Is the extent of left atrial fibrosis associated with body mass index in patients undergoing pulmonary vein isolation for atrial fibrillation?

BACKGROUND: Left atrial (LA) fibrosis is associated with a higher rate of recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI). Body mass index (BMI) is strongly associated with the prevalence of AF, but there is insufficient data about the association between BMI and LA fibrosis. AIMS: The aim of the study was to examine the association between LA fibrosis and BMI in patients with AF undergoing PVI. METHODS: In 114 patients an electro-anatomical voltage map was created using the CARTO 3 three-dimensional system before PVI. The total fibrosis area (voltage criteria ≤0.5 mV), percentage, and the number of fibrotic areas were calculated. A general linear model was used to determine the differences in BMI with confounders between groups of patients with differing extents of fibrosis and numbers of focuses. RESULTS: Advanced fibrosis was found in 53 (47%) patients, in up to 9 areas with a median of 2 and an interquartile range (IQR) of 0-3. The median total fibrotic area was 27.3 cm2 with an IQR of 0.1-30.3 cm2. Patients were stratified by percentage of fibrotic area: <5%, 5%-20%, 20%-35%, and above 35%; no significant difference in mean BMI was found between the groups (P = 0.57). When stratified by the number of fibrotic areas (0, 1, 2, and ≥3 fibrotic areas), no difference in BMI was noted between the groups (P = 0.67). CONCLUSIONS: Fibrosis of the LA, as the strongest predictor of AF recurrence after PVI, does not correlate with BMI in patients with AF where PVI is indicated.

Sudden Cardiac Death-A New Insight Into Potentially Fatal Genetic Markers.

Sudden cardiac death (SCD) is an unexpected and dramatic event. It draws special attention especially in young, seemingly healthy athletes. Our scientific paper is based on the death of a young, 23-year-old professional footballer, who died on the football field after a two-year history of cardiac symptoms. In this study we analyzed clinical, ECG and laboratory data, as well as results of genetic testing analysis in family members. To elucidate potential genetic etiology of SCD in this family, our analysis included 294 genes related to various cardiac conditions.

HERBALIFE® ASSOCIATED SEVERE HEPATOTOXICITY IN A PREVIOUSLY HEALTHY WOMAN.

Lately there has been an increased consumption of herbal preparations, distributed as nutritional supplements, often claimed to be 'natural' and harmless. However, as their use is not subjected to strict pre-marketing testing and regulations, their ingredients are not clearly defined and there is no quality control or proof of their effectiveness and safety. A growing body of references accentuate their harmful effects, in particular hepatotoxicity, which varies from minimal hepatogram changes to fulminant hepatitis requiring liver transplantation. This case report describes liver damage that was highly suspected to originate from Herbalife® products consumption. We excluded alcohol, viral, metabolic, autoimmune and neoplastic causes of liver lesions, as well as vascular liver disease, but we noticed a connection between the use of Herbalife® products and liver damage. The exact mechanism of liver damage in our patient was not determined. After removing the Herbalife® products, liver damage resolved and there was no need to perform liver biopsy. Taking into consideration the growing consumption of herbal products and their potential harmfulness, we consider that more strict regulations of their production process and sale are necessary, including exact identification of active substances with a list of ingredients, toxicologic testing and obligatory side effect report.

The quality of life of Croatian women after mastectomy: a cross-sectional single-center study.

