The CYP2C19*2 and CYP2C19*17 Polymorphisms play a Vital Role in Clopidogrel Responsiveness after Percutaneous Coronary Intervention: A Pharmacogenomics Study.

Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. A total of 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study. Platelet reactivity (PRU) and % inhibition were measured with VerifyNow P2Y12 assay in blood samples collected from patients who took a standard dose of clopidogrel (75 mg/day) for at least 7 days. The variants in the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes were genotyped using the Sequenom MassARRAY system. When grouped, the patients with PRU values >208 as non-responsiveness to clopidogrel therapy; 104 (30%) patients were non-responders and 243 (70%) patients were responders. A significant association was found between the CYP2C19*2 (G636A) polymorphism and non-responsiveness to clopidogrel therapy (p < 0.001). An allele frequency of this single nucleotide polymorphism was high in non-responders; its odds ratio was 2.92 compared with G allele (p < 0.001). PRU values of CT genotypes were lower (p = 0.029) and % inhibition values of CT genotypes were higher (p = 0.008) compared with CC genotypes for the CYP2C19*17 (C806T) polymorphism. None of the other genetic variants were found to be statistically associated with non-responsiveness to clopidogrel and antiplatelet activity. Our findings suggest that the CYP2C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2C19*17 polymorphism enhances antiplatelet activity of clopidogrel. Depending on haplotypes of these two polymorphisms, clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events.

Transitions in skin blood flow fractal scaling: the importance of fluctuation amplitude in microcirculation.

Detrended fluctuation analysis (DFA) of laser Doppler flowmetry (LDF) time series from volar skin reveals three scaling regions: cardiac, cardio-respiratory and local. Scaling exponents, slopes (αC, αCR and αL) of the straight lines, in these regions indicate correlation properties of LDF signal. Transitions from uncorrelated to positive in cardiac (αC) and positive to negative correlations in the cardio-respiratory (αCR) exponent have been observed for vasodilatation signals in response to local heating. However, positive correlation in local region (αL) did not change with vasodilatation. We studied whether the transitions in scaling exponents are correlated with the increase in peak to peak fluctuation amplitude (AF) of LDF signal. LDF signals were normalized to unity using average values of their pulsatile parts: baseline and saturation signals. If AF of normalized LDF signal is ≥0.5, we observed transitions in αC and in αCR but not in αL, in healthy subjects. It is suggested that the transition from positive to negative correlation in αCR with increasing amplitude may be explained by intact arteriolar myogenic activity in healthy young (Y) and middle aged (MA) subjects. In contrast, we did not observe transition in αCR suggesting impaired myogenic activity in patients with essential hypertension (EHT).

Angiotensin II type 1 receptor (AT1) gene A1166C is associated with the risk of hypertension.

AIM: This study was performed on primary hypertension patients in a Turkish population to determine the frequency of the A1166C polymorphism in the angiotensin II type 1 receptor (AT1) gene and to examine the role of this polymorphism in hypertension development. MATERIALS AND METHODS: In this study, 250 genomic DNA samples were collected (from 142 hypertension patients and 108 healthy subjects), randomized, and analyzed. Genomic DNA was prepared from peripheral blood using the salt extraction method. The presence of the A1166C polymorphism in the AT1 gene was determined using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. PCR products were separated by 2% agarose gel electrophoresis and visualized by a charge-coupled device camera. RESULTS: Genotype distribution and allele frequency A1166C genotype frequency was determined as AA 96.3% and AC 3.7% for controls and as AA 86.6% and AC 13.4% for patients. A statistically significant difference was found between the control group and patients in terms of genotype and allele frequency. CONCLUSION: Our results suggest that an interaction exists between the AT1 gene polymorphism and hypertension in the Turkish population.

Comparative study of the upper and lower limb skin blood flow control mechanisms in patients with essential hypertension.

