Jakob Dörler

Short-term patient-reported outcomes after different exercise-based cardiac rehabilitation programmes

Background An objective of exercise-based cardiac rehabilitation is improvement in patient-reported outcomes such as health-related quality of life as well as anxiety and depressive symptoms. There are no direct comparisons of the effectiveness of inpatient and outpatient exercise-based cardiac rehabilitation programmes on patient-reported outcomes. Methods In this non-randomized study we collected patient-reported outcomes data with the MacNew Heart Disease health-related quality of life questionnaire and the Hospital Anxiety and Depression Scale at baseline, 1 month and again 3 months after admission to exercise-based cardiac rehabilitation in a cohort of 216 consecutive patients enrolled either in a 4-week inpatient exercise-based cardiac rehabilitation (n = 62) or a 3-month outpatient exercise-based cardiac rehabilitation (n = 87) and in a usual care group (n = 67) to document the natural course in patient-reported outcome variables without exercise-based cardiac rehabilitation. Results Although MacNew health-related quality of life scores improved more with inpatient than outpatient exercise-based cardiac rehabilitation by month 1, the improvement was still significant in both groups at month 3 and also in the usual care group when compared to baseline. The health-related quality of life scores in the inpatient group, however, decreased between month 1 and 3 whereas they continued to improve in the outpatient group. The significant reduction in both anxiety and depressive symptoms in both exercise-based cardiac rehabilitation groups by month 1 was maintained at month 3 only with outpatient exercise-based cardiac rehabilitation. No significant changes over the 3 months were observed in the usual care group. Conclusion Significant improvements of 1-month patient-reported outcomes are achieved in patients attending inpatient as well as outpatient exercise-based cardiac rehabilitation when compared with no exercise-based cardiac rehabilitation. In contrast to inpatient exercise-based cardiac rehabilitation, however, outpatient exercise-based cardiac rehabilitation leads to a further improvement of patient-reported outcomes. These results suggest that, if patients have to be admitted for inpatient exercise-based cardiac rehabilitation, this programme should be followed by an outpatient exercise-based cardiac rehabilitation to further improve and stabilize these patient-reported outcome variables.

Comparison of peripheral endothelial function in shift versus nonshift workers.

Shift working is related to increased cardiovascular morbidity. Peripheral endothelial dysfunction, an inherent feature of early atherosclerosis, has been suggested as a surrogate marker of cardiovascular risk. Whether shift working is associated with peripheral endothelial dysfunction has not been investigated to date. A total of 48 male shift workers (SWs) and 47 male nonshift workers (NSWs) (mean age 43 ± 5 years) were recruited from a glass manufactory. The SWs and NSWs were matched according to age, body mass index, smoking habits, family history of premature coronary artery disease, prevalence of hypercholesterolemia and hypertension, and work place. Their sport habits were also documented. Peripheral endothelial function was assessed using the EndoPAT technique to determine the peripheral arterial tone (PAT) index. According to the study design, no difference was found in the risk factor profiles between the SWs and NSWs. Despite a greater percentage of regular physical activity among the SWs (16.7 vs 4.3%, p = 0.05), shift working was associated with a reduced PAT index compared to working only on the day shift (PAT index 1.73 ± 0.4 vs 1.94 ± 0.5, p = 0.03). In the NSW group, the participants with regular physical training (n = 16) had a greater PAT index than those without regular physical activity (n = 12; PAT index 2.28 ± 0.45 vs 1.86 ± 0.51, p = 0.03). No such difference was found in the SWs. In conclusion, SWs had a reduced PAT index compared with NSWs, suggesting endothelial dysfunction. Therefore, the known increased cardiovascular risk in those shift working might be related to endothelial dysfunction.

Neopterin, CD4+CD28− lymphocytes and the extent and severity of coronary artery disease

