Matti Tarkka

miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study

OBJECTIVE MicroRNAs are small non-coding RNAs that inversely regulate their target gene expression. The whole miRNA profile of human atherosclerotic plaques has not been studied previously. The aim of this study was to investigate the miRNA expression profile in human atherosclerotic plaques as compared to non-atherosclerotic left internal thoracic arteries (LITA), and to connect this expression to the processes in atherosclerosis. METHODS The miRNA expression profiles of six LITAs and 12 atherosclerotic plaques obtained from aortic, carotid, and femoral atherosclerotic arteries from Tampere Vascular Study were analyzed. The analyses were performed with Agilents miRNA Microarray. The expression levels of over 4-fold up-regulated miRNAs were verified with qRT-PCR from a larger population (n=50). Messenger RNA levels were analyzed with Illuminas Expression BeadChip to study miRNA target expression. RESULTS Ten miRNAs were found to be differently expressed in atherosclerotic plaques when compared to controls (p<0.05). The expression of miR-21, -34a, -146a, -146b-5p, and -210 was verified and found to be significantly up-regulated in atherosclerotic arteries versus LITAs (p<0.001, fold changes 4.61, 2.55, 2.87, 2.82, and 3.92, respectively). Several predicted targets of these miRNAs were down-regulated, and gene set enrichment analysis showed several pathways which could be differently expressed due to this miRNA profile. CONCLUSIONS The microRNA expression profile differs significantly between atherosclerotic plaques and control arteries. The most up-regulated miRNAs are involved in processes known to be connected to atherosclerosis. Interfering with the miRNA expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development.

Ischemic Preconditioning Suppresses Ventricular Tachyarrhythmias After Myocardial Revascularization

Background—Ventricular fibrillation (VF) and tachycardia (VT) are the common and potential life-threatening complications after CABG. Ischemic preconditioning (IP) has been proved effective in reducing ischemia reperfusion arrhythmia in animals and humans. Whether IP is effective in suppressing postoperative VF/VT in patients with CABG has not been studied. Methods and Results—Eighty-six patients with CABG with stable and unstable 3-vessel disease were equally randomly assigned into an IP and a control group. The patients who received IP received 2 periods of 2-minute ischemia followed by 3-minute reperfusion. Twenty-four-hour electrocardiographic data were collected. IP resulted in fewer cases of VF after declamping (48.8% versus 79.1% in IP and control, P =0.004) and a shorter VF period (2.28±0.44 versus 4.41±0.51 minutes, P =0.002). The episodes of VT were significantly reduced in patients in the IP group during early reperfusion and 24 hours after reperfusion (0.65±0.16 versus 3.71±0.46, P =0.000 and 0.07±0.04 versus 2.12±1.41, P =0.002, respectively). De novo sustained VT occurred in 3 control patients as against none in the IP group after surgery. As a result, IP significantly curtailed the mechanical ventilation period and reduced the need for inotropes. Conclusions—IP significantly reduced postoperative VF/VT in patients with CABG with 3-vessel disease. Suppression of VT during early reperfusion and 24 hours after reperfusion suggests early and delayed IP phenomena in patients undergoing CABG surgery.

Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting

Oxygen-derived free radicals constitute one part of the etiologic factors for cardiac onset harmful events. Allopurinol is able to reduce the generation of free radicals. Vitamins E and C scavenge radicals after their formation. Eighty-one patients with coronary artery disease were randomized into four study groups: Group 1 (n = 20) patients had stable disease and received oral vitamin E for 4 weeks, and vitamin C and allopurinol 2 days before and 1 day after coronary artery bypass grafting. Group 2 (n = 25) consisted of their controls. Group 3 patients (n = 17) had more unstable disease and received the same medications as group 1, except that vitamin E was given only 2 days before the operation. Group 4 (n = 19) was their controls. Groups 1 and 3 had fewer ischemic electrocardiographic events and required less dopamine perioperatively than corresponding control groups 2 and 4. Group 3 had fewer perioperative infarctions and less creatine kinase-MB release than the respective controls (group 4). Plasma levels of vitamins E and C, urate, and total free radical trapping ability were considered to support the theory about the role of free radicals in reperfusion injury. Especially the unstable patients, but also patients with stable coronary artery disease requiring coronary artery bypass grafting benefit from perioperative allopurinol and vitamin E and C treatment.