BACKGROUND: Measuring the quality of life (QoL) of women with breast cancer is an important aspect of measuring treatment success. In Croatia, no QoL studies have been carried out with a focus on patients after mastectomy. The aim of this study was to examine QoL 1 month and 1 year after mastectomy. METHODS: This cross-sectional single-center study of quality of life was conducted in 101 patients, 50 of whom had undergone a mastectomy 1 month prior, and 51 of whom had undergone a mastectomy 1 year prior. The study was conducted from July 2015 to June 2016. The questionnaires used in the study were developed by the European Organisation for Research and Treatment of Cancer (EORTC). The questionnaire EORTC QLQ-C30 assesses the QoL of cancer patients, and the questionnaire EORTC QLQ-BR23 is a disease-specific breast cancer module. A chi square test, Fisher's exact test, Kolmogorov-Smirnov test, Student's t-test and Mann-Whitney U test were performed in the statistical analysis using the statistical program SPSS (Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc.). RESULTS: Patients who had undergone a mastectomy a year earlier placed a higher value on their health state than did those who had undergone a mastectomy a month earlier. The most affected values of functional status on the EORTC QLQ-C30 scale were emotional functioning (37.5 [95% CI 33.3-61.6]) and sexual functioning (16.67 [95% CI 0-33.3]) 1 month and 1 year after mastectomy, respectively. The most affected symptoms on the EORTC QLQ-C30 scale were hair loss 66.67 [95% CI 33.3-100]) and fatigue 33.33 [95% CI 24-44]) 1 month and 1 year after mastectomy, respectively. CONCLUSION: In our study, both functional and symptom scales were more affected in women 1 month after mastectomy. QoL was considerably improved in women 1 year after the surgery compared to 1 month after mastectomy. The results of this study could contribute to the public awareness of the QoL of breast cancer patients.

Pharmacogenetics of novel oral anticoagulants: a review of identified gene variants & future perspectives.

Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

P2RY12 gene polymorphisms and effect of clopidogrel on platelet aggregation.

Objective of this study was to assess platelet response to clopidogrel and its association with certain single nucleotide polymorphisms (SNPs) of the P2RY12 gene. Several studies have shown that patients with poor in vitro response to clopidogrel have worse outcomes after coronary interventions. Pharmacological response to clopidogrel is mediated by the P2Y12 platelet receptor, therefore, SNPs of the P2RY12 gene may account for some of the observed variability in the cardiovascular risk. Fifty patients with stable coronary heart disease, undergoing percutaneous coronary intervention were included in this study. Response to clopidogrel was analysed using light transmitted aggregometry before, and 5 days after the initation of therapy. SNPs analysed: c.-15+742C > T, c.-180+2739T > C and c.18C > T. A higher proportion of non-responders to clopidogrel were noted in carriers of 18C > T[T/T] (p = 0.05), and lower prevalence in carriers of 742C > T[T/T] (p = 0.05). Participants with 742C > T[T/T] had significantly higher change in aggregation compared to other 742C > T variants ([C/C] = 20.5 +/- 21.9%; [C/T] = 20.0 +/- 31.2%; [T/T] = 48.6 +/- 21.3%; p = 0.03). Those carrying 18C > T[T/T] had smaller change in aggregation (7.6 +/- 15.0%) compared to other variants, but the difference was not statistically significant (p = 0.15). Analysis of variance showed 18C > T[T/T] was a statistically significant predictor of poor response to antiaggregation therapy, independent from other clinical and demographic variables. There was no relation between poor response to clopidogrel and any other genetic variant. Our results suggest that 18C > T SNP of the P2RY12 gene may be an independent predictor of pharmacological response to clopidogrel. Larger prospective studies are needed to confirm this link and assess its possible clinical consequences.

The prevalence of overweight and obesity among Croatian hospitalized coronary heart disease patients.

The aim of this article was to investigate the prevalence of overweight and obesity using selected anthropometric variables in a sample of hospitalized coronary heart disease (CHD) patients in Croatia (N = 1,298). Prevalence of overweight and obesity in surveyed patient population was high: 48.2% of participants were overweight and 28.6% were obese according to their body mass index; measured through waist-to-hip ratio 54.5% of participants were centrally obese. These data on prevalences of overweight, obesity and central obesity show that although there are some reassuring trends, there is still considerable amount of work to be done if the prevalence of this cardiovascular risk factor is to be reduced further among Croatian CHD patients. While the prevalence of obesity seems to be on the decline, the prevalence of overweight is rising, which may be just an early warning sign of an incoming wave of obesity epidemic in future years.

Evaluation of importance of door-to-balloon time and total ischemic time in acute myocardial infarction with ST-elevation treated with primary percutaneous coronary intervention.

