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Background: Emerging evidence suggests that elevated circulating levels of HDL-C (high-density lipoprotein cholesterol) could be linked to an increased mortality risk. However, to the best of our knowledge, the relationship between HDL-C and specific cardiovascular events has never been investigated in patients with hypertension. Methods: To fill this knowledge gap, we analyzed the relationship between HDL-C levels and cardiovascular events in hypertensive patients within the Campania Salute Network in Southern Italy. Results: We studied 11 987 patients with hypertension, who were followed for 25 534 person-years. Our population was divided in 3 groups according to the HDL-C plasma levels: HDL-C80 mg/dL (high HDL-C). At the follow-up analysis, adjusting for potential confounders, we observed a total of 245 cardiovascular events with a significantly increased risk of cardiovascular events in the low HDL-C group and in the high HDL-C arm compared with the medium HDL-C group. The spline analysis revealed a nonlinear U-shaped association between HDL-C levels and cardiovascular outcomes. Interestingly, the increased cardiovascular risk associated with high HDL-C was not confirmed in female patients. Conclusions: Our data demonstrate that there is a U-shaped association between HDL-C and the risk of cardiovascular events in male patients with hypertension.

Supplementary Figure S2 from Haploinsufficiency of the Hmga1 Gene Causes Cardiac Hypertrophy and Myelo-Lymphoproliferative Disorders in Mice

The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by murine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmga1 gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in HMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies. (Cancer Res 2006; 66(5): 2536-43)

Materials and Methods, Suppl. References, Table S1, and Legends to Figures S1 & S2.

Background: Arterial hypertension causes cardiac functional and structural alterations. In hypertensive patients without flow-limiting epicardial coronary artery disease, we investigated possible relationships between positron emission tomography/computed tomography–derived myocardial blood flow (MBF) and echocardiographic parameters of left ventricular (LV) performance, including mechano-energetic efficiency indexed for myocardial mass (MEEi). Methods: Seventy-eight patients with hypertensive without flow-limiting epicardial coronary artery disease underwent echocardiography, including MEEi computation, and cardiac positron emission tomography/computed tomography with assessment of MBF/mass ratio at rest and after stress and myocardial flow reserve. The lowest MEEi tertile (MEEi Results: Patients in the lowest MEEi tertile were older, had higher systolic blood pressure and body mass index. They also had higher prevalence of LV hypertrophy, whereas lower resting and stress MBF/mass ratio. MEEi was significantly correlated with both resting (r=0.51; P P P P =0.003) and resting (beta coefficient=0.35; P =0.008) MBF/mass ratio remained significant. Conclusions: In patients with hypertensive without flow-limiting epicardial coronary artery disease, low values of MEEi could detect an early LV dysfunction involving an impairment of both resting and hyperemic MBF/mass ratios. MEEi has the advantage of simpler detection, cheaper costs than positron emission tomography/computed tomography, and a lack of radiation exposure. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02211365.

The "Medical Assistance in Contextual Awareness" (AMICO) project proposes an infrastructure, called an "instrumented environment", consisting of the home environment and the person, both of which are suitably equipped with sensors, a telemedicine service platform (in the Internet of Things) and a Robot who acts as a mediator/master between the person, the surrounding environment and the external environment. This infrastructure, oriented to the citizen's well-being, can offer both services oriented to the person in his home environment, monitoring their behavior and psycho-physical state, and telemedicine services to support the remote monitoring of citizens affected by a cardiovascular event undergoing rehabilitation therapies from part of doctors or caregiver.

Coronary artery disease (CAD) continues to be the leading cause of mortality and morbidity in developed countries. Assessment of pre-test probability (PTP) based on patient's characteristics, gender and symptoms, help to identify more accurate patient's clinical likelihood of coronary artery disease. Consequently, non-invasive imaging tests are performed more appropriately to rule in or rule out CAD rather than invasive coronary angiography (ICA). Coronary computed tomography angiography (CCTA) is the first-line non-invasive imaging technique in patients with suspected CAD and could be used to plan and guide coronary intervention. Invasive coronary angiography remains the gold-standard method for the identification and characterization of coronary artery stenosis. However, it is recommended in patients where the imaging tests are non-conclusive, and the clinical likelihood is very high, remembering that in clinical practice, approximately 30 to 70% of patients with symptoms and/or signs of ischemia, referred to coronary angiography, have non obstructive coronary artery disease (INOCA). In this contest, physiology and imaging-guided revascularization represent the cornerstone of contemporary management of chronic coronary syndromes (CCS) patients allowing us to focus specifically on ischemia-inducing stenoses. Finally, we also discuss contemporary medical therapeutic approach for secondary prevention. The aim of this review is to provide an updated diagnostic and therapeutic approach for the management of patients with stable coronary artery disease.

