How much does hypertension in pregnancy affect the risk of future cardiovascular events?

Hypertensive disorders in pregnancy (HDP) include essential (or secondary) hypertension occurring before 20 weeks of gestation or in women already on antihypertensive therapy prior to pregnancy, gestational hypertension, developing after 20 weeks of gestation without significant proteinuria, and pre-eclampsia or AH onset after 20 weeks of pregnancy in the presence of proteinuria. The development of HDP is associated with a higher incidence of long-term cardiovascular (CV) adverse events, such as myocardial infarction, heart failure, stroke, and CV death. Women who develop high blood pressure in their first pregnancy have an increased risk of complication in a subsequent pregnancy. In the years following delivery, pregnant women with hypertensive disorders develop subclinical atherosclerosis and alterations of cardiac structure and function that may lead to CV disease and heart failure. Thus, it is recommended to monitor these changes over time and subject in pregnant women with these characteristics to CV surveillance through structured and multidisciplinary interventions for CV prevention.

Impact of myocardial revascularization on long-term outcomes in a nationwide cohort of first acute myocardial infarction survivors.

The long-term clinical benefits of myocardial revascularization in a contemporary, nationwide cohort of acute myocardial infarction (AMI) survivors are unclear. We aimed to compare the mortality rates and clinical outcomes at 8 years of patients admitted in Italy for a first AMI managed with or without myocardial revascularization during the index event. This is a national retrospective cohort study that enrolled patients admitted for a first AMI in 2012 in all Italian hospitals who survived at 30 days. The outcomes of interest were all-cause mortality, major cardio-cerebrovascular events (MACCE), and re-hospitalization for heart failure (HF) at 8 years. Time to events was analysed using a Cox and Fine and Gray multivariate regression model. A total of 127 431 patients with AMI were admitted to Italian hospitals in 2012. The study cohort consisted of 62 336 AMI events, of whom 63.8% underwent percutaneous or surgical revascularization ≤30 days of the index hospital admission. At 8 years, the cumulative incidence of all-cause death was 36.5% (24.6% in revascularized and 57.6% in not revascularized patients). After multiple corrections, the hazard ratio (HR) for all-cause mortality in revascularized vs. not revascularized patients was 0.61 (P < 0.0001). The rate of MACCE was 45.7% and 65.8% (adjusted HR 0.83; P < 0.0001), while re-hospitalizations for HF occurred in 17.6% and 29.8% (adjusted HR 0.97; P = 0.16) in AMI survivors revascularized and not revascularized, respectively. In our contemporary nationwide cohort of patients at their first AMI episode, those who underwent myocardial revascularization within 1 month from the index event compared to those not revascularized presented an adjusted 39% risk reduction in all-cause mortality and 17% in MACCE at 8-year follow-up.

The impact of in-hospital cardiac rehabilitation program on medication adherence and clinical outcomes in patients with acute myocardial infarction in the Lazio region of Italy.

BACKGROUND: Medication adherence is a recognized key factor of secondary cardiovascular disease prevention. Cardiac rehabilitation increases medication adherence and adherence to lifestyle changes. This study aimed to evaluate the impact of in-hospital cardiac rehabilitation (IH-CR) on medication adherence as well as other cardiovascular outcomes, following an acute myocardial infarction (AMI). METHODS: This is a population-based study. Data were obtained from the Health Information Systems of the Lazio Region, Italy (5 million inhabitants). Hospitalized patients aged ≥ 18 years with an incident AMI in 2013-2015 were investigated. We divided the whole cohort into 4 groups of patients: ST-elevation AMI (STEMI) and non-ST-elevation AMI (NSTEMI) who underwent or not percutaneous coronary intervention (PCI) during the hospitalization. Primary outcome was medication adherence. Adherence to chronic poly-therapy, based on prescription claims for both 6- and 12-month follow-up, was defined as Medication Possession Ratio (MPR) ≥ 75% to at least 3 of the following medications: antiplatelets, ß-blockers, ACEI/ARBs, statins. Secondary outcomes were all-cause mortality, hospital readmission for cardiovascular and cerebrovascular event (MACCE), and admission to the emergency department (ED) occurring within a 3-year follow-up period. RESULTS: A total of 13.540 patients were enrolled. The median age was 67 years, 4.552 (34%) patients were female. Among the entire cohort, 1.101 (8%) patients attended IH-CR at 33 regional sites. Relevant differences were observed among the 4 groups previously identified (from 3 to 17%). A strong association between the IH-CR participation and medication adherence was observed among AMI patients who did not undergo PCI, for both 6- and 12-month follow-up. Moreover, NSTEMI-NO-PCI participants had lower risk of all-cause mortality (adjusted IRR 0.76; 95% CI 0.60-0.95), hospital readmission due to MACCE (IRR 0.78; 95% CI 0.65-0.94) and admission to the ED (IRR 0.80; 95% CI 0.70-0.91). CONCLUSIONS: Our findings highlight the benefits of IH-CR and support clinical guidelines that consider CR an integral part in the treatment of coronary artery disease. However, IH-CR participation was extremely low, suggesting the need to identify and correct the barriers to CR participation for this higher-risk group of patients.

