Viktor Čulić

Correlation between symptomatology and site of acute myocardial infarction.

OBJECTIVE We determined the occurrence of presenting symptoms in patients with different sites of acute myocardial infarction after controlling for age and conventional risk factors. METHODS Hospital-based study of patients hospitalized because of first anterior (n=731), inferior (n=719) and lateral (n=96) infarction in Clinical Hospital Split between 1990 and 1994. Data form about presenting symptoms and clinical profile was completed for each patient. RESULTS Anterior infarctions were more often presented by headache (adjusted odds ratio (OR)=1.67, 95% CI=1.06-2.62), weakness (OR=1.60, 95% CI=1.31-1.96), dyspnea (OR=1.40, 95% CI=1.14-1.72), cough (OR=2.24, 95% CI=1.59-3.16), vertigo (OR=2.04, 95% CI=1.40-2.99) and tinnitus (OR=2.09, 95%CI=1.06-4.14). Inferior infarctions were more often associated with epigastric (OR=1.71, 95%CI=1.30-2.24), neck (OR=1.47, 95% CI=1.10-1.98) and jaw pain (OR=2.16, 95% CI=1.42-3.27), sweating (OR=1.56, 95% CI=1.27-1.92), nausea (OR=2.01, 95%CI=l.64-2.46), vomiting (OR=1.55, 95% CI=1.22-1.97), belching (OR=1.57, 95% CI=1.21-2.03) and hiccups (OR=2.88, 95%CI=1.53-5.42). Patients with lateral infarctions were more likely to complain of left arm (OR=1.80, 95% CI=1.07-3.05), left shoulder (OR=1.82, 95% CI=1.19-2.79) and back pain (OR=2.40, 95% CI=1.28-4.46). Pain was less frequently reported by hypercholesterolemic (P=l.4x10(-7)), patients over 70 years (P=0.002), women (P=0.0007) and those with non-triggered infarction (P=0.0009), whereas those over 70 (P=1.7x10(-6)) and men (P=0.0003) were less likely to report other relevant symptoms. CONCLUSIONS Our study suggests a linkage between different infarction sites and specific groups of symptoms. Furthermore, coronary patients should give their full attention to non-specific symptoms and any kind of discomfort.

Dermatological indicators of coronary risk: a case-control study

OBJECTIVE We examined the association of dermatological signs such as baldness, thoracic hairiness, hair greying and diagonal earlobe crease with the risk of myocardial infarction in men under the age of 60 years. METHODS A hospital-based, case-control study included 842 men admitted for the first non-fatal myocardial infarction, the controls were 712 men admitted with noncardiac diagnoses, without clinical signs of coronary disease. The relative risks were estimated as odds ratios. Logistic regression was used to control for the confounding variables. RESULTS Baldness, thoracic hairiness and earlobe crease were approximately 40% more prevalent in cases (P<10(-6) in each case). In both cases and controls, baldness and thoracic hairiness were frequently coexistent, as well as hair greying and earlobe crease (P<10(-4) in each case). After allowing for age and other established coronary risk factors, the relative risk of myocardial infarction for fronto-parietal baldness compared with no hair loss was 1.77 (95% CI 1.27-2.45) and it was 1.83 (95 CI 1.4-2.3) for men with thick, extended thoracic hairiness. The presence of a diagonal earlobe crease yielded a relative risk of 1.37 (95% CI 1.25-1.5), while hair greying was associated with myocardial infarction only in men under the age of 50 years. CONCLUSION It appears that baldness, thoracic hairiness and diagonal earlobe crease indicate an additional risk of myocardial infarction in men under the age of 60 years, independently of age and other established coronary risk factors.

Gender differences in triggering of acute myocardial infarction

The frequencies of potential triggers of acute myocardial infarction differ between men and women. There is a possibility that anti-ischemic drugs protect against trigger-related infarctions.

Acute myocardial infarction: differing preinfarction and clinical features according to infarct site and gender.