Changes in health-related quality of life and functional capacity following coronary artery bypass graft surgery

OBJECTIVE Improvement in survival and quality of life are the primary indications for coronary artery bypass graft (CABG) operations. Among elderly patients the main goal of surgery is not necessarily to prolong life, but to improve the health-related quality of life. Factors associated with mortality and morbidity following CABG surgery have been well defined, but the quality of life and functional capacity in elderly patients undergoing CABG are poorly documented. The aim here was to investigate changes in health-related quality of life, overall performance status and symptomatic status during 1 year after CABG surgery. METHODS Comprehensive data on 508 CABG patients were prospectively collected, including preoperative risk factors and postoperative morbidity in a surgical center and in all eighteen secondary referral hospitals up to discharge. The RAND-36 Health Survey (RAND-36) was used as indicator of quality of life. The primary outcome was change in the physical component summary, mental component summary and General Health summary scores from the RAND-36. Karnofsky dependency category was used to assess overall performance status, and symptomatic status was estimated according to New York Heart Association (NYHA) class. All assessments were made preoperatively and repeated 12 months later. Analysis was based on three age groups: 64 years or less (282 patients), 65-74 years (175 patients), and 75 or more years (51 patients). RESULTS Thirty-day and 1-year survival rates were 98.2 and 96.7%, respectively. A great majority (86.4%) of the patients recovered without major complication. In all, the present data showed significant improvement in all eight domains of QOL as well as in functional capacity and NYHA class during the 1st year after CABG. However, the mean change in RAND-36 Mental Component Summary scores among patients aged 75 years or more did not reach a statistically significant level (P=0.097) and they had significantly minor improvement as compared to younger patients (P<0.05). Moreover, their General Health score improvement was poorer and statistically insignificant (P=0.817). CONCLUSIONS Elderly patients not only have higher mortality and morbidity but also derive less benefit from CABG regarding certain aspects of QOL.

Risk indicators for varicose veins in forty- to sixty-year-olds in the tampere varicose vein study

The objectives of the study were to discover the main determinants for the prevalence of varicose veins in a general population, and to assess the possibilities for prevention of this common surgical disease. Varicose veins were evaluated in three defined cohorts of 3284 men and 3590 women aged 40, 50, and 60 years by using a validated questionnaire. The response rate was 75% among men and 86% among women, and varicose veins were determined by self-assessment. Increasing age, female sex, childbirths, standing posture at work, higher weight or height, and positive family history were significantly associated with varicose veins in a univariate analysis. These factors were further taken into a multivariate logistic regression analysis, and female gender (adjusted odds ratio, OR 2.2), increasing age (OR 2.2–2.8), a reported positive family history for varicose veins (OR 4.9), increasing number of births (OR 1.2–2.8), standing posture at work (OR 1.6), and higher weight (OR 1.2) and height (OR 1.4) were found to independent and significant risk indicators of varicose veins. Increasing age, positive family history of varicose veins, and child-births in women were the most important factors in terms of population etiologic fractions. Familial predisposition and pregnancy-related factors bear important associations with varicose veins. Thus prevention of varicose veins appears to be difficult. Varicose veins are nonlethal and, therefore, higher age is related to higher prevalence.RésuméLes objectifs de cette étude ont été de déterminer les facteurs favorisants des varices, si fréquentes dans la population générale, et d’évaluer la possibilité de leur prévention. Les varices ont été évaluées dans trois cohortes bien définies de 3284 hommes et 3590 femmes, âgés respectivement de 40, 50 et 60 ans, par l’intermédiaire d’un questionnaire validé au préalable. Le taux de réponse a été de 75% parmi les hommes et de 86% parmi les femmes; l’évaluation des varices a été réalisée par ê malade lui-même. Les principaux facteurs retrouvés en analyse univariée comprenaient l’âge, le sexe féminin, l’accouchement, la position debout au travail, le poids et la taille, ainsi qu’une histoire familiale. En analyse multivariée (régression logistique) les facteurs indépendants étaient le sexe féminin (rapport de côte ajusté (RCA): 2.2), l’âge (RCA: 2.2–2.8), l’antécédent familial (RCA: 4.9), un nombre élevé d’accouchements (RCA: 1.2–2.8), position debout au travail (RCA: 1.6) et un poids élevé (RCA: 1.2) et une grande taille (RCA: 1.4). En termes d’étiologies, les facteurs les plus importants étaient l’âge, des antécédents familiaux de varices, et un nombre élevé d’accouchements chez la femme. La prédisposition familiale et les facteurs en rapport avec la grossesse sont les facteurs les plus liés à l’apparition des varices. Ainsi, la prévention apparat comme étant difficile. Les varices étaint une maladie non létale, l’âge est donc un facteur de prévalence élevée.ResumenEl objetivo de este estudio fue intentar averiguar los factores etiológicos más importantes causantes de varices para tratar así de prevenir esta tan frecuente afección quirúrgica. Empleando un cuestionario valoramos las varices en tres cohortes bien definidos que comprenden 3284 hombres y 3590 mujeres cuyas edades fueron 40, 50 y 60 años. El porcentaje de cuestionarios contestados fue del 75% para los hombres y 86% para las mujeres, que valoraran por sí mismos las características de sus varices. En un análisis uni y multivariante se constató que las varices: aumentaban con la edad; eran más frecuentes en las mujeres y guardaban una estrecha relación con el número de partos, la permanencia de pie en el trabajo, el peso y talla así como con antecedentes familiares de varices. Todos estos factores se analizaron mediante una regresión logística multivariante, registrándose como factores independientes y significativos indicadores de riesgo de desarrollar varices: el sexo femenino (cociente de odds ajustado: OR 2.2), el incremento de la edad (OR 2.2–2.8) antecedentes familiares positivos (OR 4.9) número de embarazos (OR 1.2–2.8), posición erecta en el trabajo (OR 1.6), sobrepeso (OR 1.2), elevada talla (OR 1.4). En las mujeres los factores etiológicos más importantes fueron: el envejecimiento, número de partos y los antecedentes familiares. La predisposición familiar y las alteraciones producidas por los embarazos son los factores más importantes en la génesis de venas varicosas. Por ello, la prevención parece difícil. Las varices no constituyen una afección letal y por tanto cuando mayor sea la edad mayor será la su frecuencia.