The aim of the study was to evaluate the influence of door-to-balloon time and symptom onset-to-balloon time on the prognosis of patients with acute ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) in the Croatian Primary PCI Network. A total of 1190 acute STEMI patients treated with primary PCI were prospectively investigated in eight centers across Croatia (677 non-transferred, 513 transferred). All patients were divided according to door-to-balloon time in three subgroups (< 90, 90-180, and > 180 minutes) and according to symptom onset-to-balloon time in three subgroups (<180, 180-360, and > 360 minutes). The postprocedural Thrombolysis in Myocardial Infarction flow, in-hospital mortality, and major adverse cardiovascular events (mortality, pectoral angina, restenosis, reinfarction, coronary artery by-pass graft and cerebrovascular accident rate) in six-month follow-up were compared between the subgroups. The Croatian Primary PCI Network ensures results of treatment of acute STEMI comparable with randomized studies and registries abroad. None of the result differences among the door-to-balloon time subgroups was statistically significant. Considering the symptom onset-to-balloon time subgroups, a statistically significant difference at multivariate level was highest for in-hospital mortality in the subgroup of patients with longest onset-to-balloon time (4.5 vs. 2.6 vs. 5.7%; p = 0.04). Door-to-balloon time is one of the metrics of organization quality of primary PCI network and targets for quality improvement, but without an impact on early and six-month follow-up results of treatment for acute STEMI. Symptom onset-to-balloon time is more accurate for this purpose; unfortunately, reduction of the symptom onset-to-balloon time is more complex than reduction of the former.

Results of the Croatian Primary Percutaneous Coronary Intervention Network for patients with ST-segment elevation acute myocardial infarction.

The Republic of Croatia, with a gross domestic product per capita of US$11,554 in 2008, is an economically less-developed Western country. The goal of the present investigation was to prove that a well-organized primary percutaneous coronary intervention network in an economically less-developed country equalizes the prospects of all patients with acute ST-segment elevation myocardial infarction at a level comparable to that of more economically developed countries. We prospectively investigated 1,190 patients with acute ST-segment elevation myocardial infarction treated with primary PCI in 8 centers across Croatia (677 nontransferred and 513 transferred). The postprocedural Thrombolysis In Myocardial Infarction flow, in-hospital mortality, and incidence of major adverse cardiovascular events (ie, mortality, pectoral angina, restenosis, reinfarction, coronary artery bypass graft, and cerebrovascular accident rate) during 6 months of follow-up were compared between the nontransferred and transferred subgroups and in the subgroups of older patients, women, and those with cardiogenic shock. In all investigated patients, the average door-to-balloon time was 108 minutes, and the total ischemic time was 265 minutes. Postprocedural Thrombolysis In Myocardial Infarction 3 flow was established in 87.1% of the patients, and the in-hospital mortality rate was 4.4%. No statistically significant difference was found in the results of treatment between the transferred and nontransferred patients overall or in the subgroups of patients >75 years, women, and those with cardiogenic shock. In conclusion, the Croatian Primary Percutaneous Coronary Intervention Network has ensured treatment results of acute ST-segment elevation myocardial infarction comparable to those of randomized studies and registries of more economically developed countries.

Secondary hypertension due to isolated interrupted aortic arch in a 60-year-old person--one-year follow up.

Interrupted aortic arch (IAA) is a congenital defect characterized by loss of luminal continuity between the ascending and descending aorta1. It is a rare malformation with an estimated incidence of perinatally diagnosed cases of 3 per million live births3. The condition is considered extremely rare in adults. However, its true prevalence in this population is unknown. We have found 30 case reports of IAA in adults in literature, 5 of whom were older than 50 years. Four of them had type A IAA. Arterial hypertension is a typical co-morbidity. In this report we describe a 60-year-old male patient who had a type A asymptomatic IAA. Although we initially suspected the aortic coarctation, further invasive procedures revealed complete interruption of the aortic arch just distal to the origin of the left subclavian artery. The patient underwent surgical repair, followed by full recovery and near-normalization of blood pressure.

Diversity of bone cell activity as a histomorphometric feature of idiopathic osteoporosis in men.