While differences between anterior and inferior acute myocardial infarction have been observed, clinical features of lateral infarction are poorly investigated. However, the impact of gender on clinical course and prognosis after myocardial infarction is not fully understood. Electrocardiographically determined infarct site, demographic and clinical variables were prospectively recorded for 1623 consecutive patients admitted to Clinical Hospital Split between 1990 and 1994 due to a first Q-wave acute myocardial infarction. Anterior infarctions were correlated with a higher prevalence of diabetes (P=4 x 10(-6)) or pulmonary venous congestion (P=2 x 10(-12)); inferior infarctions were correlated with a lower prevalence of hypertension (P=0.001), hypercholesterolemia (P=0.02) or diabetes (P=10(-5)), and a higher prevalence of smoking (P=0.001); lateral infarctions were characterized by a smaller infarction size and lower prevalence of pulmonary congestion (P=0.002). Among men under the age of 50 with inferior infarction there were 90% smokers, which was significantly more than among their gender (P=0.005) or infarct site (P=2 x 10(-5)) counterparts. After adjustment for age and other confounding factors, the prevalence of inferior infarction was higher in men (P=0.002). Increased age (P=0.002), female gender (P=0.0006), anterior site (P=10(-5)), diabetes (P=0.0003), greater creatine kinase-MB fraction level (P=0.001) and pulmonary congestion (P=9 x 10(-6)) were independent predictors of an adverse hospital outcome. Each site of acute myocardial infarction has relatively specific preinfarction and clinical features. Our results suggest a greater importance of vasoconstriction in the pathophysiology of inferior infarction, especially in young male smokers, and greater importance of advanced atherosclerotic process in occurrence of anterior infarction.

Gender differences in in-hospital mortality and mechanisms of death after the first acute myocardial infarction

BACKGROUND There are conflicting data about gender differences in short-term mortality after acute myocardial infarction (AMI) after adjusting for age and other prognostic factors. Therefore, we investigated the risk profile, clinical presentation, in-hospital mortality and mechanisms of death in women and men after the first AMI. METHODS The data were obtained from a chart review of 3382 consecutive patients, 1184 (35%) women (69.7±10.9 years) and 2198 (65%) men (63.5±11.8 years) with a first AMI. The effect of gender and its interaction with age, risk factors and thrombolytic therapy on overall mortality and mechanisms of death were examined using logistic regression. RESULTS Unadjusted in-hospital mortality was higher in women (OR 1.77, 95% CI 1.47–2.15). Adjustment that included both age only and age and other base-line differences (hypertension, diabetes mellitus, hypercholesterolemia, smoking, AMI type, AMI site, mean peak CK value, thrombolytic therapy) decreased the magnitude of the relative risk of women to men but did not eliminate it (OR 1.26, 95% CI 1.03–1.54 and OR 1.31 95% CI 1.03–1.66, respectively). Multivariate analysis revealed that female gender was an independent predictor of in-hospital mortality after the first AMI. Women were dying more often because of mechanical complications—refractory pulmonary edema and cardiogenic shock (P=0.02) or electromechanical dissociation (P=0.03), and men were dying mostly by arrhythmic death, primary ventricular tachycardia/fibrillation (P=0.002). Female gender was independently associated with mechanical death (OR 1.56, 95% CI 1.35–2.58; P=0.01) and anterior AMI was independently associated with arrhythmic death (OR 0.54, 95% CI 0.34–0.86; P=0.01). CONCLUSION Our results demonstrate significant differences in mechanisms of in-hospital death after the first AMI in women and men, suggesting the possibility that higher in-hospital mortality in women exists primarily because of the postponing AMI death due to the gender-related differences in susceptibility to cardiac arrhythmias following acute coronary events.

Triggering of supraventricular tachycardia by physical activity and meteorologic factors.