Nowadays, there are robust clinical and pathophysiological evidence supporting the beneficial effects of physical activity on cardiovascular (CV) system. Thus, the physical activity is considered a key strategy for CV prevention. In fact, exercise training exerts favourable effects on all risk factors for CV diseases (i.e. essential hypertension, type 2 diabetes mellitus, hypercholesterolemia, obesity, metabolic syndrome, etc…). In addition, all training modalities such as the aerobic (continuous walking, jogging, cycling, etc.) or resistance exercise (weights), as well as the leisure-time physical activity (recreational walking, gardening, etc) prevent the development of the major CV risk factors, or delay the progression of target organ damage improving cardio-metabolic risk. Exercise training is also the core component of all cardiac rehabilitation programs that have demonstrated to improve the quality of life and to reduce morbidity in patients with CV diseases, mostly in patients with coronary artery diseases. Finally, it is still debated whether or not exercise training can influence the occurrence of atrial and ventricular arrhythmias. In this regard, there is some evidence that exercise training is protective predominantly for atrial arrhythmias, reducing the incidence of atrial fibrillation. In conclusion, the salutary effects evoked by physical acitvity are useful in primary and secondary CV prevention.

Background Emerging evidence suggests that elevated circulating levels of HDL-C (high-density lipoprotein cholesterol) could be linked to an increased mortality risk. However, to the best of our knowledge, the relationship between HDL-C and specific cardiovascular events has never been investigated in patients with hypertension. Methods To fill this knowledge gap, we analyzed the relationship between HDL-C levels and cardiovascular events in hypertensive patients within the Campania Salute Network in Southern Italy. Results We studied 11 987 patients with hypertension, who were followed for 25 534 person-years. Our population was divided in 3 groups according to the HDL-C plasma levels: HDL-C80 mg/dL (high HDL-C). At the follow-up analysis, adjusting for potential confounders, we observed a total of 245 cardiovascular events with a significantly increased risk of cardiovascular events in the low HDL-C group and in the high HDL-C arm compared with the medium HDL-C group. The spline analysis revealed a nonlinear U-shaped association between HDL-C levels and cardiovascular outcomes (Figure 1). Interestingly, the increased cardiovascular risk associated with high HDL-C was not confirmed in female patients. Conclusions Our data demonstrate that there is a U-shaped association between HDL-C and the risk of cardiovascular events in male patients with hypertension.

Background Chronic left ventricular (LV) pressure overload determines both morphological and functional alterations in the heart and in the vascular system with occurrence of LV hypertrophy, coronary rarefaction and metabolic impairment, predisposing to heart failure. We aim at investigating early cardiac involvement in hypertensive disease by both Positron emission tomography (PET) and echo assessment and possible associations between alterations of PET-derived myocardial blood flow (MBF) and echocardiographic parameters of LV performance including mechano-energetic efficiency indexed for myocardial mass (MEEi), in a population of symptomatic hypertensive patients without flow-limiting epicardial coronary artery disease (CAD). Methods The study population included 78 symptomatic hypertensive patients without flow-limiting epicardial CAD. All patients underwent standard echocardiographic assessment, including evaluation of LV MEEi, and PET assessment with evaluation of MBF and MBF/mass ratio at rest and after stress and myocardial flow reserve (MFR). Results The study population included 67% males, 55% with dyslipidaemia, 42% with smoking habits and 21% obese. Prevalence of LV hypertrophy was of 43%. Among parameters of LV systolic performance, hyperaemic MBF/mass ratio resulted significantly correlated with LV MEEi (r=0.54, p In a multiple linear regression analysis, after adjusting for sex, systolic blood pressure, prevalence of LV hypertrophy and therapy with diuretics, the association between LV MEEi and hyperaemic MBF/mass ratio remained significant (beta coefficient =0.40, p=0.007). In a subsequent multivariate model, adjusting for the same confounders, by replacing hyperaemic MBF/mass ratio with resting MBF/mass ratio, LV MEEi and resting MBF/mass ratio continued to be significantly associated (beta coefficient =0.32, p=0.015). Conclusions In a population of hypertensive patients without flow-limiting epicardial CAD, an early myocardial impairment possibly related to coronary rarefaction and inadequate angiogenesis contributing to the altered myocardial metabolic demand and efficacy is detectable by both PET and echo-derived LV MEEi. Indeed, an independent association between LV MEEi and both MBF/mass ratio at rest and after stress exists, LV MEEi having the advantage over PET of being easily derived from standard echocardiography and not needing radiation exposure.