Although osteoporosis in men is an increasing health problem, studies on osteoporosis in males are still scarce. The aim of our study was to determine the characteristics of bone tissue and bone turnover in men with idiopathic osteoporosis. Transiliac crest bone samples were histomorphometrically analyzed after double tetracycline labeling in 32 men aged 37-65 years who were diagnosed with idiopathic osteoporosis by densitometry of the lumbar spine and hip. Bone volume, osteoid surface, osteoblast surface, eroded surface, osteoid thickness, trabecular thickness, trabecular number, trabecular separation, and mineral apposition rate (MAR) were determined in all trabecular bone specimens. Bone volume and structural parameters indicated trabecular bone loss in most patients. Cellular parameters and MAR indicated variations in bone cell actions. No age-related decrease in histomorphometric parameters was found. After the patients were grouped according to MAR values, osteoblast and eroded surfaces were found to be lower in the group with decreased MAR values and elevated in the group of patients with increased MAR parameter. Trabecular thickness was greater in patients with lower than normal MAR, due to reduced resorption and probably loss of very thin trabeculae. Our results suggest that idiopathic osteoporosis in man resembles many characteristics of postmenopausal osteoporosis in women resulting in impaired trabecular structure due to unbalanced cellular activity and bone turnover rate.

[Invasive versus noninvasive approach in the treatment of nonstable angina pectoris and NSTEMI: pro and con]. / Invazivni vs. neinvazivni pristup u lijecenju nestabilne angine pektoris i NSTEMI: pro et contra.

Acute coronary syndrome, although unique in its pathophysiologic mechanism, in its different clinical presentations is characterized by different diagnostic and therapeutic approaches. Conservative approach is complementary rather than competitive to modern invasive percutaneous procedures on coronary arteries. The guidelines are clear but have been subject to dynamic changes in the last several years and we can expect further changes and be open to them. Two issues are discussed in the article. The first is whether we need to be still more efficient in the invasive approach as an adjunct to medical therapy, and second is whether all patients with low risk should be submitted to diagnostic coronary angiography and when.

Association of CYP2C9 gene polymorphism with bleeding as a complication of warfarin therapy.

The aim of this study was to determine the association of bleeding as a complication of warfarin therapy with polymorphism of CYP2C9 gene (alleles 1, 2 and 3). The CYP2C9 is the main enzyme for warfarin metabolism. Study included 181 patients receiving warfarin for at least one month. Allele 1 of CYP2C9 gene (in 94.5%) and genotype *1/*1 (57.5%) prevailed. Allele 3 was found in 12.7% patients. Bleeding side-effects occurred in 18 patients (10%). Patients with allele *1 needed significantly higher maintenance warfarin dose (p=0.011). Those with allele *3 had significantly lower maintenance warfarin dose (p=0.005) and higher prothrombin time (PT) at induction (p=0.034). Bleeding occurred significantly more often in those with lower maintenance warfarin dose (p=0.017). Patients with allele *3 had increased risk of bleeding, with marginal significance (p=0.05). Polymorphism of CYP2C9 could determine dose of warfarin therapy and thus it could be related to the risk of bleeding complications. Allele *3 carriers need lower warfarin dose. Therefore, initially reduced warfarin induction dose in allele *3 carriers could avoid more prolonged PT and decrease the risk of bleeding complication.

Anti-inflammatory effects of exercise training in the early period after myocardial infarction.

The aim of this investigation was to determine the effect of exercise training on the levels of plasma cytokines and acute phase reactants in the early post acute myocardial infarction (AMI) period. Sixty patients were enrolled into this three-week cardiac rehabilitation study. The mean time from AMI was 7.08 +/- 1.60 days, and the patient mean age was 60 +/- 10 years. Subjects were randomly assigned to one of the two groups: the control group treated with standard measures, and the group with additional regular moderate-intensity exercise training. Physical activity was based on the ergospirometry test results. Apart from clinical follow-up and routine laboratory analysis we determined the levels of plasma cytokines: tumor necrosis factor (TNF-alpha), soluble TNF-alpha receptor 1 (TNF-alphaSR1), interleukin (IL)-8, IL-10, and acute phase reactants: high sensitivity C-reactive protein (hsCRP) and fibrinogen. The obtained results confirmed the hypothesis that the early post AMI period is an inflammatory state the intensity of which gradually decreases with standard treatment during the first month after AMI, while including patients into early exercise training improves their inflammatory profile by decreasing the level of acute phase reactant and TNF-alphaSR1.