Sex differences in factors associated with heart failure and diastolic left ventricular dysfunction: a cross-sectional population-based study.

BACKGROUND: Although sex differences in cardiovascular diseases are recognised, including differences in incidence, clinical presentation, response to treatments, and outcomes, most of the practice guidelines are not sex-specific. Heart failure (HF) is a major public health challenge, with high health care expenditures, high prevalence, and poor clinical outcomes. The objective was to analyse the sex-specific association of socio-demographics, life-style factors and health characteristics with the prevalence of HF and diastolic left ventricular dysfunction (DLVD) in a cross-sectional population-based study. METHODS: A random sample of 2001 65-84 year-olds underwent physical examination, laboratory measurements, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiography, and echocardiography. We selected the subjects with no missing values in covariates and echocardiographic parameters and performed a complete case analysis. Sex-specific multivariable logistic regression models were used to identify the factors associated with the prevalence of the diseases, multinomial logistic regression was used to investigate the factors associated to asymptomatic and symptomatic LVD, and spline curves to display the relationship between the conditions and both age and NT-proBNP. RESULTS: In 857 men included, there were 66 cases of HF and 408 cases of DLVD (77% not reporting symptoms). In 819 women, there were 51 cases of HF and 382 of DLVD (79% not reporting symptoms). In men, the factors associated with prevalence of HF were age, ischemic heart disease (IHD), and suffering from three or more comorbid conditions. In women, the factors associated with HF were age, lifestyles (smoking and alcohol), BMI, hypertension, and atrial fibrillation. Age and diabetes were associated to asymptomatic DLVD in both genders. NT-proBNP levels were more strongly associated with HF in men than in women. CONCLUSIONS: There were sex differences in the factors associated with HF. The results suggest that prevention policies should consider the sex-specific impact on cardiac function of modifiable cardiovascular risk factors.

COVID-19 pandemic: what consequences for cardiac rehabilitation?

The ongoing COVID-19 pandemic spreading all around the world has stressed over its capabilities and determined profound changes in the health systems in all countries and has caused hundreds of thousand deaths. Health professionals have been called to a tremendous effort to deal with this emergency, often contaminating or succumbing themselves to the disease.

Cardiac rehabilitation activities during the COVID-19 pandemic in Italy. Position Paper of the AICPR (Italian Association of Clinical Cardiology, Prevention and Rehabilitation).

The COVID-19 outbreak is having a significant impact on both cardiac rehabilitation (CR) inpatient and outpatient healthcare organization. The variety of clinical and care scenarios we are observing in Italy depends on the region, the organization of local services and the hospital involved. Some hospital wards have been closed to make room to dedicated beds or to quarantine the exposed health personnel. In other cases, CR units have been converted or transformed into COVID-19 units.  The present document aims at defining the state of the art of CR during COVID-19 pandemic, through the description of the clinical and management scenarios frequently observed during this period and the exploration of the future frontiers in the management of cardiac rehabilitation programs after the COVID-19 outbreak.

Predictive value of interatrial block for atrial fibrillation in elderly subjects enrolled in the PREDICTOR study.