Arterial hypertension represents a systemic burden, and it is responsible of various morphological, functional and tissue modifications affecting the heart and the cardiovascular system. Advanced imaging techniques, such as speckle tracking and three-dimensional echocardiography, cardiac magnetic resonance, computed tomography and PET-computed tomography, are able to identify cardiovascular injury at different stages of arterial hypertension, from subclinical alterations and overt organ damage to possible complications related to pressure overload, thus giving a precious contribution for guiding timely and appropriate management and therapy, in order to improve diagnostic accuracy and prevent disease progression. The present review focuses on the peculiarity of different advanced imaging tools to provide information about different and multiple morphological and functional aspects involved in hypertensive cardiovascular injury. This evaluation emphasizes the usefulness of the emerging multiimaging approach for a comprehensive overview of arterial hypertension induced cardiovascular damage.

An empathetic approach may be particularly useful in patients with therapy-resistant hypertension (TRH), defined as the failure to achieve target blood pressure (BP) despite a maximal doses of 3 antihypertensive drugs including a diuretic. However, the effects of therapeutic concordance have not been determined in hypertensive patients.We designed a study to explore the impact of therapeutic concordance in patients with TRH, who were included in an intervention arm based on a protocol in which trained personnel periodically verified the pharmacological regimen of these patients.From a cohort of 5331 hypertensive patients followed-up for 77.64 ± 34.44 months, 886 subjects were found to have TRH; of these, 322 had apparent TRH (aTRH: uncontrolled office BP but optimal home BP) and 285 refused to participate in a second follow-up study, yielding a population of 279 patients with true TRH (tTRH). These tTRH patients were followed according to the therapeutic concordance protocol for 91.91 ± 54.7 months, revealing that 210 patients (75.27%) remained with uncontrolled BP (uncontrolled tTRH, Group I) while 69 patients (24.73%) reached an optimal BP control (average BP140/90 mmHg in at least 50% of follow-up visits, Group II). Strikingly, at the end of the second follow-up, the percentage of patients displaying a decline in kidney function was significantly smaller in Group II than in Group I (8.5% vs 23.4%, p 0.012).Taken together, our findings indicate for the first time that therapeutic concordance significantly improves the outcome of antihypertensive treatment in a population of patients with TRH.

Background Coronary microvascular dysfunction is a powerful prognostic factor in patients with coronary artery disease. We investigated the role of reactive digital hyperemia peripheral arterial tonometry (RH-PAT) as a non-invasive tool to identify patients with impaired coronary microvasculature. Methods Patients undergoing elective coronary angiography were consecutively assessed for peripheral microvascular endothelial function before coronary angiography: both the Reactive Hyperemic Index (RHI) and the Framingham reactive hyperemic index (Endoscore) were measured. During coronary angiography, the Index of microvascular resistance (IMR) was measured in all patients, and an IMR value > 25 identified patients with coronary microvascular impairment. Results A total of 47 patients with chronic coronary syndromes candidate to coronary angiography were included. Those with coronary microvascular impairment (n = 18 [38%]) presented with significantly lower RHI (1.68 ± 0.38 vs. 1.94 ± 0.93, p = 0.04) and Endoscore 0.50 ± 0.23 vs. 0.64 ± 0.23, p = 0.04) values as compared with patients with preserved coronary microvasculature. A significant relationship was observed between IMR with both RHI (r = 0.35, p = 0.02) and Endoscore (r = 0.34, p = 0.02). At the multivariable analysis, RHI and Endoscore were the only independent predictors of an IMR > 25. Conclusions Our study demonstrates that digital reactive hyperemia indexes are lower in patients with high IMR values, suggesting a role for RH-PAT as non-invasive tool for identifying patients with coronary microvascular impairment.