Helicobacter pylori infection and coronary artery disease.

The aim of this investigation was to determine the seroprevalence of H. pylori in patients with coronary artery disease (CAD). Patients with coronary artery disease (n = 90) and control group (n = 90) were enrolled into this randomized, multi-centre study. CAD risk factors analyzed included age, male gender, diabetes mellitus, systemic hypertension, cigarette smoking, hypercholesterolemia and socioeconomic status. The results of this study showed a higher seroprevalence of Helicobacter pylori infection in patients with CAD compared to controls (78.8% versus 58.3%, p < 0.05). However, Helicobacter pylori seropositivity was not associated with coronary artery risk factors (smoking, body mass index, diabetes mellitus, hypertension, total cholesterol and socioeconomic status) either in the whole study population or in the patients and control subjects analyzed separately (P > 0.05). Further study are needed to clarify the precise role of Helicobacter pylori infection on the development of coronary artery disease.

Abnormal systolic blood pressure during treadmill test and brachial artery flow-mediated vasodilatation impairment.

The aim of the study was to assess the relationship between systolic blood pressure during maximal treadmill test (SBP9mtt)) and flow-mediated vasodilation (FMD). Abnormal rise of SBP(mtt) is the phenomenon more frequent in hypertensive persons but it could be found in normotensive subjects too. 199 subjects referred to treadmill test were enrolled in the study. Four groups were formed: hypertensives with abnormal SBP(mtt) (group A), hypertensives with normal SBP(mtt) (group B), normotensives with abnormal SBP(mtt) (group C) and normotensives with normal SBP(mtt) (group D). Rise of SBP(mtt) above 200 mmHg was considered abnormal reaction. Simple linear regression analysis showed significant inverse relationship between SBP(mtt) and FMD (F = 20.2036, p < 0.001, R2 = 0.0956). Mean FMD index was worst in hypertensive subjects with abnormal SBP(mtt) (group A), followed by normotensives with abnormal SBP(mtt) (group C), hypertensives with normal SBP(mtt) (group B) and the best was in normotensives with normal SBP(mtt) (3.56 +/- 5.17, 4.19 +/- 5.14, 6.81 +/- 8.43 and 10.92 +/- 7.48%, respectively). In multivariate regression analysis FMD showed significant association with abnormal SBP(mtt) (p < 0.001) along with brachial artery diameter (p < 0.001), male gender (p < 0.001), but not with hypertension (p = 0.073), BMI (p = 0.137) and total cholesterol (p = 0.23) (coefficients: -0.26, -0.40, -0.27, -0.13, -0.11 and -0.07, respectively). There was a significant inverse relationship between SBP(mtt) and FMD. An impairment of FMD exists in normotensive subjects with abnormal SBP(mtt). In hypertensives with abnormal SBP(mtt) an additional impairment of FMD exists when compared to hypertensives with normal SBP(mtt). Abnormal SBP(mtt) should be taken into account in global cardiovascular risk assessment.

Erectile dysfunction after myocardial infarction--myth or a real problem?

Erectile dysfunction is a common problem whose relation to cardiovascular diseases has scientifically been proved, but it has not been studied sufficiently in patients recovering from myocardial infarction. The objective of this study was to establish the frequency of erectile dysfunction in patients recovering from myocardial infarction. We examined 89 patients (aged 30 to 75 years) included in the program of cardiac rehabilitation after myocardial infarction. The results were compared with 91 healthy examinees of the same age. Even 82% of the patients who recovered from myocardial infarction have problems with erectile dysfunction, compared to 42.9% of healthy examinees. The prevalence of erectile dysfunction increases with the age in both groups. In the group of patients recovering from myocardial infarction aged 30 do 39 years, the erectile dysfunction decreased after 6 months, while in other age subgroups and between controls, there were no significant changes in erectile dysfunction prevalence during the analysed time period. We concluded that erectile dysfunction is a significant problem in patients recovering from myocardial infarction. It should be recognized on time in order to provide a better life quality for the patient with a multidisciplinary approach.

