Mitochondrial a Kinase Anchor Proteins in Cardiovascular Health and Disease: A Review Article on Behalf of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology.

Second messenger cyclic adenosine monophosphate (cAMP) has been found to regulate multiple mitochondrial functions, including respiration, dynamics, reactive oxygen species production, cell survival and death through the activation of cAMP-dependent protein kinase A (PKA) and other effectors. Several members of the large family of A kinase anchor proteins (AKAPs) have been previously shown to locally amplify cAMP/PKA signaling to mitochondria, promoting the assembly of signalosomes, regulating multiple cardiac functions under both physiological and pathological conditions. In this review, we will discuss roles and regulation of major mitochondria-targeted AKAPs, along with opportunities and challenges to modulate their functions for translational purposes in the cardiovascular system.

Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology.

Despite important advances in diagnosis and treatment, heart failure (HF) remains a syndrome with substantial morbidity and dismal prognosis. Although implementation and optimization of existing technologies and drugs may lead to better management of HF, new or alternative strategies are desirable. In this regard, basic science is expected to give fundamental inputs, by expanding the knowledge of the pathways underlying HF development and progression, identifying approaches that may improve HF detection and prognostic stratification, and finding novel treatments. Here, we discuss recent basic science insights that encompass major areas of translational research in HF and have high potential clinical impact.

Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis.

AIMS: Gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE). METHODS AND RESULTS: MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26 167 subjects. The mean follow-up in our study population was 4.3 ± 1.5 years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15 662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, P < 0.0001, I2 = 94%] and MACCE (5 studies for 6 cohorts enrolling 13 944 subjects, HR: 1.67, 95% CI: 1.33-2.11, P < 0.00001, I2 = 46%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10 µmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), P < 0.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. CONCLUSIONS: This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

MicroRNA-133 modulates the ß1-adrenergic receptor transduction cascade.

RATIONALE: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate ß-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of ß-adrenergic receptors leads to impaired cardiac function, and ß-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. OBJECTIVE: To determine whether miR-133 affects ß-adrenergic receptor signaling during progression to heart failure. METHODS AND RESULTS: Based on bioinformatic analysis, ß1-adrenergic receptor (ß1AR) and other components of the ß1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective ß1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic ß1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice. CONCLUSIONS: miR-133 controls multiple components of the ß1AR transduction cascade and is cardioprotective during heart failure.

Transradial approach for the endovascular treatment of type I endoleak after aortic aneurysm repair: a case report.

BACKGROUND: Endovascular repair of aortic aneurysms (EVAR) is obtained through the positioning of an aortic stent-graft, which excludes the aneurysmatic dilation. Type I endoleak is the most common complication, and it is caused by an incompetent proximal or distal attachment site, causing the separation between the stent-graft and the native arterial wall, and in turn creating direct communication between the aneurysm sac and the systemic arterial circulation. Endoleak occurrence is associated with high intrasac pressures, and requires a quick repair to prevent abdominal aortic aneurysm rupture. CASE PRESENTATION: We report the first case of a 80-year-old man undergoing percutaneous closure of a peri-graft endoleak (type I) by transcatheter embolization through radial arterial access. CONCLUSION: The transradial approach has been shown to be a safe and effective alternative to the traditional transfemoral approach. A decrease in vascular complications and improved patient comfort are the primary benefits of this technique in patients with previous EVAR.

Statins and the elderly: recent evidence and current indications.

Cardiovascular disease (CVD) is estimated to remain as the main cause of death in developed nations over the next 30 years, with increased prevalence in the older population. This is because the observed decline in the incidence of CVD owing to improvements in prevention has now been counterbalanced by the increased shift toward an older and thus more fragile population. Statin treatment reduces cardiovascular morbidity and mortality in middle-aged adults. However, few studies have included older individuals, particularly those aged 80 years or over. The adverse effects associated with high doses of statins and their interactions with other drugs may give rise to more problems in the elderly population. Evidence remains limited regarding the overall benefit of starting statin therapy in adults aged 80 and over; so that clinical judgment remains necessary in making the decision to use them. In this review, we present available evidence from randomized clinical trials, as well as relative community and post-approval data directly applicable to the management of CVD in the elderly, in both primary and secondary prevention. Also discussed is the latest evidence regarding the putative protective effects of statins on senile dementia and the relationship between statin treatment and cancer.