AIMS Adherence to medical therapy following acute coronary syndrome (ACS) affects a patient's prognosis. In this cohort study, we sought to assess the factors that could affect a patient's adherence to therapy after ACS. METHODS We prospectively collected information from patients (N = 964) hospitalized at the coronary care unit of the Federico II University Hospital, from 1 January 2015 to 30 June 2017, for ACS. Adherence to three classes of drugs including statins, antiplatelets [dual or single antiplatelet agent (SAPT)] and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) and their composites were assessed at 1 month, 1 and 2 years after discharge. RESULTS At 30 days adherence to prescribed therapy was 94.4% for dual antiplatelet therapy (DAPT), 78.2% for statins, 92.7% for ACE-I/ARB and 70.7% for multitherapy. At 1 year, it was 91.1% for DAPT, 81.2% for ACE-I/ARB, 84.9% for statins and 71.4% for multitherapy. At 2 years, it was 97.1% for SAPT, 78.1% for ACE-I/ARB, 91.8% for statins, 72.8% for multitherapy. Multivariable logistic analysis demonstrated that at each time point, a telephone follow-up assessment predicts nonadherence to multitherapy and that a percutaneous coronary intervention at the index hospitalization is an independent predictor of adherence to composite therapy at 1 month and 1 year. CONCLUSION Up to 2 years after ACS, three out of four patients are adherent to multitherapy prescription; percutaneous coronary intervention during the index hospitalization improves a patient's adherence, whereas telephone follow-up is associated with reduced adherence to multitherapy.Campania Salute Network Registry (Clinical Trials.gov Identifier: NCT02211365).

Background: Elderly status is steadily increasing among patients with acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 receptor inhibitor is the cornerstone of treatment to prevent recurrent thrombotic complications in patients with ACS. However, DAPT in older patients is challenged by a concurrent heightened risk of ischemia and bleeding. The aim of this study is to evaluate the pharmacodynamic and pharmacokinetic profile of a lower dose of ticagrelor (60 mg twice daily) among elderly patients during the early phase of ACS. Study Design: PLINY THE ELDER (PLatelet INhibition with two different doses of potent P2y12 inhibitors in THE ELDERly population) (NCT04739384) is a prospective, randomized, open-label, crossover trial to evaluate the non-inferiority of a lower dose of ticagrelor (60 mg twice daily) compared with a standard dose (90 mg twice daily) among elderly patients with ACS undergoing percutaneous coronary intervention (PCI). A total of 50 patients, aged 75 years or more, with indication to potent P2Y12 receptor inhibitors will be randomized within 3 days from PCI for the index ACS. Patients with indication to oral anticoagulant therapy, treatment with glycoprotein IIb/IIIa inhibitors, or active bleeding will be excluded. The primary endpoint is platelet reactivity determined by P2Y12 reaction units (PRU) (VerifyNow, Accumetrics, San Diego, CA, USA) after treatment with ticagrelor 60 or 90 mg twice daily for 14 days. Secondary endpoints will include other pharmacodynamic tests of ADP-induced aggregation (light transmittance aggregometry and multiple electrode aggregometry) and determination of pharmacokinetic profile (plasma levels of ticagrelor and its metabolite AR-C124910XX) by high performance liquid chromatography-tandem mass spectrometry. Conclusions: The PLINY THE ELDER trial will determine whether a lower dose of ticagrelor confers non-inferior platelet inhibition compared with the standard dose in the early phase of ACS among elderly patients undergoing PCI, informing future clinical investigation.

INTRODUCTION: The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y12 inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI).OBJECTIVE: In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel.METHODS: A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y12 inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y12 inhibitors, and equal distribution of thrombotic events between the two strategies).RESULTS: Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant.CONCLUSION: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings.TRIAL REGISTRATION: Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.