Exercise induced von Willebrand Factor release -- new model for routine endothelial testing.

Endothelial dysfunction (ED) is actively involved in the mechanism of occurrence, development and progression of all the degrees of atherosclerosis. The established impact of ED on the progress and outcome of cardiovascular diseases, together with convincing indications of a possible successful therapeutic modification, necessitate the changeover of ED assessment from experimental to a routine practice. As there is no appropriate method for a clinical practice, scientists anticipate significant research efforts in the further development. Among numerous methods already available, von Willebrand Factor (vWF) stands out significantly. In accordance with the accepted leading diagnostic role of vWF baseline levels in the group of peripheral endothelial markers, and earlier scientific observations on the absence of its expected reactivation during physical exercise, we hypothesised this promising theory. We believe that a constant stronger release of vWF in endothelial cell injury leads to the exhaustion of its stores in Weibel-Palade bodies with the consequent absence of the expected rise of concentration during the exercise. Therefore, we hypothesised that ED could be exhaustible vWF endothelopathy and the exercise induced release of vWF a new, simple, safe and reliable test for the detection of ED and monitoring of the expected therapeutic effect. In order to have a final clinical usability of the proposed diagnostic model, it is necessary to test its reliability in different pathological and risk states, and establish susceptibility in therapeutic procedures. The correlation with invasive functional angiographic tests and the flow mediated dilatation test of peripheral arteries also needs to be validated. We expect the proposed test of vWF inducibility to find its place in clinical practice, i.e. in prevention, prediction and therapy of cardiovascular diseases.

[Physical activity in the prevention and treatment of cardiovascular diseases]. / Tjelesna aktivnost u prevenciji i lijecenju kardiovaskularnih bolesti.

Cardiovascular diseases represent the leading health problem of the modern age. They are the first cause of mortality in developed as well as in transition countries. Physical activity has a beneficial impact on the cardiovascular system, both directly by improving endothelial function and indirectly by normalizing risk factors of atherosclerosis, such as dyslipidemia, high blood pressure, obesity and by positive effects on coagulation mechanism. The impact of physical activity on the cardiovascular system is manifested by immediate changes in hemodynamics, blood pressure and heart rate during physical training. After some time, consequences of continuous training are manifested as a decrease in the basal heart rate, blood pressure and heart rate responsiveness to physical activity stress, which indicates good conditioning i.e. increased physical capacity. Prospective epidemiological studies have shown that sedentary style of life has a twice-higher risk of sudden death and cardiovascular mortality. Physical activity should be permanent to have positive effects on the cardiovascular system; it means 4 to 5 times weekly depending on duration and intensity of exercises. In case of exercises 60-75% of the maximum, duration should be 30 to 45 minutes. Evidence based data show a 20-25 % lower mortality rate after myocardial infarction in the patients submitted to rehabilitation program of physical exercises. Physical activity in patients with coronary artery disease must be individualized, quantified and under control. In subjects with impaired function of the heart muscle, physical activity is limited with characteristic symptoms - dyspnea and stenocardia. These patients are classified into groups with mild, moderate and high risk, and based on this the allowed intensity of their physical activity is assessed, as well as the grade of its control. Physical exercises must be without range of tolerance and must not exceed this limit of symptoms. The aim of physical activity and training is increasing threshold of tolerance of symptoms. It has been shown that physical training in controlled quantities decrease relative risk of mortality by 35% and hospitalization by 28% in chronic heart failure. Physical training is beneficial for all forms of heart failure in terms of decreased mortality and improvements of the muscle mass and physical status.

[Endothelial function in clinical practice]. / Endotelna funkcija u klinickoj praksi.

Endothelial dysfunction is the essential occurrence in an early phasis of atherogenic process, pointing at the first functional disturbances of cardiovascular system at endothelial level. By the assessment of endothelial dysfunction, subjects with the increased risk for cardiovascular incidents in preclinical phasis, can be selected. Non-invasive assessment of endothelial function with ultrasound test is the new non-invasive measurement that has enabled the assessment, observation and the repeated tests without any limit or risk for the patient, and all in a frame of primary and secondary prevention of cardiovascular diseases.