OBJECTIVE: To investigate limb specific differences in cutaneous vascular function in patients (n=33) with essential hypertension (EHT). METHODS: In this observational cross-sectional study, baseline skin blood flow and the response to local heating were measured with a laser Doppler flowmeter (LDF) from the volar region of the forearm and the gaiter area of the foot at supine rest. The fractal analysis, detrended fluctuation analysis (DFA), was used to calculate the correlation properties of skin blood flow, LDF signal. The paired t-test and repeated measures ANOVA were used to determine the response to local heating and compare the scaling exponents of different anatomical locations respectively. RESULTS: We found three linear scaling regions that describe the fractal behavior of LDF signal with their slopes, scaling exponents. For cardiac (α(C)) and cardio-respiratory (α(CR)) scaling exponents, thermal hyperemia (T) induced greater change in the leg (α(C)=1.49 ± 0.26; α(CT)=1.62 ± 0.20 p<0.01 and α(CR)=0.84 ± 0.29 α(CRT)=0.42 ± 0.28 p<0.001) than in forearm (α(C)=1.28 ± 0.13; α(CT)=1.33 ± 0.13 p>0.05 and α(CR)=0.73 ± 0.15; α(CRT)=0.65 ± 0.018 p<0.05). Local scaling exponents (α(L) ≈ α(LT) ~ 1) were not significantly different (p>0.05) and, local lines did not shift in parallel with local heating in both extremities. CONCLUSION: The results of the present study suggest that skin microvascular function is impaired in both extremities in EHT patients. However, myogenic response is not uniform in both extremities and pronounced response to local thermal hyperemia has been observed in the gaiter area compared with the volar region. Further studies are needed to determine if these limb specific microvascular differences is the result of posture-induced structural and functional adaptation.

Diagnostic value of heart-type fatty acid binding protein determined by the rapid qualitative chromatographic immunoassay method for the detection of minor myocardial damage in patients presenting with non-ST elevation acute coronary syndrome.

OBJECTIVE: The aim of this prospective study was to evaluate the diagnostic value of heart-type fatty acid binding protein (H-FABP) determined by qualitative immunoassay method for the detection of minor myocardial damage (MMD) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). METHODS: The study consisted of 62 patients with NSTE-ACS. Cardiac troponin I (cTnI) and creatine kinase MB isoenzyme (CK-MB) values were measured at arrival. Myoglobin and H-FABP were obtained if cTnI level was found to be elevated. A control group included 20 subjects with normal cTnI and CK-MB values. H-FABP was determined by a rapid qualitative immunochromatographic test. Patients were classified as MMD-ACS group if they had abnormal cTnI and normal CK-MB (n=24) and as NSTEMI-ACS group if they had elevated both cTnI and CK-MB (n=38). The diagnostic accuracy of H-FABP for minor myocardial damage was determined using ROC analysis. RESULTS: The sensitivity of the H-FABP was significantly higher for NSTEMI-ACS than for MMD-ACS (44.7% vs 0%, p<0.001) and its specificity was 95% for both groups. The diagnostic efficacy rates for myoglobin and H-FABP were 75% and 43% for MMD-ACS, 74% and 62% for NSTEMI-ACS. Positive predictive value for H-FABP and myoglobin were found to be 0% and 80.8% in MMD-ACS, 94% and 87% in NSTEMI-ACS and negative predictive value was 44% and 69.5% in MMD-ACS, 47.5% and 59% in NSTEMI-ACS, respectively. AUC for myoglobin was significantly greater than that for H-FABP in MMD-ACS group (0.754 vs 0.525, p=0.027). The sensitivity of the H-FABP was significantly higher in patients with >3-fold increase in cTnI than those with <3-fold increase in cTnI (46.8% vs. 6.7%, p<0.001). A positive correlation was found between the magnitude of cTnI rise and H-FABP results (r=0.45, p<0.001). CONCLUSIONS: H-FABP determined by the rapid qualitative immunochromatographic test has almost similar diagnostic value to that of myoglobin for identifying NSTEMI-ACS, however, does not seem to represent diagnostic potential for the detection of MMD.