Epidemiological studies have documented a high incidence of diabetes in hypertensive patients.Insulin resistance is defined as a less than expected biologic response to a given concentration of the hormone and plays a pivotal role in the pathogenesis of diabetes. However, over the last decades, it became evident that insulin resistance is not merely a metabolic abnormality, but is a complex and multifaceted syndrome that can also affect blood pressure homeostasis. The dysregulation of neuro-humoral and neuro-immune systems is involved in the pathophysiology of both insulin resistance and hypertension. These mechanisms induce a chronic low grade of inflammation that interferes with insulin signalling transduction. Molecular abnormalities associated with insulin resistance include the defects of insulin receptor structure, number, binding affinity, and/or signalling capacity. For instance, hyperglycaemia impairs insulin signalling through the generation of reactive oxygen species, which abrogate insulin-induced tyrosine autophosphorylation of the insulin receptor. Additional mechanisms have been described as responsible for the inhibition of insulin signalling, including proteasome-mediated degradation of insulin receptor substrate 1/2, phosphatase-mediated dephosphorylation and kinase-mediated serine/threonine phosphorylation of both insulin receptor and insulin receptor substrates. Insulin resistance plays a key role also in the pathogenesis and progression of hypertension-induced target organ damage, like left ventricular hypertrophy, atherosclerosis and chronic kidney disease. Altogether these abnormalities significantly contribute to the increase the risk of developing type 2 diabetes.

Increased intima-media thickness (IMT) of common carotid artery (CA) is considered the hallmark of vascular hypertension-mediated target organ damage, even if vessel remodeling due to mechanical stress may also induce changes in diameter. We developed a method computing both diameter and IMT of CA, to assess correlates and prognostic impact of carotid cross-sectional area (CCSA) in a large registry of treated hypertensive patients. We selected 6300 hypertensive patients of the Campania Salute Network registry free of overt cardiovascular (CV) disease and with available CA ultrasound (54 ± 11 years; 57% male). CCSA was computed as:π×(CAdiameter+2×(meanIMT)2)2−π×(CAdiameter2)2. CCSA was considered high if >90th percentile of the sex-specific distribution (>48 mm2 in men and >41 mm2 in women). Patients with high CCSA were male, with older age, higher pulse pressure (PP), more prevalent obese and diabetic, with higher total and LDL cholesterol (p < 0.01 for all). During a median follow-up of 60 months (IQR 19–87), 206 incident composite major and minor CV events occurred. In Cox regression analysis high CCSA was associated with more than 100% increased risk of incident CV events ((HR 2.11, 95%CI 1.46–3.1, p < 0.0001), independently of the effect of older age, male sex, PP > 60 mmHg, presence of left ventricular hypertrophy (LVH), carotid plaque (CP), and less anti-RAS therapy (p < 0.05 for all). In treated hypertensive patients, increased CCSA is associated with worse metabolic and lipid profile and predict incident CV events, independently of high PP, presence of LVH and CP.

BACKGROUND Hypertensive urgencies (HypUrg) are defined as severe elevation in blood pressure (BP) without acute target organ damage. In the office setting, treated asymptomatic patients, with severe BP elevation meeting criteria for urgency are often seen. We evaluate incident Cardiovascular (CV) events (n = 311) during follow-up (FU) in patients with HypUrg at first outpatient visit. METHODS HypUrg was defined by systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg. Patients were >18 years old, with available ultrasound data, without prevalent CV disease, and no more than stage III Chronic Kidney Disease. BP control was defined as the average BP during FU RESULTS Four hundred and sixty-nine of 6,929 patients presented with HypUrg at first visit. Patients with HypUrg were more likely to be women, obese and diabetic and with higher prevalence of left ventricle (LV) hypertrophy and carotid plaque (all P < 0.05). During FU patients with HypUrg had 5-fold higher risk of uncontrolled BP (95% confidence interval (CI) 4.1–6.8, P < 0.0001). In Cox regression presenting with HypUrg was not associated with increased CV risk after adjusting for significant covariates, including age, sex, BP control, LV hypertrophy, and carotid plaque (hazard ratio (HR) 1.42, 95% CI (0.96–2.11), P = 0.08). CONCLUSIONS Patients with HypUrg have worst CV risk profile, reduced probability of BP control during FU and greater prevalence of target organ damage, but the excess CV event risk appears to be mediated through BP control, non-BP cardio-vascular disease risk factors, and demographic attributes. CLINICALTRIALS.GOV IDENTIFIER NCT02211365.