Supraventricular tachycardia (SVT) is an episode of paroxysmal tachycardia that requires either atrial tissue or atrioventricular node, or both, for its initiation andmaintenance [1].With the prevalenceof about 2.25 per 1000, SVT affects about 35 of 100000 persons per year [1,2]. Clinical presentation of this arrhythmia includes symptoms such as palpitations, chest pain or discomfort, dyspnea, light headedness, anxiety, fear, syncope and polyuria [1,3,4]. Physical activity, various kinds of emotional stress, air pollution, and unfavorable weather conditions have been established as triggers of both cardiac arrhythmias [5–10] and acute coronary syndrome [11–14]. The objective of the present study was to separate the influence of chronic modifying factors from the effect of external triggers on the occurrence of episodes of SVT. Consecutive inand outpatients assigned to undergo continuous 24-hour Holter monitoring between January and April 2001 in the Diagnostic Units of the Division of Cardiology, Department of Internal Medicine, University Hospital Centre Split, Split, Croatiawere eligible for inclusion in this prospective observational study (n= 501). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the University Hospital Centre Split. All participants gave their informed consent. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Patientswhowere unable to complete the diary, had atrialfibrillation or flutter, or their ECG recordings were inaccurate due to artifacts were excluded from the analysis (n = 94). The data forms covered demographic characteristics, clinical risk factors, medication used, and information on the exact time of exposure to physical activity or emotional upset. An activity compatiblewith level 4 or more according to a metabolic equivalents scale from 1 to 8 was considered as physical activity. An emotional state compatiblewith level 3 or more according to the Onset Anger Scale was considered as emotional upset [5,6,8]. Meteorologic data were provided by the State Hydrometeorological Institute, Marine Meteorological Centre, Split for every 3 h during the days of the study period. The 24-hour Holter recordings were first analyzed and edited automatically and then carefully visually and manually monitored by a cardiologist to annotate artifacts and morphological and rhythm irregularities. A SVT was defined as regular or irregular narrow QRS complex tachycardiawith3ormore consecutive beatswith aheart rate of 100 or more beats per minute. The frequency of SVT in an hour was expressed as a percentage of all episodes during recording. The influence of both absolute levels and change in level of meteorologic parameters during 3-hour intervals on SVT occurrence was assessed. Linear regression analysis was used to investigate the impact of continuousmeteorologic factors. Repeated measures analysis of variance (ANOVA) was used to estimate whether the frequencies of SVT episodes differed according to time of day. A two-way ANOVAwas run to assess whether the circadian pattern of SVT occurrence depended on participant baseline characteristics. Multi-way ANOVA was used to adjust the diurnal and wind directiondependent variation in frequency of SVT for other triggering factors. A stepwise multiple regression analysis was used to assess the independent predictive significance of triggering and modifying factors on occurrence of SVT. Characteristics of the study participants are presented in Table 1. Multivariate selection models for the independent significance of modifying factors in predicting the occurrence of SVT according to gender and age are given in Table 2. The episodes of SVT were significantlymore frequent during the periods of physical activity (7.19% vs. 2.52%, p b 0.0001) but showed no association with the periods of emotional upset (2.81% vs. 2.77%, p = 0.97). Physical activity remained the leading independent predictor of SVT in thefinalmultiple regression models in all participant subgroups (Tables 3 and 4).

Triggering of supraventricular premature beats. The impact of acute and chronic risk factors.

Supraventricular premature beat (SPB) is usually considered a benign heart rhythm disturbance. However, an isolated SPB can trigger episodes of atrial fibrillation [1,2], supraventricular tachycardia [3] and malignant ventricular tachyarrhythmia [4,5]. A high frequency of SPB has been linked to the increased risk of death or stroke [6,7]. Circadian, weekly and annual variations in the occurrence of ventricular tachyarrhythmias and triggering by emotional and physical stress have been well-described [8–14]. Until now, factors that could be involved in the triggering of supraventricular arrhythmias have not been rigorously investigated. Consecutive patients who underwent continuous 24-hour Holter monitoring between January and April 2001 in the Diagnostic Units of the Division of Cardiology, Department of Internal Medicine, University Hospital Split, Split, Croatia (n=501), were eligible for inclusion in the analysis. Patients who were unable to complete the diary, had atrial fibrillation, or their ECG recordings were inaccurate due to artifacts were excluded from the analysis (n=63). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the University Hospital Split. All participants gave their informed consent. The authors of this article have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [15]. The identification of SPB was based on 3 criteria: prematurity, morphology, and postcontraction pause. An SPBwas defined as a QRS of less than 0.12 seconds with a minimum shortening of 20% in the R-R interval. QRS complexes of duration of more than 0.12 seconds were considered SPB only if aberration was suspected. The postcontraction pause had to be noncompensatory. Differentiation from sinus arrhythmia was made according to the P-wave morphology, cyclic changes in preceding R-R intervals, or both. Activity compatible with level 4 or more according to a metabolic equivalents scale from 1 to 8 was considered as exposure to physical activity. Exposure to emotional upset was defined as an emotional state compatible with level 3 or more according to the Onset Anger Scale [8,10,16]. Meteorologic parameters (atmospheric temperature and pressure, relative airmoisture, wind speed and direction, rainfall and passages of coldorwarmatmospheric fronts)wereprovided for every 3 hours (at 1, 4, 7 and10AM, and1, 4, 7 and10PM). The frequencyof SPB in anhourwas expressed as a percentage of all episodes during recordingwhich reduced the distribution of absolute number of SPB during monitoring and made the data normally distributed. Linear regression analysis was used to investigate the direct impact of continuous meteorologic factors, repeated measures analysis of variance (ANOVA) to estimate whether the frequencies of SPB differed according to time of day, a two-way ANOVA to assess whether the circadian pattern of SPB occurrence depended on baseline characteristic and multi-way ANOVA was used to investigate the frequency of SPB according to physical, emotional and meteorologic stressors. A stepwise multiple regression analysis was used to simultaneously assess the independent predictive significance of both acute triggering and chronic (conventional) risk factors and medication. Baseline characteristics of the 438 participants are given in Table 1 and preliminary models for multivariate analysis according to age and gender are given in Table 2. Physical activity, followed by the periods of increasing relative air moisture (Fig. 1), showed the strongest association with the occurrence of SPB and both remained significant predictors in all participant subgroups (Tables 3 and 4). The occurrence of SPB was somewhat higher during blowing of southerly and westerly winds (Fig. 2), but after adjustment for other external triggering factors the significance of this difference disappeared (p=0.77). Atmospheric pressure was a predictor of SPB in men, while lower levels of relative air moisture and passage of