Effectiveness of cardiac simulator on the acquirement of cardiac auscultatory skills of medical students.

BACKGROUND: Cardiac simulators have been developed as an alternative training model in order to improve the cardiac auscultation skills of medical students. The effectiveness of the cardiac simulator's use in cardiac auscultatory training is presently not yet well established. OBJECTIVES: The authors aimed to investigate whether the use of a cardiac simulator can improve the auscultation skills of medical students. MATERIAL AND METHODS: The students taking the auscultation training on the cardiac simulator were grouped as Group A and the students not taking the auscultation training on the cardiac simulator were grouped as Group B (before). The students in Group B (before) were grouped as Group B (after) after receiving the auscultation training on the cardiac simulator. The percentages of accurate diagnoses for the tested heart murmurs were compared between Group A and Group B (before), and between Group B (before) and Group B (after). RESULTS: The rate of making correct diagnoses of normal heart sounds was similar in all the groups (Group A, Group B (before), and Group B (after)). By contrast, the percentage of accurate diagnoses for the tested heart murmurs was notably improved among the students in Group A with respect to Group B (before) (p < 0.01). Similarly, the rate of correct diagnoses for the tested heart murmurs was markedly higher among the students in Group B (after) than in Group B (before) (p < 0.01). CONCLUSIONS: The use of a cardiac simulator as a training tool can improve the auscultation skills of medical students quickly and efficiently.

Fractal scaling of laser Doppler flowmetry time series in patients with essential hypertension.

The full diagnostic potential of the fractal complexity measure, α, of detrended fluctuation analysis (DFA) has not been realized yet. To reveal the impaired mechanisms in the blood flow regulation in patients with essential hypertension (EHT), we studied the laser Doppler flowmetry (LDF) time series by applying DFA. Forearm microvascular blood flow was measured by LDF during supine rest. After a 15 min baseline recording, microvascular response to thermal hyperemia was measured over 30 min. We found three distinct scaling regions; corresponding to the integration of local mechanisms, cardiac effect on local blood flow, and the coupling of extrinsic factors (cardiac and respiratory) to local blood flow by myogenic mechanism. In the control group, local scaling exponent, α(L)=0.96 ± 0.08, did not change but cardiac scaling exponent, α(C)=1.53 ± 0.05, for baseline signal was increased to α(CT)=1.73 ± 0.10 and cardio-respiratory scaling exponent, α(CR)=0.73 ± 0.19, was decreased to α(CRT)=0.24 ± 0.06 during vasodilatation in response to local heating. However, we found significantly different scaling exponents, α(LT)<1, α(CT) ≥ α(C)<1.5 and α(CR) ≈ α(CRT)>0.5 in patients with EHT. Our findings suggest that the local regulatory and the cushioning peripheral vascular functions are impaired in patients with EHT, and vascular/microvascular pathology can be evaluated by applying DFA to LDF signal.

[Our initial experience with stent implantation for aortic coarctation in adults]. / Eriskinlerde aort daralmasinin stent ile tedavisine iliskin ilk deneyimlerimiz.

OBJECTIVES: We evaluated the procedural success and short-mid term results of stent implantation for aortic coarctation in adults. STUDY DESIGN: The study included 15 consecutive patients (9 women, 6 men; mean age 27±7 years; range 17 to 45 years) treated with stent implantation for aortic coarctation. Fourteen patients had native, one patient had recurrent coarctation. Nine patients received bare metal and six patients received covered Cheatham-Platinum stents. Covered stents were used in patients with accompanying patent ductus arteriosus (n=2), severe coarctation (n=3), and recurrent coarctation (n=1). Procedural success was defined as the reduction in the pressure gradient across the coarctation site to less than 20 mmHg. The mean follow-up period was 10.4±4.6 months (range 3 to 18 months). RESULTS: Stent implantation was successful in all the patients. Compared to the preprocedure figures, systolic gradient across the aortic coarctation decreased from 37.2±11.3 mmHg to 3.5±2.9 mmHg, the diameter of the coarcted aortic segment increased from 5.4±1.5 mm to 17.2±1.4 mm, and systolic blood pressure declined from 154±9.7 mmHg to 130±7.3 mmHg following stenting (for all, p<0.001). There were no procedure-related major complications. CONCLUSION: Stent implantation for aortic coarctation in adults is a safe and effective alternative to surgical correction.