OBJECTIVES Macrophages and pro-inflammatory CD3+CD4+CD28- T lymphocytes are involved in atherosclerotic plaque destabilization. Whether neopterin, a macrophage-specific activation-marker, and circulating CD3+CD4+CD28- cells are also related to the severity and extent of coronary artery disease (CAD) in stable patients is still unclear. METHODS Coronary angiograms of 30 patients with stable angina pectoris were graded using the Gensini severity and an extent score. Patients were grouped according to the median of each score. Lymphocyte subsets were determined by FACS analysis and neopterin by radioimmunoassay. Peripheral endothelial function of the brachial artery (FMD) shown to correlate with cardiovascular risk factors was evaluated using high-resolution ultrasound. RESULTS More extensive CAD was associated with increased neopterin levels (8.3 +/- 3.3 vs. 5.5 +/- 1.2 nmol/L, p < 0.001) and increased CD3+CD4+CD28- cells (3.1 +/- 1.6 vs. 2.0 +/- 1.2%, p < 0.05). A high Gensini severity score was associated with increased neopterin levels (7.8 +/- 2.7 vs. 6.3 +/- 1.7 nmol/L, p < 0.05), but not with CD3+CD4+CD28- cells. Neopterin correlated with both the extent (r = 0.59, p < 0.001) and the Gensini score (r = 0.57, p < 0.003). FMD was not correlated with both scores. CONCLUSIONS Neopterin and CD3+CD4+CD28- lymphocytes are associated with CAD extent in stable patients, thereby emphasizing the inherent role of inflammation in atherogenesis itself beyond plaque destabilization. Neopterins correlation with CAD severity might be additionally useful in identifying patients eligible for revascularization procedures.

Use, patient selection and outcomes of P2Y12 receptor inhibitor treatment in patients with STEMI based on contemporary European registries

AIMS Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in patients with STEMI based on the data from contemporary European ACS registries. METHODS AND RESULTS Twelve registries provided data in a systematic manner on outcomes in STEMI patients overall, and seven of these also provided data for P2Y12 receptor inhibitor-based dual antiplatelet therapy. The registries were heterogeneous in terms of site, patient, and treatment selection, as well as in definition of endpoints (e.g. bleeding events). All-cause death rates based on the data from 84 299 patients (9612 patients on prasugrel, 11 492 on ticagrelor, and 27 824 on clopidogrel) ranged between 0.49 and 6.68% in-hospital, between 3.07 and 7.95% at 30 days (reported in 6 registries), between 8.15 and 9.13% at 180 days, and between 2.41 and 9.58% at 1 year (5 registries). Major bleeding rates were 0.09-3.55% in-hospital (8 registries), 0.09-1.65% at 30 days, and 1.96% at 1 year (only 1 registry). Fatal/life-threatening bleeding was rare occurring between 0.08 and 0.13% in-hospital (4 registries) and 1.96% at 1 year (1 registry). CONCLUSIONS Real-world evidence from European contemporary registries shows that death, ischaemic events, and bleeding rates are lower than those reported in Phase III studies of P2Y12 inhibitors. Regarding individual P2Y12 inhibitors, patients on prasugrel, and, to a lesser degree, ticagrelor, had fewer ischaemic and bleeding events at all time points than clopidogrel-treated patients. These findings are partly related to the fact that the newer agents are used in younger and less ill patients.

Effect of atorvastatin on peripheral endothelial function and systemic inflammatory markers in patients with stable coronary artery disease

