratios (RR) and 95% confidence intervals. RESULTS A total of 11 trials were included, with 19,957 patients followed for a median of 6months. One trial focused on screening, 3 on stable CAD, and 7 on acute CAD. Meta-analysis showed that coroCT was associated with a trend toward fewer deaths or myocardial infarctions (RR=0.84 [0.70-1.01]) whereas no significant difference was found for the risk of death (RR=0.91 [0.71-1.18]). Conversely, the risk of myocardial infarction tended to be lower with coroCT at the overall analysis (RR=0.77 [0.59-1.02]), and this effect reached statistical significance in studies focusing on subjects with stable CAD (RR=0.69 [0.49-0.99]). These potential benefits were offset (or mediated) by a significant albeit modest increase in the need for invasive angiography (RR=1.36 [1.08-1.72]), and ensuing coronary revascularization (RR=1.76 [1.29-2.40]). CONCLUSIONS According to the current evidence base, coroCT is associated with an increased usage of invasive angiography and coronary revascularization when compared to standard of care, with possible benefits on nonfatal myocardial infarction, but without significant benefits on death or the composite of death or myocardial infarction.

Role of Computed Tomography for Diagnosis and Risk Stratification of Patients With Suspected or Known Coronary Artery Disease

Cardiac computed tomographic angiography (CCTA) has emerged as a powerful imaging modality for the detection and prognostication of individuals with suspected coronary artery disease. Because calcification of coronary plaque occurs in proportion to the total atheroma volume, the initial diagnostic potential of CCTA focused on the identification and quantification of coronary calcium in low- to intermediate-risk individuals, a finding that tracks precisely with the risk of incident adverse clinical events. Beyond noncontrast detection of coronary calcium, CCTA using iodinated contrast yields incremental information about the degree and distribution of coronary plaques and stenosis, as well as vessel wall morphology and atherosclerotic plaque features. This additive information offers the promise of CCTA to provide a more comprehensive view of total atherosclerotic burden because it relates to myocardial ischemia and future adverse clinical events. Furthermore, emerging data suggest the prognostic and diagnostic importance of stenosis severity detection and atherosclerotic plaque features described by CCTA including positive remodeling, low-attenuation plaque, and spotty calcification, which have been associated with the vulnerability of plaque. We report a summary of the evidence supporting the role of CCTA in the detection of subclinical and clinical coronary artery disease in both asymptomatic and symptomatic patients and discuss the potential of CCTA to augment the identification of at-risk individuals. CCTA and coronary artery calcium scoring offer the ability to improve risk stratification, discrimination, and reclassification of the risk in patients with suspected coronary artery disease and to noninvasively determine the measures of stenosis severity and atherosclerotic plaque features.

Rac1 Pharmacological Inhibition Rescues Human Endothelial Dysfunction

Background Endothelial dysfunction contributes significantly to the development of vascular diseases. However, a therapy able to reduce this derangement still needs to be identified. We evaluated the effects of pharmacological inhibition of Rac1, a small GTPase protein promoting oxidative stress, in human endothelial dysfunction. Methods and Results We performed vascular reactivity studies to test the effects of NSC23766, a Rac1 inhibitor, on endothelium‐dependent vasorelaxation of saphenous vein segments collected from 85 subjects who had undergone surgery for venous insufficiency and from 11 patients who had undergone peripheral vascular surgery. The endothelium‐dependent vasorelaxation of the varicose segments of saphenous veins collected from patients with venous insufficiency was markedly impaired and was also significantly lower than that observed in control nonvaricose vein tracts from the same veins. Rac1 activity, reactive oxygen species levels, and reduced nicotine adenine dinucleotide phosphate (NADPH) oxidase activity were significantly increased in varicose veins, and NSC23766 was able to significantly improve endothelium‐dependent vasorelaxation of dysfunctional saphenous vein portions in a nitric oxide–dependent manner. These effects were paralleled by a significant reduction of NADPH oxidase activity and activation of endothelial nitric oxide synthase. Finally, we further corroborated this data by demonstrating that Rac1 inhibition significantly improves venous endothelial function and reduces NADPH oxidase activity in saphenous vein grafts harvested from patients with vascular diseases undergoing peripheral bypass surgery. Conclusions Rac1 pharmacological inhibition rescues endothelial function and reduces oxidative stress in dysfunctional veins. Rac1 inhibition may represent a potential therapeutic intervention to reduce human endothelial dysfunction and subsequently vascular diseases in various clinical settings.

Cardiac Magnetic Resonance Evaluation of the Impact of Interventricular and Intraventricular Dyssynchrony on Cardiac Ventricular Systolic and Diastolic Function in Patients With Isolated Left Bundle Branch Block

Ventricular dyssynchrony significantly impairs cardiac performance. However, the independent role of interventricular dyssynchrony (interVD) and intraventricular dyssynchrony (intraVD) in the development of abnormalities of systolic and diastolic performance is unclear. Cardiac magnetic resonance imaging was performed in 39 patients with left bundle branch block and 13 healthy patients. Structural and functional parameters of the left ventricle and degrees of interVD and intraVD were measured. We found that interVD was inversely correlated with left ventricular (LV) ejection fraction (r = -0.8, p <0.0001) and positively correlated with LV end-diastolic volume (r = 0.4, p <0.01), LV end-systolic volume (r = 0.6, p <0.0001), and LV mass (r = 0.4, p <0.01), thus indicating that interVD significantly affects systolic function and favors ventricular remodeling. Multivariate analysis further confirmed that interVD was an independent predictor of systolic dysfunction. Interestingly, we found that interVD was not associated with abnormalities of diastolic performance. Conversely, we found that intraVD significantly impaired diastolic function, whereas it had no effect on systolic function. IntraVD was inversely correlated with peak filling rate (r = -0.7, p <0.0001) and 1/2 filling fraction (r = 0.4, p = 0.04) and positively correlated with time to peak filling rate (r = 0.6, p <0.0001), validated parameters of diastolic function. Multivariate analysis confirmed that intraVD was an independent predictor of diastolic dysfunction. In conclusion, our study suggests that the 2 components of ventricular dyssynchrony differently affect cardiac performance. If confirmed in prospective studies, our results may help to predict the prognosis of patients with left bundle branch block and different degrees of interVD and intraVD, particularly those subjects undergoing cardiac resynchronization therapy.

The Impact of Environmental Factors in Influencing Epigenetics Related to Oxidative States in the Cardiovascular System

Oxidative states exert a significant influence on a wide range of biological and molecular processes and functions. When their balance is shifted towards enhanced amounts of free radicals, pathological phenomena can occur, as the generation of reactive oxygen species (ROS) in tissue microenvironment or in the systemic circulation can be detrimental. Epidemic chronic diseases of western societies, such as cardiovascular disease, obesity, and diabetes correlate with the imbalance of redox homeostasis. Current advances in our understanding of epigenetics have revealed a parallel scenario showing the influence of oxidative stress as a major regulator of epigenetic gene regulation via modification of DNA methylation, histones, and microRNAs. This has provided both the biological link and a potential molecular explanation between oxidative stress and cardiovascular/metabolic phenomena. Accordingly, in this review, we will provide current insights on the physiological and pathological impact of changes in oxidative states on cardiovascular disorders, by specifically focusing on the influence of epigenetic regulation. A special emphasis will highlight the effect on epigenetic regulation of humans current life habits, external and environmental factors, including food intake, tobacco, air pollution, and antioxidant-based approaches. Additionally, the strategy to quantify oxidative states in humans in order to determine which biological marker could best match a subjects profile will be discussed.