Severity of acute heart failure in men according to diabetes mellitus: The role of testosterone and renal dysfunction

A large body of evidence suggests multi-directional mechanisms linking diabetes mellitus (DM) with heart failure (HF) including a worse prognosis of HF in patients with coexisting DM [1–4]. Several comorbidities commonly associated with DM, primarily secondary anemia [3,5–7] and chronic renal failure [3,5,6], have been proposed to explain this link. Apart from that, a decline in the testosterone levels (TL), also commonly and independently linked to the DM [8–10], seems to be one of the most salient factors for the prognosis of HF patients [11–14]. At the moment, the nature of interactions among DM, low TL, renal function, anemia and HF are not fully understood. We sought to investigate the independent influence of DM and associated comorbidities on the severity of cardiovascular dysfunction in men hospitalized because of an acute episode of HF. To objectively assess the severity of cardiovascular failure, we used the N-terminal pro-type B natriuretic peptide (NT-proBNP), a reliable laboratorymarker of the severity and prognosis of left ventricular failure [15,16]. We included 82 consecutive male patients hospitalized with heart failure at the Division of Cardiology, Department of Internal Medicine, University Hospital Centre Split, between December 1, 2011, and November 1, 2012. The inclusion criteria were: 1) clinical presentation typical for HF; 2) LVEF equal to or less than 45% (using the Simpson method), and/or diastolic dysfunction determined by echocardiography; and 3) unchangedmedications for at least 1 month prior to the study. Exclusion criteria were: 1) acute coronary syndrome or coronary revascularization within the 6 months preceding the study; 2) acute or chronic disease that could affect hormonal metabolism (i.e., acute or chronic infections, autoimmune or malignant diseases, previously established primary endocrine disorders, primary liver diseases, terminal renal failure); 3) any hormonal treatment or drugs noticeably inhibiting hormone production either at the time of the study or in the past. The study protocol was approved by the Ethics Committee of the University Hospital Centre Split. All patients gave a written informed consent. Blood samples were taken within the first 24 hours of hospitalization. Serum concentration of testosterone (in nmol/L) and plasma concentration of NT-proBNP (in pmol/L) were measured by using immunoassays (Roche Diagnostics GmbH, Mannheim, Germany). Renal function was assessed by using the estimated glomerular filtration rate (GFR, in mL/min/1.73 m) calculated from the Modification of Diet in Renal Disease equation [17].

Lower Contribution of Factor V Leiden or G202104 Mutations to Ischemic Stroke in Patients With Clinical Risk Factors Pair-Matched Case-Control Study