Use of statins in lower extremity artery disease: a review.

BACKGROUND: Lower extremity artery disease (LE-PAD) is one of the most common manifestations of atherosclerosis, particularly in elderly patients, and it is related to a high cardiovascular risk. DESCRIPTION: It is well established that statin therapy is characterized by crucial benefits on cardiovascular system by limiting atherosclerotic progression and reducing cardiovascular events and mortality. A growing body of evidence support efficacy of statins in LE-PAD due to the ability of both reducing cardiovascular risk and improving walking distance and, hence, quality of life. Consequently, statin therapy should be considered in all LE-PAD patients and new LDL-cholesterol targets should be reached. CONCLUSIONS: Our opinion is that statin therapy remains still underutilized or with inadequate dosage, so therapy of LE-PAD patients should be improved to obtain all the demonstrated benefits of statins.

Abdominal aortic aneurysm in patients affected by intermittent claudication: prevalence and clinical predictors.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a frequent cause of death among elderly. Patients affected by lower extremity peripheral arterial disease (LE-PAD) seem to be particularly at high risk for AAA. We aimed this study at assessing the prevalence and the clinical predictors of the presence of AAA in a homogeneous cohort of LE-PAD patients affected by intermittent claudication. METHODS: We performed an abdominal ultrasound in 213 consecutive patients with documented LE-PAD (ankle/brachial index ≤ 0.90) attending our outpatient clinic for intermittent claudication. For each patient we registered cardiovascular risk factors and comorbidities, and measured neutrophil count. RESULTS: The ultrasound was inconclusive in 3 patients (1.4%), thus 210 patients (169 males, 41 females, mean age 65.9 ± 9.8 yr) entered the study. Overall, AAA was present in 19 patients (9.0%), with a not significant higher prevalence in men than in women (10.1% vs 4.9%, p = 0.300). Patients with AAA were older (71.2 ± 7.0 vs 65.4 ± 9.9 years, p = 0.015), were more likely to have hypertension (94.7% vs 71.2%, p = 0.027), and greater neutrophil count (5.5 [4.5 - 6.2] vs 4.1 [3.2 - 5.5] x 10(3)/µL, p = 0.010). Importantly, the c-statistic for neutrophil count (0.73, 95% CI 0.60 - 0.86, p = 0.010) was higher than that for age (0.67, CI 0.56-0.78, p = 0.017). The prevalence of AAA in claudicant patients with a neutrophil count ≥ 5.1 x 10(3)/µL (cut-off identified at ROC analysis) was as high as 29.0%. CONCLUSIONS: Prevalence of AAA in claudicant patients is much higher than that reported in the general population. Ultrasound screening should be considered in these patients, especially in those with an elevated neutrophil count.

Ankle/brachial index to everyone.

BACKGROUND: In the last years significant attention has been paid in identifying markers of subclinical atherosclerosis or of increased cardiovascular risk. METHOD: An abnormal ankle/brachial index (ABI) identifies patients affected by lower extremity peripheral arterial disease, and even more important, represents a powerful predictor of the development of future ischemic cardiovascular events. CONCLUSIONS: In our opinion, ABI is a cardiovascular risk prediction tool with very desirable properties that might become a routine measurement in clinical practice.

Endovascular treatment of lower extremity arteries is associated with an improved outcome in diabetic patients affected by intermittent claudication.