The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2YIn this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel.A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2YBase-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant.In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings.Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

The second half of the last century was characterized by intense research in the field of arterial hypertension and related therapies. These studies showed that the management of arterial hypertension requires a robust coordination with close integration of the "health care systems" and "health care professionals". In 1998, the health care organization named "Campania Salute Network" was set up at the University of Naples Federico II. The Campania Salute Network involves 23 outpatient hypertensive clinics distributed in different community hospitals of the Regione Campania's area, 60 randomly selected general practitioners uniformly distributed in the same area, and the Hypertension Clinic of the Federico II University in Naples (coordinating centre). Through this network, clinical data collected at each visit are shared (via text messages or emails) with peripheral units (general practitioners and community hospital outpatient hypertensive clinics). The coordinating centre works in co-operation with the peripheral units in the treatment and follow-up of all hypertensive patients (i.e. assessing hypertension mediated organ damage and associated diseases). Informations about patients are shared through on-line access to the remote web-based database. The integrated approach to the mamangement of hyperetension determined a better control of blood pressure, that was associated with a reduction of hypertension mediated organ damage and decreased incidence of fatal or non-fatal cardiovascular events. Furthermore, this innovative approach improved the adherence and the persistence to the initial pharmacologic treatment. Campania Salute Network is also a powerful tool for the clinical and translational research with more 15,000 hypertensive patients followed for more than 15 years. This database allowed, in prospetic, large scale studies, to identify the hemodimìnamic and metabolic determinants of hypertension mediated organ damage and major cardiovascular events. The experience of Campania Salute Netwiork indicates that the creation of large databases from real life experiences becomes an indispensable condition also for artificial intelligence which, in the near future, thanks to scientific knowledge, the availability of particularly advanced hardware and software, will also be able to transform the management of arterial hypertension.

Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype–guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y 12 inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19 *2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19 *17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel–treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. Results: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19 *17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45–2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48–1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56–0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68–1.90]). Conclusions: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19 *17 polymorphism. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/ ; Unique identifier: NL2872.

Aims Fractional flow reserve (FFR) has never been investigated in patients with reduced ejection fraction and associated coronary artery disease (CAD). We evaluated the impact of FFR on the management strategies of these patients and related outcomes. Methods and results From 2002 to 2010, all consecutive patients with left ventricular ejection fraction (LVEF) ≤50% undergoing coronary angiography with ≥1 intermediate coronary stenosis [diameter stenosis (DS)% 50–70%] treated based on angiography (Angiography-guided group) or according to FFR (FFR-guided group) were screened for inclusion. In the FFR-guided group, 433 patients were matched with 866 contemporary patients of the Angiography-guided group. For outcome comparison, 617 control patients with LVEF >50% were included. After FFR, stenotic vessels per patient were significantly downgraded compared with the Angiography-guided group (1.43 ± 0.98 vs. 1.97 ± 0.84; P Conclusions In patients with reduced LVEF and CAD, FFR-guided revascularization was associated with lower rates of death and MACCE at 5 years as compared with the Angiography-guided strategy. This beneficial impact was observed in parallel with less coronary artery bypass grafting and more patients deferred to percutaneous coronary intervention or medical therapy.

Insulin resistance (IR) and the related hyperinsulinamia play a key role in the genesis and progression of the continuum of cardiovascular (CV) disease. Thus, it is reasonable to pursue in primary and secondary CV prevention, the pharmacological strategies that are capable to interfere with the development of IR. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of IR. In particular, angiotensin II (Ang II) through the generation of reactive oxygen species, induces a low grade of inflammation, which impairs the insulin signal transduction. The angiotensin converting enzyme (ACE) inhibitors are effective not only as blood pressure-lowering agents, but also as modulators of metabolic abnormalities. Indeed, experimental evidence indicates that in animal models of IR, ACE inhibitors are capable to ameliorate the insulin sensitivity. The Ang II receptor blockers (ARBs) modulate the peroxisome proliferator-activated receptor (PPAR)-γ activity. PPAR–γ is a transcription factor that controls the gene expression of several key enzymes of glucose metabolism. A further mechanism that accounts for the favorable metabolic properties of ARBs is the capability to modulate the hypothalamic–pituitary-adrenal (HPA) axis. The available clinical evidence is consistent with the concept that both ACE inhibitors and ARBs are able to interfere with the development of IR and its consequences like type 2 diabetes. In addition, pharmacological inhibition of the RAAS has favourable effects on dyslipidaemias, metabolic syndrome and obesity. Therefore, the pharmacological antagonism of the RAAS, nowadays, represents the first choice in the prevention of cardio-metabolic diseases.