It was suggested that factor V Leiden and prothrombin G20210A mutations increase the risk of ischemic stroke only in combination with clinical risk factors of arterial ischemic disease. In these studies the controls were derived from the general population, with fewer clinical risk factors, which might have produced biased results. The factor V Leiden and prothrombin G20210A mutations were examined by polymerase chain reaction technique in 120 ischemic stroke patients and 120 controls younger than 65 years of age. Each patient had his own control, tightly matched in clinical risk factors. The prevalences of factor V Leiden and prothrombin G20210A mutations in patients were 8.3% (P = 0.02) and 7.5% (P = 0.04), respectively, and 2.5% for controls for both mutations. All carriers were single heterozygotes. In patients, but not in controls, the carriers of either mutation were mostly women and with fewer clinical risk factors for arterial ischemic events. In particular, considering both mutations as a single coagulation deficit, their presence increased the likelihood of ischemic stroke (odds ratio [OR] = 3.6; 95% confidence interval [CI] 1.4—9.3), especially among women (OR = 4.6; 95% CI: 1.2—17.8), normotensive persons (OR = 9.2; 95% CI: 1.1—17.8) and those having normal cholesterol (OR = 5.9; 95% CI: 1.6—21.2) and triglyceride serum concentrations (OR = 4.3; 95% CI: 1.5—12.8). In the studied sample of adult North Mediterranean population younger than 65 years the prevalences of factor V Leiden and prothrombin G20210A mutations were greater in patients with ischemic stroke than in matched controls. Unlike in studies with unmatched controls, we observed an apparently negative interaction of these mutations with clinical risk factors.

Diagonal Ear Lobe Crease and Coronary Artery Disease

A recent paper published in the AJE1 regarding the relation of diagonal ear lobe crease (DELC) with coronary artery disease (CAD) raised our great interest, because it addressed an important issue linked to our previous research about dermatologic indicators of coronary risk.2 In the study by Shmilovich et al, the observation that DELC is independently and significantly associated with the increased prevalence, extent, and severity of CAD supports the results of several investigations, including our one, that have been published within last decades. However, because the prevalence of DELC increases with age, as does atherosclerotic diseases, other investigators denied this association and pointed out that age most importantly influences the appearance of DELC. Since age is one of the most important cardiovascular risk factors, and advanced age is associated with an increased incidence of DELC, baldness, hair graying and wrinkling of the skin, we set the hypothesis that the premature or extensive occurrence of these dermatological signs in males under 60 could suggest a person with an accelerated atherosclerosis. In our hospital-based case-control study, which included 842 men under the age of 60 years admitted for the first nonfatal myocardial infarction (MI) and 712 controls admitted with noncardiac diagnoses without clinical signs of CAD, we examined the association of above mentioned dermatological signs with the risk of MI. All of those signs were more common among cases compared to control, while the parietal baldness and DELC were the strongest predictors of MI. By using highly sensitive and specific imaging method in a large cohort of consecutive patients, the study by Smilovich et al.1 in vivo confirmed our hypothesis. In this consideration, other dermatological indicators of cardiovascular risk should not be ignored. Several studies have demonstrated an independent association between parietal baldness, hair graying and wrinkling of the skin with CAD. It seems that these dermatological features in CAD patients have more than esthetic meaning. Because younger persons with such features appear older than their age pairs, and perhaps these changes could be an omen of premature biological aging. Recently published data suggest that free radical oxidative stress (ROS) could be a mechanism linking dermatological signs with cardiovascular diseases. Namely, ROS – a mechanism important in atherogenesis - is enhanced in the hair follicle melanocytes and leads to their selective premature aging and apoptosis. A similar mechanism could be involved in the pathogenesis of skin damage, causing its aging, wrinkling or DELC development, by activating the metalloproteinases that break down type I collagen. ROS is one of the principal mechanisms in the shortening of telomeres, which represent ‘biological clock’ of the cell. Telomeres shortening in leukocytes may reflect cumulative burden of oxidative stress and inflammation in circulation during an individual’s lifetime. A close relationship between telomeres length in leukocytes and vascular cells confirms the leukocytes telomeres shortening as a useful marker of accelerated cardiovascular aging. In that same line, shorter leukocytes telomeres in patients with DELC than in their age matching pairs without that sign, supports appearance of DELC at an earlier age as a sign of disproportion between chronological and biological age of an individual. Finally, a positive association of DELC with carotid IMT and arterial stiffness, widely accepted markers of subclinical atherosclerosis, has also been demonstrated. Therefore, the presence of DELC may be an independent surrogate marker of atherosclerosis, even in patients with no traditional cardiovascular risk factors or clinically expressed cardiovascular diseases. A man is as old as his arteries said English physician Thomas Sydenham in the seventeenth century. Presence of some dermatological signs might indicate an advanced arterial age regardless of the number, duration or magnitude of traditional cardiovascular risk factors. That is why above mentioned potential dermatological indicators of premature biological aging should be further investigated and could be considered together with traditional factors in assessing cardiovascular risk and diagnostic approach in some patient