BACKGROUND: Lower extremity peripheral arterial disease (LE-PAD) is a highly prevalent condition among diabetic patients, associated with reduced walking capacity and a high incidence of cardiovascular events. Endovascular revascularization of lower extremities arteries improves walking performance and quality of life of diabetic patients affected by intermittent claudication, but few studies evaluated the impact of revascularization on cardiovascular outcome in this high-risk population. Accordingly, in the present study we evaluated if leg-ischemia resolution by effective lower limbs percutaneous revascularization can also impact cardiovascular outcome in a homogeneous group of diabetic patients affected by intermittent claudication. METHODS: 236 diabetic patients affected by LE-PAD at stage II of Fontaine's classification, with ankle/brachial index ≤ 0.90 and one or more hemodynamically significant stenosis in at least one artery of the ileo-femoro-popliteal axis were enrolled in the study. According to the Trans-Atlantic Inter Society Consensus II recommendations, 123 (52.1%) underwent percutaneous transluminal angioplasty (PTA group), while 113 (47.9%) underwent conservative medical therapy only (MT group). The incidence of major cardiovascular events (cardiovascular death, myocardial infarction, ischemic stroke, coronary or carotid revascularization) was prospectively analyzed with Kaplan-Meier curves and the risk of developing a cardiovascular event calculated by Cox analyses. RESULTS: No baseline difference in cardiovascular risk factors were observed between the PTA and MT groups, except for a lower prevalence of males in PTA group (74.8% vs. 85.8%, p=0.034). Furthermore, patients in the PTA group showed a worse walking capacity as expressed by maximum walking distance (108.7 ± 300.9 vs 378.4 ± 552.3 meters, p<0.001). During a median follow-up of 20 months (12.0-29.0), the incidence of cardiovascular events was markedly lower in patients in the PTA group with respect to patients in the MT group (7.3% vs. 22.1%, p=0.001), and patients of the MT group had at Cox analysis a 3.9 increased risk with respect to PTA group, after adjustment for potential confounding factors (95% CI 1.1-15.3, p=0.049). CONCLUSIONS: The present study shows that lower limbs revascularization of diabetic patients affected by intermittent claudication, in addition to improve walking performance, is associated with a reduction in the incidence of future major cardiovascular events.

Cardiovascular effects of treadmill exercise in physiological and pathological preclinical settings.

Exercise adaptations result from a coordinated response of multiple organ systems, including cardiovascular, pulmonary, endocrine-metabolic, immunologic, and skeletal muscle. Among these, the cardiovascular system is the most directly affected by exercise, and it is responsible for many of the important acute changes occurring during physical training. In recent years, the development of animal models of pathological or physiological cardiac overload has allowed researchers to precisely analyze the complex cardiovascular responses to stress in genetically altered murine models of human cardiovascular disease. The intensity-controlled treadmill exercise represents a well-characterized model of physiological cardiac hypertrophy because of its ability to mimic the typical responses to exercise in humans. In this review, we describe cardiovascular adaptations to treadmill exercise in mice and the most important parameters that can be used to quantify such modifications. Moreover, we discuss how treadmill exercise can be used to perform physiological testing in mouse models of disease and to enlighten the role of specific signaling pathways on cardiac function.

Total occlusion of the abdominal aorta in a patient with renal failure and refractory hypertension: a case report.

Total occlusion of the abdominal aorta is unusual, and potentially catastrophic. It occurs in patients with advanced atherosclerotic occlusive disease, and can cause severe ischemic manifestations, depending on the site of obstruction. Prompt and appropriate diagnostic and therapeutic approaches are important whenever this condition is suspected, in order to avoid a fatal outcome. The development of a complex network of collaterals may prevent the manifestation of acute ischemic phenomena, and cause a delay in diagnosis and treatment. Here we report the clinical case of a 59-year-old man who was referred to our Department for evaluation of renal failure and refractory hypertension. Ultrasonography and 99mTc-DTPA scintigraphy showed a shrunken, non-functioning left kidney, while CT angiography and aortography showed the complete occlusion of the aorta from below the right renal artery down to the bifurcation of both common iliac arteries, with a critical stenosis of the origin of the right renal artery, an occlusion of the left renal artery as well as of the origin of the inferior mesenteric artery. The patient was referred to the surgery department for aorto-bifemoral bypass surgery and re-implantation of the right renal artery.

Endovascular treatment of carotid artery stenosis: evidences from randomized controlled trials and actual indications.

Atherosclerotic stenosis of common and internal carotid arteries is a well-recognized risk factor for ischemic stroke, and revascularization has been proven to be the main tool of prevention, particularly for patients with stenosis-related symptoms. While for many years surgical carotid endarterectomy (CEA) has been considered the gold-standard strategy to restore vascular patency, recently the endovascular treatment through percutaneous angioplasty and stent implantation (CAS) has become a valid alternative. In the last years, interesting data about the comparison of these strategies have emerged. CAS seems to cause more peri-procedural strokes, but may also avoid many adverse events related to surgery and general anaesthesia, including peri-procedural myocardial infarction. For these reasons, it was initially considered a second-choice strategy to be adopted in patients for whom surgery was contraindicated. However, more recent trials have shown that CAS might be considered an effective alternative to CEA. Moreover, the rapid evolution of CAS technique and materials suggests its potential to improve outcome and possible superiority compared to CEA in the next future. Purpose of this review is to discuss the most recent clinical evidences concerning the treatment of carotid artery stenosis, with a special focus on the endovascular treatment.