Mode of onset of polymorphic ventricular tachycardia in acute myocardial infarction.

BACKGROUND: Polymorphic ventricular tachycardia (PVT) can occur during acute myocardial infarction (MI). In the past, studies investigated the initiation pattern of ventricular tachycardias in different patient populations; however, the mode of onset of PVT in acute MI patients has not been investigated previously. OBJECTIVE: To retrospectively investigate the electrophysiological features of PVT with different initiation patterns in acute MI patients to assess whether there is a relationship of the initiation patterns of PVT with clinical and electrophysiological characteristics. METHODS: Sixty-two rhythm strips defined as PVT from 53 patients (mean [± SD] age 63±8 years) with acute ST elevation MI were analyzed. All patients were monitored while they were hospitalized in the coronary care unit, and the electrocardiogram strips were obtained from continuous monitoring. PVT was defined as sudden-onset tachycardia if it was not preceded by ventricular ectopic beats. PVT that was preceded by single or multiple ectopic beats was defined as nonsudden-onset tachycardia. RESULTS: Nonsudden-onset episodes were more common than suddenonset episodes (40 episodes [64.5%] versus 22 episodes [35.5%]). In the nonsudden-onset group, 25 episodes (62.5%) were initiated after a single ectopic beat, while 15 episodes (37.5%) were initiated after multiple complexes. The mean (± SD) left ventricular ejection fraction of patients with nonsudden-onset PVT was decreased (53±6% versus 65±7%, P<0.01). Nonsudden-onset tachycardias had lower coupling intervals than suddenonset tachycardias. Similarly, the PVT cycle length was shorter in the presence of nonsudden-onset initiation. When nonsudden-onset PVT episodes were further subclassified based on the morphology of the first beat of tachycardia, 26 PVTs (65%) had a first beat of tachycardia similar to the subsequent PVT beats and 14 (35%) did not. CONCLUSIONS: These results demonstrate that PVT is often preceded by ventricular ectopy in acute MI patients. Nonsudden-onset PVT is usually characterized by a lower coupling interval, shorter PVT cycle length and an associated lower ejection fraction.

Plasminogen activator inhibitor type-1 gene 4G/5G polymorphism is associated with hypertensive patients in the Turkish population.

This study has been performed on hypertensive patients in the Turkish population to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene and with the aim of examining the role of this polymorphism in hypertension development. Genomic DNA obtained from 284 persons (176 patients with hypertension and 108 healthy controls) was used in the study. DNA was multiplied by polymerase chain reaction using 4G and 5G allele-specific primers. Polymerase chain reaction products were assessed by being exposed to 2% agarose gel electrophoresis. Results were evaluated with the chi-square test. The 4G allele frequency was 31.25% and the 5G allele frequency was 68.75% in patients, whereas it was 49/51% in a control group. 5G5G genotype was found statistically high (p < 0.001) in patients relative to controls. This study showed that the plasminogen activator inhibitor type-1 gene 4G/5G polymorphism and the 5G5G genotype appear to be associated with an elevated risk of developing hypertension in a representative sample of Turkish population.

[Levosimendan and dobutamine have a similar profile for potential risk for cardiac arrhythmias during 24-hour infusion in patients with acute decompensated heart failure]. / Levosimendan ve dobutamin akut dekompanse kalp yetersizliginde 24 saatlik infüzyon sirasinda benzer aritmi potansiyeli göstermektedir.