Fear and anxiety in patients at different time-points in the coronary artery bypass process

The purpose of this study was to examine fear and anxiety of coronary artery bypass patients at different time-points in the coronary artery bypass process and changes between different time-points. Patients (n = 171) from one university hospital completed questionnaires while awaiting surgery at home, in hospital the evening before surgery and 3 months later. The Bypass Grafting Fear scale was developed to measure fear. Anxiety was measured using state-trait-anxiety inventory and HAD. The highest levels of fear and anxiety were measured in the waiting period to coronary artery bypass grafting (CABG). Compared with the waiting period, fear and anxiety levels dropped in hospital and 3 months later. Female gender was related to change in fear and HAD anxiety. Marital status and vocational education were related to changes in STATE-A. Age under 55 years was related to higher TRAIT-A especially in the recovery period. These findings warrant concern for fear and anxiety in patients awaiting CABG, especially women and patients who do not have partner relationship.

High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis

AIMS High-throughput metabolite quantification holds promise for cardiovascular risk assessment. Here, we evaluated whether metabolite quantification by nuclear magnetic resonance (NMR) improves prediction of subclinical atherosclerosis in comparison to conventional lipid testing. METHODS AND RESULTS Circulating lipids, lipoprotein subclasses, and small molecules were assayed by NMR for 1595 individuals aged 24-39 years from the population-based Cardiovascular Risk in Young Finns Study. Carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, was measured in 2001 and 2007. Baseline conventional risk factors and systemic metabolites were used to predict 6-year incidence of high IMT (≥ 90 th percentile) or plaque. The best prediction of high intima-media thickness was achieved when total and HDL cholesterol were replaced by NMR-determined LDL cholesterol and medium HDL, docosahexaenoic acid, and tyrosine in prediction models with risk factors from the Framingham risk score. The extended prediction model improved risk stratification beyond established risk factors alone; area under the receiver operating characteristic curve 0.764 vs. 0.737, P =0.02, and net reclassification index 17.6%, P =0.0008. Higher docosahexaenoic acid levels were associated with decreased risk for incident high IMT (odds ratio: 0.74; 95% confidence interval: 0.67-0.98; P = 0.007). Tyrosine (1.33; 1.10-1.60; P = 0.003) and glutamine (1.38; 1.13-1.68; P = 0.001) levels were associated with 6-year incident high IMT independent of lipid measures. Furthermore, these amino acids were cross-sectionally associated with carotid IMT and the presence of angiographically ascertained coronary artery disease in independent populations. CONCLUSION High-throughput metabolite quantification, with new systemic biomarkers, improved risk stratification for subclinical atherosclerosis in comparison to conventional lipids and could potentially be useful for early cardiovascular risk assessment.