The role of mitochondrial dynamics in cardiovascular diseases.

The process of mitochondrial dynamics is emerging as a core player in cardiovascular homeostasis. This process refers to the co-ordinated cycles of biogenesis, fusion, fission and degradation to which mitochondria constantly undergo to maintain their integrity, distribution and size. These mechanisms represent an early response to mitochondrial stress, confining organelle portions that are irreversibly damaged and preserving mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to myocardial damage and cardiac disease progression in a variety of disease models, including pressure overload, ischaemia/reperfusion and metabolic disturbance. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in cardiovascular diseases. In this review, we discuss the current evidence about the role of mitochondrial dynamics in cardiac pathophysiology, with a particular focus on the mechanisms underlying the development of cardiac hypertrophy and heart failure, metabolic and genetic cardiomyopathies, ischaemia/reperfusion injury, atherosclerosis and ischaemic stroke. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.

Transverse aortic constriction induces gut barrier alterations, microbiota remodeling and systemic inflammation.

Accumulating evidence suggests that modifications of gut function and microbiota composition might play a pivotal role in the pathophysiology of several cardiovascular diseases, including heart failure (HF). In this study we systematically analysed gut microbiota composition, intestinal barrier integrity, intestinal and serum cytokines and serum endotoxin levels in C57BL/6 mice undergoing pressure overload by transverse aortic constriction (TAC) for 1 and 4 weeks. Compared to sham-operated animals, TAC induced prompt and strong weakening of intestinal barrier integrity, long-lasting decrease of colon anti-inflammatory cytokine levels, significant increases of serum levels of bacterial lipopolysaccharide and proinflammatory cytokines. TAC also exerted effects on microbiota composition, inducing significant differences in bacterial genera inside Actinobacteria, Firmicutes, Proteobacteria and TM7 phyla as shown by 16S rDNA sequencing of fecal samples from TAC or sham mice. These results suggest that gut modifications represent an important element to be considered in the development and progression of cardiac dysfunction in response to TAC and support this animal model as a valuable tool to establish the role and mechanisms of gut-heart crosstalk in HF. Evidence arising in this field might identify new treatment options targeting gut integrity and microbiota components to face adverse cardiac events.

AngioJet rheolytic thrombectomy for acute superficial femoral artery stent or femoropopliteal by-pass thrombosis.

Thrombosis of superficial femoral artery (SFA) nitinol stents or polytetrafluoroethylene (PTFE) femoropopliteal bypass grafts after discontinuation of antiplatelet therapy is an emergent clinical challenge of acute limb ischemia (ALI), requiring immediate percutaneous intervention. Currently, there is no evidence-based approach for the management of such complications. We describe the cases of two patients presenting with ALI due to nitinol stent thrombosis after discontinuation of antiplatelet therapy and the case of a patient presenting with ALI due to PTFE femoropopliteal graft thrombosis in which limb salvage was obtained by AngioJet rheolytic thrombectomy and re-stenting. In both cases, the thrombus was successfully removed using the Possis AngioJet mechanical thrombectomy catheter and percutaneous transluminal angioplasty (PTA) was performed to recanalize two femoropopliteal nitinol stents and a femoropopliteal PTFE graft. In both cases, optimal angiographic result was obtained. To the best of our knowledge, these are the first three cases reporting the use of the AngioJet rheolytic thrombectomy in ALI due to stent or graft thrombosis. Taken together, these cases suggest that AngioJet rheolytic thrombectomy might represent a novel effective strategy in the percutaneous treatment of stent or graft thrombosis determining ALI.

Perivascular fibrosis and the microvasculature of the heart. Still hidden secrets of pathophysiology?

Perivascular fibrosis, the deposition of connective tissue around the vessels, has been demonstrated crucially involved in the development of cardiac dysfunction. Although cardiac fibrosis has been shown to be reversible under certain experimental conditions, effective anti-fibrotic therapies remain largely elusive. Therefore, perivascular fibrosis currently represents a major therapeutic target for cardiovascular diseases. The main topic of this review will be to address the mechanisms underlying perivascular fibrosis of the vasculature within the myocardium, with a special focus on perivascular fibrosis of small vessels, microvascular dysfunction and disease.