AIMS: The principal aims of this prospective multicentre study were to relate the presence of interatrial block (IAB) with a late occurrence of atrial fibrillation (AF) and to demonstrate the independence of the IAB effect on risk of AF from structural cardiac alterations. METHODS: This prospective study was the follow-up of subjects included in the PREDICTOR cross-sectional population-based study. Subjects were divided into groups according to IAB status. Socio-demographic and health characteristic were collected during enrolment in the PREDICTOR along with ECGs, echocardiograms and NT-proBNP dosages. Follow up was performed on administrative data. The mean time of follow up was 6.6 years. RESULTS: 1626 subjects were included in the analysis. Four hundred-fifteen subjects out of 1626 (25.5%) had IAB. The survival analysis suggests an association between IAB alone and AF (HR = 1.50, p = 0.058) and, in normal-weight subjects, IAB strongly predicted AF indicating more than triple the risk (HR = 3.05; p = 0.002 95% CI: 1.51-6.18). The association seems to be independent of possible confounders such as history of IHD, left ventricular hypertrophy, CHA2DS2-VASc, left atrial dimension, or NT-proBNP dosage. CONCLUSION: Our analysis suggests that IAB is an electric condition that can increase the risk of AF independently of any structural cardiac alterations, at least in normal-weight subjects.

Secondary cardiovascular prevention in clinical practice: what do we need today?

In the last decades, the post-hospital mortality from coronary artery disease (CAD) has significantly increased. This new trend in the epidemiology of CAD has been largely attributed to the improvement of survival from acute coronary syndromes that generated increasing incidence of population at high risk of recurrences and rehospitalization for major adverse cardiovascular events (MACE) and heart failure (HF). Thus, much longer after the acute event than we had thought, we have now been facing with higher complexity of "chronic" CAD phenotypes which deserve high clinical attention and more and more intricate pharmacological management. Although the guidelines recommend implementing secondary prevention programs through cardiac rehabilitation (CR) facilities in order to achieve a better outcome, i.e. decreased morbidity, re-hospitalization and increased adherence to evidence-based interventions, the referral rate to CR is paradoxically scarce. The Italian Association of Clinical Preventive Cardiology and Rehabilitation (AICPR) has been launching a survey involving the Network of Italian CR centers, which will make possible to observe trends, implement guidelines recommendations and then verify the effectiveness of the interventions and outcomes in post-acute and chronic CAD.

Utility and limitations of ejection fraction and of diastolic dysfunction in heart failure patients.

The echocardiographic evaluation of left ventricular (LV) systolic function, and especially of ejection fraction (EF) plays a central role in the diagnosis of heart failure (HF) due to its undisputed prognostic value. Limitations of EF are substantially: i) the variability and reproducibility of measurements, and ii) the load-dependence. Measurement of stroke volume, longitudinal function and myocardial strain can overcome the limitations of EF in assessing the contractile reserve of patients with HF and may help to define both the phenotype and prognosis of the disease. The recognition of diastolic dysfunction (mainly by echocardiography) is the pathophysiological basis to make diagnosis of HF with preserved ejection fraction (HFpEF). The limitations are essentially related to its feasibility, since performing a multi-parametric quantitative echocardiographic evaluation, as indicated by the guidelines, may be difficult in clinical practice. Difficulties in method standardization, the poor attitude of cardiologists to test their reproducibility (test-retest, variability) favor the evaluation "at-a-glance" of LV structural and functional LV abnormalities.

High thrombotic risk increases adverse clinical events up to 5 years after acute myocardial infarction. A nationwide retrospective cohort study.

The risk of recurrent events among survivors of acute myocardial infarction (AMI) is understudied. The aim of this analysis was to investigate the role of residual high thrombotic risk (HTR) as a predictor of recurrent in-hospital events after AMI. This retrospective cohort study included 186,646 patients admitted with AMI from 2009 to 2010 in all Italian hospitals who were alive 30 days after the index event. HTR was defined as at least one of the following in the 5 years preceding AMI: previous myocardial infarction, ischemic stroke/other vascular disease, type 2 diabetes mellitus, renal failure. Risk adjustment was performed in all multivariate survival analyses. Rates of major cardiac and cerebrovascular events (MACCE) within the following 5 years were calculated in both patients without fatal readmissions at 30 days and in those free from in-hospital MACCE at 1 year from the index hospitalization. The overall 5-year risk of MACCE was higher in patients with HTR than in those without HTR, in both survivors at 30 days [hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.45-1.52; p<0.0001] and in those free from MACCE at 1 year (HR, 1.46; 95% CI, 1.41-1.51; p<0.0001). The risk of recurrent MACCE increased in the first 18 months after AMI (HR, 1.49) and then remained stable over 5 years. The risk of MACCE after an AMI endures over 5 years in patients with HTR. This is also true for patients who did not have any new cardiovascular event in the first year after an AMI. All patients with HTR should be identified and addressed to intensive preventive care strategies.