ZusammenfassungGRUNDLAGEN: Eine endotheliale Dysfunktion, messbar an einer verminderten Fluss-vermittelten Vasodilatation (FMD) der Brachialarterie, geht mit erhöhten Konzentrationen systemischer Entzündungsparameter, wie man es bei Patienten mit koronarer Herzkrankheit (KHK) findet, einher. Therapeutische Interventionen wie etwa eine Lipidsenkung mit Statinen, verbessern die FMD und vermindern systemische Entzündungsparameter wie zum Beispiel das lösliche E-Selectin (sE-selectin), das lösliche interzelluläre Ahäsionsmolekül-1 (sICAM-1) oder des hochsensitive C-reaktive Protein (hsCRP). Die Wirkung einer Behandlung mit Atorvastatin sowohl auf die FMD als auch auf diese zirkulierenden Entzündungsstoffe in Patienten mit stabiler KHK wurde bisher noch nicht eingehend untersucht. METHODIK: Dreißig hypercholesterinämische Patienten mit einer angiographisch dokumentierten KHK und stabiler Angina pectoris wurden für 3 Monate doppelblind randomisiert zu Plazebo oder Atorvastatin (20 mg täglich). Die FMD der Brachialarterie wurde mittels hochauflösendem Ultraschall (13 MHz; Acuson Sequioa C256) bestimmt. Das hochsensitive C-reaktive Protein wurde mit einem Latex-Agglutinations-Test und das sE-Selectin sowie das sICAM-1 wurden mit einem ELISA gemessen. ERGEBNISSE: Die Patientencharakteristik zu Beginn war in beiden Gruppen gleich. Die FMD verbesserte sich in den mit Atorvastatin behandelten Patienten (6,7 ± 3,8 % to 8,5 ± 4,4 %; p < 0,01), blieb aber unverändert in den zu Plazebo randomisierten Patienten (8,2 ± 3,3 % to 8,9 ± 5,1 %; p = NS). Die Therapie mit Atorvastatin ging einher mit einer Reduktion des sICAM-1 (von 274,2 ± 92,2 auf 197,9 ± 70,0 ng/ml; p < 0,01) und des hsCRP (von 0,57 ± 0,45 auf 0,18 ± 0,15 mg/dl; p < 0,01), wohingegen Plazebo auf diese Entzündungsparameter keinen Einfluss hatte. sE-Selectin wurde weder durch Atorvastatin noch durch Plazebo beeinflusst. Darüber hinaus fand sich keine Korrelation zwischen den Veränderungen der FMD, der Lipide und der systemischen Entzündungsparameter. SCHLUSSFOLGERUNGEN: Eine Therapie mit Atorvastatin verbessert die periphere Endothelfunktion und reduziert systemische Entzündungsparameter in Patienten mit stabiler koronarer Herzkrankheit. Die fehlende Korrelation zwischen der Veränderung der Endothelfunktion und der Entzündungsparameter unterstützt das Konzept der pleiotropen Effekte von Statinen in Menschen.SummaryBACKGROUND: Endothelial dysfunction, detectable by an impaired flow-mediated vasodilation (FMD) of the brachial artery, has been shown to be associated with increased levels of circulating proinflammatory markers. Therapeutic interventions such as lipid-lowering with statins increase FMD and decrease inflammatory markers, like soluble (s) E-selectin, soluble intercellular adhesion molecule-1 (sICAM-1) or high-sensitivity Creactive protein (hsCRP). The effect of atorvastatin therapy on both FMD and inflammatory markers in patients with stable coronary artery disease (CAD) has not been investigated. METHODS: Thirty hypercholesterolemic patients with angiographically documented stable coronary artery disease (CAD) were randomized to placebo or atorvastatin (20 mg/d) for 3 months. FMD was assessed using highresolution ultrasound (13 MHz, Acuson Sequoia, C256). High-sensitivity CRP was measured with Latex agglutination assay, sE-selectin and sICAM-1 were determined with ELISA. RESULTS: Baseline characteristics were not different between groups. FMD improved in patients on atorvastatin (6.7 ± 3.8 % to 8.5 ± 4.4 %; p < 0.01), but remained unchanged in placebo-treated patients (8.2 ± 3.3 % to 8.9 ± 5.1 %; p = NS). Atorvastatin treatment was associated with decreases of sICAM-1 (from 274.2 ± 92.2 to 197.9 ± 70.0 ng/ml; p < 0.01) and hsCRP (from 0.57 ± 0.45 to 0.18 ± 0.15 mg/dl; p < 0.01), whereas placebo treatment had no effect on these markers. sE-selectin levels were not influenced by either treatment. No correlations were found between changes in FMD, lipids and inflammatory markers. CONCLUSIONS: Treatment with atorvastatin leads to an improvement in endothelial function and a reduction in inflammatory markers in patients with stable CAD. The lack of correlation between changes in FMD and inflammatory markers may support the concept of pleiotropic effects of statins in humans.

Comparison of Brachial Artery Wall Thickness Versus Endothelial Function to Predict Late Cardiovascular Events in Patients Undergoing Elective Coronary Angiography

An increased brachial artery intima media thickness (BA-IMT) has been shown to be of prognostic value. Conflicting prognostic data have been reported for brachial artery flow-mediated vasodilation (BA-FMD), and the longest evaluated follow-up period to date is 5.5 years. We sought to investigate the very late prognostic value of BA-IMT and BA-FMD in 396 consecutive patients (age 54 ± 9 years) admitted for invasive evaluation of chest pain. BA-IMT and BA-FMD were measured using high-resolution ultrasonography. The patients were divided according to the median BA-IMT (0.37 mm) and median BA-FMD (7.6%). After a mean follow-up of 141 ± 12 months, cardiovascular events were documented. More cardiovascular events were found in patients with an increased BA-IMT (50 vs 78 events, p = 0.003). When the groups were compared according to the median BA-FMD, no differences in the number of events were documented (70 vs 75 events, p = 0.60). On multivariate Cox regression analysis, including age, number of risk factors, BA diameter, presence of coronary artery disease, BA-FMD, and BA-IMT, only the presence of coronary artery disease and BA-IMT remained significantly associated with outcome. In conclusion, BA-IMT, but not BA-FMD, predicted cardiovascular events and cardiovascular death with ≤12 years of follow-up in patients undergoing an invasive evaluation of chest pain. Our results represent, by far, the longest follow-up of BA-IMT and peripheral endothelial function testing compared with previously reported data.