EGFR activation triggers cellular hypertrophy and lysosomal disease in NAGLU-depleted cardiomyoblasts, mimicking the hallmarks of mucopolysaccharidosis IIIB.

Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease caused by the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The defective lysosomal clearance of undigested HS results in dysfunction of multiple tissues and organs. We recently demonstrated that the murine model of MPS IIIB develops cardiac disease, valvular abnormalities, and ultimately heart failure. To address the molecular mechanisms governing cardiac dysfunctions in MPS IIIB, we generated a model of the disease by silencing NAGLU gene expression in H9C2 rat cardiomyoblasts. NAGLU-depleted H9C2 exhibited accumulation of abnormal lysosomes and a hypertrophic phenotype. Furthermore, we found the specific activation of the epidermal growth factor receptor (EGFR), and increased phosphorylation levels of extracellular signal-regulated kinases (ERKs) in NAGLU-depleted H9C2. The inhibition of either EGFR or ERKs, using the selective inhibitors AG1478 and PD98059, resulted in the reduction of both lysosomal aberration and hypertrophy in NAGLU-depleted H9C2. We also found increased phosphorylation of c-Src and a reduction of the hypertrophic response in NAGLU-depleted H9C2 transfected with a dominant-negative c-Src. However, c-Src phosphorylation remained unaffected by AG1478 treatment, posing c-Src upstream EGFR activation. Finally, heparin-binding EGF-like growth factor (HB-EGF) protein was found overexpressed in our MPS IIIB cellular model, and its silencing reduced the hypertrophic response. These results indicate that both c-Src and HB-EGF contribute to the hypertrophic phenotype of NAGLU-depleted cardiomyoblasts by synergistically activating EGFR and subsequent signaling, thus suggesting that EGFR pathway inhibition could represent an effective therapeutic approach for MPS IIIB cardiac disease.

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus.

BACKGROUND: Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho-related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus. METHODS AND RESULTS: We used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia-induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho-associated coiled-coil serine/threonine kinase-1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs. CONCLUSIONS: Our data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.

Effects of Carvedilol Versus Metoprolol on Platelet Aggregation in Patients With Acute Coronary Syndrome: The PLATE-BLOCK Study.

Platelet aggregation plays a pivotal role in acute coronary syndrome (ACS). In this setting, ß-blockers (BBs) are used to counteract the effects of catecholamines on heart. Circulating catecholamines can also potentiate platelet reactivity, mainly through α2- and ß2-adrenoceptors on human platelets' surface, thus BB may affect platelet aggregation; however, the effects of different BBs on platelet aggregation in contemporary-treated patients with ACS have been poorly investigated. One hundred patients with ACS on dual antiplatelet therapy with aspirin and ticagrelor were randomized to receive treatment with carvedilol, a nonselective BB (n = 50), or metoprolol, a selective ß1-blocker (n = 50), at maximum tolerated dose. Light transmission aggregometry was performed at randomization (T0) and at 30-day follow-up (T30), and the results were expressed as a percentage of maximum platelet aggregation (MPA). The primary end point was epinephrine-induced MPA at 30 days. Patients were predominantly men (80%), and mean age was 57.3 ± 9.7 years. The 2 randomized groups were well balanced for baseline characteristics. At T0, mean MPA was similar between the groups (18.96 ± 9.05 vs 18.32 ± 9.21 with 10 µM epinephrine, 14.42 ± 9.43 vs 15.98 ± 10.08 with 20 µM adenosine diphophate (ADP), and 13.26 ± 9.83 vs 14.30 ± 9.40 with 10 µM ADP for carvedilol and metoprolol, respectively, all p = NS). At 30 days, platelet aggregation induced by epinephrine was significantly lower in the carvedilol group than in the metoprolol group (23.52 ± 10.25 vs 28.72 ± 14.37, p = 0.04), with a trend toward the lower values of ADP-induced MPA (20 µM ADP 19.42 ± 13.84 vs 24.16 ± 13.62, p = 0.09; 10 µM ADP 19.12 ± 12.40 vs 22.57 ± 13.59, p = 0.19). In conclusion, carvedilol, a nonselective BB, reduces residual platelet reactivity in patients with ACS compared with the selective BB, metoprolol.