Referral from vascular surgery to cardiovascular rehabilitation and related outcomes in patients with peripheral arterial disease: the THINKPAD-RELOADED survey.

The utilization of cardiovascular rehabilitation (CR) programmes in patients with Lower Extremity Peripheral Artery Disease (LEPAD) is generally poor, with limited evidence of current policies for referral. The aim of the study was to evaluate, within a cohesive network of CR and vascular surgery facilities with facilitated referral process, the clinical characteristic of LEPAD patients referred to CR and related outcomes, as compared to patients not referred. The present is an observational prospective study of consecutive patients recruited at vascular surgery facilities. Out of 329 patients observed, the average referral rate to CR was 34% (28% and 39% in patients with and without recent peripheral revascularization, p<0.05). LEPAD patients entering the CR programme were similar to those who did not according to sex, age, the vascular surgery setting of evaluation, and localization of arterial lesions. Patients with moderate intermittent claudication and patients with acute limb ischemia as index event were more represented among those who attended CR (41% vs 21% and 9% vs 2% respectively, p<0.05). Patients referred to CR had five times more episodes of acute coronary syndrome and heart failure as complication of the index event. The cardiovascular risk profile (obesity 29.5% vs 11%, p<0.05; hypercholesterolemia 80% vs 61%, p<0.05) was much worse in LEPAD patients referred to CR, but conversely, they better achieved secondary prevention targets, particularly for blood pressure control (97% vs 57%, p<0.05). All-cause 2-year mortality in the whole patients' population was 6%. Patients entering the CR programme displayed less events (13.5% vs 37.7%, p<0.05), mainly death (3.1% vs 11.3%, p<0.05) and limb-related events (4.2% vs 15.2%, p<0.05). The results of our study suggest that when a cohesive network of vascular surgery and CR facilities becomes available, the referral rate to rehabilitation may increase up to one third of eligible patients. Patients with higher comorbidity and cardiovascular risk seem to have priority in the referral process, nevertheless those with peripheral revascularization are still underestimated. Entering CR may ensure better cardiovascular risk profile and cardiovascular prognosis in LEPAD patients, and consequently the systematic adoption of this care model needs to be strongly recommended and facilitated.

Awareness and appropriateness of the management of preclinical heart failure in outpatient clinics in Italy: Insights from the VASTISSIMO study - EValuation of the AppropriateneSs of The preclInical phase (Stage A and Stage B) of Heart FaIlure Management in Outpatient Clinics in Italy.

A key factor in cardiovascular prevention is the detection and appropriate management of preclinical heart failure (HF), but information on the subject is scarce. We designed VASTISSIMO as a prospective, observational study to investigate Outpatient Clinic Cardiologists' skills in detecting and managing preclinical HF in Italy. Quality scores were used to assess the appropriateness of clinical management according to guideline recommendations. The feasibility of making a diagnosis of preclinical HF in a cardiology outpatient clinical setting, cardiologists' awareness of preclinical HF and consistency between physician's perceived risk of HF and the patient's classification into the preclinical HF Stages A [(SAHF) or B (SBHF)] have been investigated. Consistency was defined acceptable if the concordance between perceived risk and actual risk was >70%. Out of 3322 patients included in the study data necessary for identifying SBHF were collected in 2106 (63.4%). Many SBHF patients had their risk underestimated: 16.2% of those with previous acute myocardial infarction (AMI), 23.1% with left ventricular hypertrophy (LVH) at ECG/echocardiography, 30% with systolic/diastolic dysfunction, and 14.3% with valve disease. Cardiologists' awareness of preclinical HF in the outpatient setting should be improved. This is a critical area of cardiovascular prevention that requires attention to improve good clinical practice and adherence to guidelines.

Refined 4-group classification of left ventricular hypertrophy based on ventricular concentricity and volume dilatation outlines distinct noninvasive hemodynamic profiles in a large contemporary echocardiographic population.