Safe time limits of aortic cross-clamping and cardiopulmonary bypass in adult cardiac surgery

Objectives: We evaluated the impact of aortic cross-clamping time (XCT) and cardiopulmonary bypass time (CPBT) on the immediate and late outcome after adult cardiac surgery and attempted to identify their safe time limits. Methods: This study includes 3280 patients who underwent adult cardiac surgery of various complexities. Myocardial protection was achieved with tepid continuous antegrade/retrograde blood cardioplegia. Results: Receiver operating characteristics (ROC) curve analysis showed that XCT (area under the curve, AUC: 0.66), CPBT (AUC: 0.73) and CPBT with unclamped aorta (AUC: 0.77) were significantly associated with 30-day postoperative mortality. XCT of increasing 30-minute intervals (Odds Ratio (OR) 1.21, 95%C.I. 1.01-1.52) and CPBT of increasing 30-minute intervals (OR 1.47, 95%C.I. 1.27-1.71) were independent predictors of 30-day mortality. The best cutoff value for XCT was 150 min (30-day death: 1.8% vs. 12.2%, adjusted OR 3.07, 95%C.I. 1.48-6.39, accuracy 91.5%) and for CPBT 240 min (30-day death: 1.9% vs. 31.5%, adjusted OR 8.78, 95%C.I. 4.64-16.61, accuracy 96.0%). These parameters were significantly associated also with postoperative morbidity, particularly with postoperative stroke. Conclusions: XCT and CPBT are predictors of immediate postoperative morbidity and mortality. In our experience, cardiac procedures with CPBT<240 min and XCT<150 min were associated with a rather low risk of immediate postoperative adverse events independently of the complexity of surgery patient’s operative risk.

Postoperative delirium and health related quality of life after coronary artery bypass grafting.

Objectives. We wanted to identify determinants for postoperative delirium and its influence on health related quality of life (HRQoL) during 36-month follow-up of coronary artery bypass (CABG) patients. Design. A total of 302 patients were retrospectively analyzed. HRQoL was assessed prospectively by the15D instrument. Delirium was diagnosed clinically. Results. The incidence of delirium was 6.0%. The cumulative survival (all-cause death) in 36 months was 96.1% in patients without delirium and 77.8% in patients with delirium. Age, cerebral disease, chronic heart failure, male gender, postoperative pneumonia and low output syndrome were predictors for delirium. Delirium patients needed more resources i.e. intensive care or total duration of hospitalization and experienced no positive change in HRQoL. Moreover patients with high preoperative 15D score tended to suffer fairly severe but reversible impairment during the first 6 months after the operation. Conclusions. Preoperatively older and sicker patients with complicated postoperative course are at higher risk of developing delirium after CABG. Preoperative status and operative complications together with delirium may exert negative influence on forthcoming HRQoL, which is seen especially in patients with a relatively high preoperative level of HRQoL.

Cytokine responses and myocardial injury in coronary artery bypass grafting.

Objective: Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex systemic inflammatory response after cardiac surgery, and it may contribute to postoperative complications and even multiple organ dysfunction. We here compared the cytokine responses and the degree of myocardial injury after coronary artery bypass grafting with or without cardiopulmonary bypass. MethodsOBJECTIVE Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex systemic inflammatory response after cardiac surgery, and it may contribute to postoperative complications and even multiple organ dysfunction. We here compared the cytokine responses and the degree of myocardial injury after coronary artery bypass grafting with or without cardiopulmonary bypass. METHODS Nine patients underwent off-pump revascularization and 13 with cardiopulmonary bypass. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-10 were measured before anesthesia induction, and 5 min, 1, 4, and 20 h after reperfusion to the myocardium. Levels of the MB isoenzyme of creatine kinase (CK-MB) were also measured after the operation. RESULTS Levels of TNF-alpha were low in both groups. A delayed elevation of IL-6 was noted in the off-pump group. IL-8 and IL-10 levels were significantly higher in the CPB than in the off-pump patients after reperfusion (p=0.006 and 0.001 respectively). Postoperative CK-MB levels were significantly higher in the CPB than in the off-pump group (p=0.001). Cytokine levels correlated with CK-MB values. CONCLUSION The results indicated that off-pump revascularization was associated with reduced cytokine responses and less severe myocardial injury. The degree of myocardial injury, as defined by CK-MB release, correlated with cytokine release. Intervention designed to reduce cytokine responses in cardiac surgery may be advantageous for patients with severe comorbidity.