OBJECTIVES: Unlike traditional inotropic agents, levosimendan is thought to have a lower potential to induce arrhythmias because it does not increase intracellular calcium levels and myocardial oxygen consumption. We compared the potential effect of levosimendan and dobutamine to induce cardiac arrhythmias in patients with decompensated heart failure. STUDY DESIGN: Fifty patients with acute decompensated heart failure (NYHA class III-IV, ejection fraction <35%) who were in need of inotropic support were randomized to dobutamine (n=25; mean age 69±10 years) or levosimendan (n=25; mean age 67.5±11.5 years) and underwent 24-hour Holter monitoring before and during inotropic infusion. Holter recordings were analyzed with respect to heart rate (HR), ventricular premature contraction (VPC), couplets of VPC, supraventricular premature contraction (SVPC), paroxysmal atrial fibrillation (PAF), and nonsustained ventricular tachycardia (NSVT). RESULTS: Before infusions, the two groups were similar with respect to HR, VPC, couplets of VPC, SVPC, and PAF episodes, but the number of NSVT episodes was significantly higher in the levosimendan group. Heart rate and the number of VPCs increased significantly during infusions of levosimendan (p=0.036 and p<0.001, respectively) and dobutamine (for both p<0.001). Increase in couplets of VPC was significant only with dobutamine (p=0.012). The episodes of NSVT and PAF increased with levosimendan, without reaching significance. Levosimendan and dobutamine groups were similar in terms of percentage changes in arrhythmias (55±224% vs. 11±16% for VPC; 2±2.7% vs. 12±9% for couplets of VPC; 3.4±5.8% vs. 16±39% for SVPC, 0.4±2.8% vs. -2±0% for NSVT) and percentage change in total arrhythmias (41±190% vs. 18±35.4%), and the mean HR, VPC, couplets of VPC, SVPC, and episodes of NSVT and PAF (p>0.05). CONCLUSION: Our findings suggest that levosimendan and dobutamine have a similar profile for potential risk for cardiac arrhythmias.

Levosimendan is not effective in reducing pulmonary pressures in patients with idiopathic pulmonary arterial hypertension: report of two cases.

Currently, prostacyclin, endothelin receptor antagonists and phosphodiesterase inhibitors are recommended therapy in idiopathic pulmonary arterial hypertension. However, each of these drugs has limited efficacy in the improvement of clinical symptoms, pulmonary hemodynamics and long-term survival. Levosimendan, a novel calcium-sensitizing inodilator agent, has been shown to have pulmonary vasodilatory action. However, the potential pulmonary vasodilating effect of levosimendan in patients with idiopathic pulmonary arterial hypertension remains unclear. Levosimendan administered in two patients with nonvasoreactive idiopathic pulmonary arterial hypertension exhibited deterioration in clinical status, and, contrary to what was expected, levosimendan was found to increase pulmonary pressures and did not lead to a substantial improvement of the patient's condition.

[Utilization of intravascular ultrasound in coronary artery disease]. / Koroner arter hastaliklarinda intravasküler ultrason uygulamasi.

Intravascular ultrasound (IVUS) that found a significant place for itself in cardiac imaging area in recent years was able to penetrate into the field of use thanks to putting the ultrasound probe in the tip of catheter, which can navigate through the vein by miniaturizing it on a much smaller scale than we used to see. Various recent scientific studies showed IVUS is a valuable tool in assessing the natural course of coronary atherosclerosis and effects of different pharmacological and non-pharmacological approaches on the progression-regression of atherosclerosis. In addition, IVUS is also applied in studies evaluating the short- and long-term outcomes of different percutaneous coronary interventions including the implantation of drug-eluting stents.

Initiation patterns of monomorphic ventricular tachycardia in acute myocardial infarction: analysis of rhythm strips.