BACKGROUND: Left ventricular hypertrophy (LVH) may reflect a wide variety of physiologic and pathologic conditions. Thus, it can be misleading to consider all LVH to be homogenous or similar. Refined 4-group classification of LVH based on ventricular concentricity and dilatation may be identified. To determine whether the 4-group classification of LVH identified distinct phenotypes, we compared their association with various noninvasive markers of cardiac stress. METHODS: Cohort of unselected adult outpatients referred to a seven tertiary care echocardiographic laboratory for any indication in a 2-week period. We evaluated the LV geometric patterns using validated echocardiographic indexation methods and partition values. RESULTS: Standard echocardiography was performed in 1137 consecutive subjects, and LVH was found in 42%. The newly proposed 4-group classification of LVH was applicable in 88% of patients. The most common pattern resulted in concentric LVH (19%). The worst functional and hemodynamic profile was associated with eccentric LVH and those with mixed LVH had a higher prevalence of reduced EF than those with concentric LVH (P < .001 for all). CONCLUSIONS: The new 4-group classification of LVH system showed distinct differences in cardiac function and noninvasive hemodynamics allowing clinicians to distinguish different LV hemodynamic stress adaptations in patients with LVH.

Consensus Document ANMCO/ANCE/ARCA/GICR-IACPR/GISE/SICOA: Long-term Antiplatelet Therapy in Patients with Coronary Artery Disease.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of pharmacologic management of patients with acute coronary syndrome (ACS) and/or those receiving coronary stents. Long-term (>1 year) DAPT may further reduce the risk of stent thrombosis after a percutaneous coronary intervention (PCI) and may decrease the occurrence of non-stent-related ischaemic events in patients with ACS. Nevertheless, compared with aspirin alone, extended use of aspirin plus a P2Y12 receptor inhibitor may increase the risk of bleeding events that have been strongly linked to adverse outcomes including recurrent ischaemia, repeat hospitalisation and death. In the past years, multiple randomised trials have been published comparing the duration of DAPT after PCI and in ACS patients, investigating either a shorter or prolonged DAPT regimen. Although the current European Society of Cardiology guidelines provide a backup to individualised treatment, it appears to be difficult to identify the ideal patient profile which could safely reduce or prolong the DAPT duration in daily clinical practice. The aim of this consensus document is to review contemporary literature on optimal DAPT duration, and to guide clinicians in tailoring antiplatelet strategies in patients undergoing PCI or presenting with ACS.

Arterial hypertension. Does the J curve exist? And then?

The concept that 'the lower the blood pressure (BP) achieved the better the outcome' rests on the demonstration of a direct relationship between BP and incident outcomes, down to levels of 115 mmHg of systolic BP (sBP) and 75 mmHg of diastolic BP (dBP) carried out in 1 million individuals from 61 cohorts recruited between 1950 and 1990 and followed for about 14 years. The alternative to the 'lower the better' concept is the hypothesis of a J-shaped relationship, according to which the benefits of reducing sBP or dBP to low values may be dangerous leading even to an increase in total mortality and/or in CV outcomes. Data from contemporary epidemiologic observations,  (CALIBER study), showed that the relationships between rising BP  and increased incidence of outcomes rise continuous even over 85 years of age without the evidence of a  J-shaped  association  with  any  of  the  outcomes at any age strata. In the English Longitudinal  Study  of  Ageing  study (ELSA), a tailored analysis for octogenarians showed that the increase in mortality rates associated with BP ranges appears at sBP  <110 mmHg and ≥170 mmHg.  In randomized controlled trials (SPRINT, HYVET and INVEST), the J curve seems to concern mainly patients with an  extensive atherosclerotic burden, rather than. An impaired autoregulation of coronary blood flow (CBF) leading to a fall in diastolic BP and resulting in a lowering in the perfusion pressure distal to the epicardial coronary artery stenosis, can eventually lead  to myocardial ischemia.  Diastolic dysfunction can concur in worsening CBF in diastole.  These features are often seen in elderly patients with heart failure with preserved ejection fraction. The steeper position of the slope of the end-systolic elastance can lead to dramatic increases and decreases in BP for the same change in afterload or preload. This may explain why elderly hypertensives are more prone to suffer of hypertensive crisis and/or hypotension than younger hypertensives. "Pseudo-hypertension" caused by structural sclerotic changes in the brachial artery wall may cause overtreatment related falls in blood pressure. Thus, the J curve exists but only in patients with multiple comorbidities and/or extensive atherosclerotic burden.

