Olavi Parkkonen

Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential

Summary Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors.

Cohort Profile: The Corogene study

Coronary artery disease (CAD) risk factor profiles change over time. The death rate from coronary disease has been decreasing mainly due to changes in levels of risk factors, and improvement in CAD treatments. However, there are risk factors, whose prevalence is increasing, such as diabetes and obesity. When the risk factor profile changes, we can assume that gene profiles and epigenetics also change. This has not been studied widely. The Corogene study was designed as a large cohort to study mainly CAD, but also other related heart diseases such as heart failure and aortic valve disease. We selected the patients from the CAD point of view, and decided to include over 5000 consecutive patients assigned for coronary angiogram. In Finland, coronary angiogram is performed to practically all patients assigned for invasive heart examination. Despite technical developments in diagnostics, coronary angiogram is still the gold standard for evaluating coronaries. The purpose of this study is to follow contemporary trends in coronary heart disease, and related heart disease risk factors, genetics and epigenetics by collecting cohorts referred to heart examination. New cohorts will be collected at 5-year intervals in order to see trends in CAD, its risk factors and epigenetics.

Differences in ST-elevation and T-wave amplitudes do not reliably differentiate takotsubo cardiomyopathy from acute anterior myocardial infarction

BACKGROUND Previous efforts to distinguish acute anterior ST-elevation myocardial infarction (anterior-STEMI) from various forms of takotsubo cardiomyopathy (TTC) by electrocardiography (ECG) have produced differing results. METHODS We performed a retrospective comparison of acute ECGs between 48 apical and 9 mid-ventricular TTC patients, with 96 anterior-STEMI patients. ECG was recorded in acute phase (<24h from onset of pain), and analyzed for ST-changes, negative T-waves, abnormal Q-waves and QT-interval duration. Time from onset of pain to ECG was gathered from patient records. RESULTS Anterior-STEMI patients had ST-elevation in lead V1 more frequently than apical (70% vs 15%, p<0.0001) or mid-ventricular TTC patients (70% vs 0%, p<0.0001), and higher ST-elevation amplitudes in leads V2-V5 (p<0.02). Lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 distinguished TTC from anterior-STEMI patients with 63% sensitivity and 93% specificity, with 79% predictive value. CONCLUSIONS In patients with anterior ST-elevation and acute chest pain, lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 suggests a TTC diagnosis. However, this criterion is not reliable enough in clinical practice to distinguish between TTC and anterior-STEMI patients.

Mortality rate increases steeply with nonadherence to statin therapy in patients with acute coronary syndrome.

In a prospective cohort of consecutive acute coronary syndrome (ACS) patients, we compared the adherence rate of statin usage and mortality rate during a median follow‐up of 23 months.

Genetic Risk Scores Predict Recurrence of Acute Coronary Syndrome

Background—Several clinical risk estimation tools have established their role in the prediction of recurrence of acute coronary syndrome (ACS), but the value of genetic risk scores (GRSs) remains unclear. We examined how well 2 different GRSs estimate recurrent ACS and whether clinical factors are associated with GRSs. Methods and Results—A cohort of 2090 consecutive patients with ACS who underwent coronary angiography between July 2006 and March 2008 in a single tertiary center was genotyped and prospectively followed up for a median of 5.5 years. We formed 2 partially overlapping GRSs: GRS47 of 47 single-nucleotide polymorphisms with previously reported significant association with coronary artery disease and GRS153 of 153 single-nucleotide polymorphisms with significant or suggestive association with coronary artery disease. GRS47 showed association with recurrent ACS independent of clinical factors (P=0.037; hazard ratio, 1.17; 95% confidence interval, 1.01–1.36). GRS153 had no association with either recurrent ACS or composite of recurrent ACS or death. Also, GRS47 was associated inversely with smoking and ST-segment–elevation myocardial infarction (P=0.004; odds ratio, 0.22; 95% confidence interval, 0.08–0.62 and P=0.041; odds ratio, 0.36; 95% confidence interval, 0.13–0.96, respectively). Conclusions—GRSs combined of 47 known coronary artery disease risk single-nucleotide polymorphisms were associated with recurrent ACS after multivariable adjustments in a heterogenic ACS population for the first time. Smoking and ST-segment–elevation myocardial infarction had an inverse association with the GRSs. The significance of smoking in relation to genetic coronary artery disease predisposition may merit further evaluation in patients with ACS.

Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIM P-1 may help to differentiate it from acute coronary syndrome

Background Matrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity. Methods and results In 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0–186.3) (median (interquartile range)), TTC 115.7 (94.3–137.7) and controls 80.9 (73.2–90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13–0.51) from decreased EF<50% at 0.08 (0.05–0.20), (p = 0.04) in TTC, but not in ACS. Conclusions Even with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment.

GENETIC RISK SCORES PREDICT RECURRENCE OF ACUTE CORONARY SYNDROME

Clinical risk estimation tools have established their role in the prediction of recurrence of acute coronary syndrome (ACS). The value of genetic risk scores (GRS) for this purpose remains unclear. We examined how well three different GRSs estimate recurrent ACS. A cohort of 2,090 consecutive ACS