OBJECTIVE: Monomorphic ventricular tachycardias (MVT) frequently occur in the acute phase of myocardial infarction (MI). In the past, some studies aimed to investigate the initiation pattern of ventricular tachycardias, although not in acute MI patients. The aim of the present study was to analyse the initiation pattern of MVT in acute MI using rhythm strips. METHODS: This study utilized data on 255 rhythm strips defined as MVT, from 173 patients with acute ST-segment elevation MI. Monomorphic ventricular tachycardias that were not preceded by ventricular ectopic beats were defined as sudden onset MVT. Monomorphic ventricular tachycardias which were preceded by a single or multiple ectopic beats, including a short-long-short sequence, were defined as non-sudden onset MVT. RESULTS: Non-sudden onset episodes were more common than sudden onset episodes (172 episodes, 67.4% versus 83 episodes, 32.5%). The morphology of the ventricular ectopic beat initiating tachycardia was similar to the first beat of MVT in 127 episodes (73.8%), but not in the remaining 45 episodes (26.1%). In the non-sudden onset group, 117 episodes (68%) initiated with a single ectopic beat, while 55 episodes (32%) initiated with multiple complexes. The left ventricular ejection fraction of the patients with non-sudden onset MVT was lower (50 +/- 6 versus 56 +/- 5, P < 0.05). Monomorphic ventricular tachycardias with no sudden onset also had shorter coupling intervals (CI) (P < 0.001) and shorter prematurity index (PI) (P < 0.001) than MVT with sudden onset. Similarly, the ventricular tachycardia cycle length was shorter in the group of MVT subjects with non-sudden onset as compared with sudden onset (P < 0.05). In contrast, tachycardias with sudden onset were associated with a shorter preceding RR interval (P < 0.01). CONCLUSIONS: Analysis of rhythm strips demonstrated that MVT is most often preceded by ventricular ectopic beats in the acute phase of MI.

Can short-long-short sequences predict atrial fibrillation in acute inferior myocardial infarction?

Short-long-short sequences (SLSS), related to atrial ectopic beats (AEBs), predict the recurrence of atrial fibrillation (AF) in some clinical situations. We investigated whether SLSS predict the occurrence of AF in acute phase of inferior myocardial infarction (MI). In patients who developed AF AEBs were more frequent. We concluded that the presence of frequent SLSS could be predictors or preceding factors of the occurrence of AF in acute inferior MI.

Both levosimendan and dobutamine treatments result in significant reduction of NT-proBNP levels, but levosimendan has better and prolonged neurohormonal effects than dobutamine.

Levosimendan and dobutamine are comparable inotropic drugs as regards their hemodynamic effects and clinical outcomes in decompensated heart failure (HF). The aim of this study was to compare the effects of levosimendan and dobutamine treatment on NT-proBNP levels in patients with decompensated HF. Forty-four patients with decompensated HF and ejection fraction <35% received either a 24-h infusion of levosimendan (n=26) or dobutamine (n=18). NT-proBNP was measured at baseline and 12 h, 24 h and 48 h after the initiation of drug infusion. NT-proBNP levels at baseline, 12 h, 24 h and 48 h were 16,879+/-2437, 16,004+/-2635, 12,881+/-2305 and 11,078+/-2092 pg/ml, respectively, in the levosimendan group and 16,031+/-3463, 15,908+/-3806, 12,271+/-3299 and 14,840+/-4009 pg/ml, respectively, in the dobutamine group. NT-proBNP decreased significantly at 24 h in response to both levosimendan and dobutamine treatment (p<0.01 and p<0.05, respectively) with no significant difference among the treatment groups. In the dobutamine group, NT-proBNP increased at 48 h (p=n.s. vs. baseline), in contrast, NT-proBNP reduction continued for up to 48 h in the levosimendan group (p<0.001 vs. baseline). Although not statistically different, a greater percentage of NT-proBNP reduction was observed with levosimendan treatment at both 24 h (-25+/-7% vs. -20+/-10%) and 48 h (-32+/-7% vs. -20+/-11%) compared to dobutamine. Both levosimendan and dobutamine treatments result in significant reduction of NT-proBNP levels at the end of the 24-h infusion. However, compared to dobutamine, levosimendan has better and prolonged effects on NT-proBNP levels in decompensated HF.