Cardiac Prevention and Rehabilitation "3.0": From acute to chronic phase. Position Paper of the ltalian Association for Cardiovascular Prevention and Rehabilitation (GICR-IACPR).

Cardiac rehabilitation (CR) is the subspecialty of clinical cardiology dedicated to the treatment of cardiac patients, early and in the long term after an acute event. The aim of CR is to improve both quality of life and prognosis through prognostic stratification, clinical stabilization and optimization of therapy (pharmacological and non), management of comorbidities, treatment of disability, as well as through the provision and reinforcement of secondary prevention interventions and maintenaince of adherence to treatment. The mission of CR has changed over time. Once centered on the acute phase, aimed primarily at short-term survival, the healthcare of cardiac patients now increasingly involves the chronic phase where the challenge is to guarantee continuity and quality of care in the medium and long-term. The aim of the present position paper is to provide the state-of-the-art of CR in Italy, discussing its trengths and weaknesses as well as future perspectives.

Galectin-3 and the Mineralocorticoid Receptor Antagonist Canrenone in Mild Heart Failure.

BACKGROUND: Galectin-3 (Gal-3) is involved in collagen deposition and inflammation and is a prognostic biomarker in heart failure (HF).Methods and Results:Gal-3 and other markers of fibrosis or cardiac stress were measured serially in 413 patients with mild HF randomized to the mineralocorticoid receptor antagonist canrenone or placebo to evaluate treatment effect and association with clinical outcome. Gal-3 increased slightly over 6 months in both arms of the study and was associated with clinical endpoints. CONCLUSIONS: Although Gal-3 showed prognostic value, the effect of canrenone on clinical outcomes was unaffected by baseline concentrations of biomarkers of fibrosis or cardiac stress.

ANMCO Scientific Statement: clinical management of hypercholesterolaemia in patients with acute coronary syndromes.

LDL cholesterol (LDL-C) reduction after Acute Coronary Syndromes (ACS) is associated with a significant decrease in subsequent atherosclerotic cardiovascular events. Accordingly, international guidelines recommend a reduction of LDL-C below 70 mg/dL in ACS patients. Such a result can be effectively accomplished in most cases by using high intensity statins. In selected cases, the association with ezetimibe may be necessary in order to achieve recommended LDL-C targets. This document outlines management strategies that can be consistently implemented in clinical practice in order to achieve and maintain guidelines recommended therapeutic goals.

ANMCO Position Paper: diagnostic-therapeutic pathway in patients with hypercholesterolaemia and statin intolerance.

Statins are a class of drugs used to lower total and low-density lipoprotein (LDL)-cholesterol. Clinical trials performed over the last 25 years have shown that these agents are effective in improving cardiovascular outcomes in several different clinical settings. However, in some cases statin treatment may be associated with significant side effects and adverse reactions. The occurrence of these adverse events during statin therapy may cause discontinuation of treatment, and hence the impossibility of achieving recommended lipid goals. The clinical condition in which patients experience major unacceptable symptoms and/or develop laboratory abnormalities during statin therapy is defined as statin intolerance. This document outlines the diagnostic and therapeutic pathways for the clinical management of patients with hypercholesterolaemia and statin intolerance.

ANMCO/GICR-IACPR/SICI-GISE Consensus Document: the clinical management of chronic ischaemic cardiomyopathy.

Stable coronary artery disease (CAD) is a clinical entity of great epidemiological importance. It is becoming increasingly common due to the longer life expectancy, being strictly related to age and to advances in diagnostic techniques and pharmacological and non-pharmacological interventions. Stable CAD encompasses a variety of clinical and anatomic presentations, making the identification of its clinical and anatomical features challenging. Therapeutic interventions should be defined on an individual basis according to the patient's risk profile. To this aim, management flow charts have been reviewed based on sustainability and appropriateness derived from recent evidence. Special emphasis has been placed on non-pharmacological interventions, stressing the importance of lifestyle changes, including smoking cessation, regular physical activity, and diet. Adherence to therapy as an emerging risk factor is also discussed.