Contemporary registries on P2Y12 inhibitors in patients with acute coronary syndromes in Europe: overview and methodological considerations

Patient registries that document real-world clinical experience play an important role in cardiology as they complement the data from randomized controlled trials, provide valuable information on drug use and clinical outcomes, and evaluate to what extent guidelines are followed in practice. The Platelet Inhibition Registry in ACS EvalUation Study (PIRAEUS) project is an initiative of registry holders who are managing national or international registries observing patients with acute coronary syndromes (ACS). The aim of PIRAEUS is to systematically compare and combine available information/insights from various European ACS registries with a focus on P2Y12 inhibitors. The present publication introduces the 17 participating registries in a narrative and tabular form, and describes which ACS groups and which dual antiplatelet therapies were investigated. It sets the basis for upcoming publications that will focus on effectiveness and safety of the antiplatelets used.

External validation and extension of a diagnostic model for obstructive coronary artery disease: a cross-sectional predictive evaluation in 4888 patients of the Austrian Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort

Objective To externally validate and extend a recently proposed prediction model to diagnose obstructive coronary artery disease (CAD), with the ultimate aim to better select patients for coronary angiography. Design Analysis of individual baseline data of a prospective cardiology cohort. Setting Single-centre secondary and tertiary cardiology clinic. Participants 4888 patients with suspected CAD, without known previous CAD or other heart diseases, who underwent an elective coronary angiography between 2004 and 2008 as part of the prospective Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort. Relevant data were recorded as in routine clinical practice. Main outcome measures The probability of obstructive CAD, defined as a stenosis of minimally 50% diameter in at least one of the main coronary arteries, estimated with the predictors age, sex, type of chest pain, diabetes status, hypertension, dyslipidaemia, smoking status and laboratory data. Missing predictor data were multiply imputed. Performance of the suggested models was evaluated according to discrimination (area under the receiver operating characteristic curve, depicted by the c statistic) and calibration. Logistic regression modelling was applied for model updating. Results Among the 4888 participants (38% women and 62% men), 2127 (44%) had an obstructive CAD. The previously proposed model had a c statistic of 0.69 (95% CI 0.67 to 0.70), which was lower than the expected c statistic while correcting for case mix (c=0.80). Regarding calibration, there was overprediction of risk for high-risk patients. All logistic regression coefficients were smaller than expected, especially for the predictor ‘chest pain’. Extension of the model with high-density lipoprotein and low-density lipoprotein cholesterol, fibrinogen, and C reactive protein led to better discrimination (c=0.72, 95% CI 0.71 to 0.74, p<0.001 for improvement). Conclusions The proposed prediction model has a moderate performance to diagnose obstructive CAD in an unselected patient group with suspected CAD referred for elective CA. A small, but significant improvement was attained by including easily available and measurable cardiovascular risk factors.

Upregulation of the aging related LMNA splice variant progerin in dilated cardiomyopathy

Background Mutations in the LMNA gene are a common cause (6–8%) of dilated cardiomyopathy (DCM) leading to heart failure, a growing health care problem worldwide. The premature aging disease Hutchinson-Gilford syndrome (HGPS) is also caused by defined mutations in the LMNA gene resulting in activation of a cryptic splice donor site leading to a defective truncated prelamin A protein called progerin. Low levels of progerin are expressed in healthy individuals associated with ageing. Here, we aimed to address the role of progerin in dilated cardiomyopathy. Methods and results mRNA expression of progerin was analyzed in heart tissue of DCM (n = 15) and non-failing hearts (n = 10) as control and in blood samples from patients with DCM (n = 56) and healthy controls (n = 10). Sequencing confirmed the expression of progerin mRNA in the human heart. Progerin mRNA levels derived from DCM hearts were significantly upregulated compared to controls (1.27 ± 0.42 vs. 0.81 ± 0.24; p = 0.005). In contrast, progerin mRNA levels in whole blood cells were not significantly different in DCM patients compared to controls. Linear regression analyses revealed that progerin mRNA in the heart is significantly negatively correlated to ejection fraction (r = -0.567, p = 0.003) and positively correlated to left ventricular enddiastolic diameter (r = 0.551, p = 0.004) but not with age of the heart per se. Progerin mRNA levels were not influenced by inflammation in DCM hearts. Immunohistochemistry and Immunofluorescence analysis confirmed increased expression of progerin protein in cell nuclei of DCM hearts associated with increased TUNEL+ apoptotic cells. Conclusion Our data suggest that progerin is upregulated in human DCM hearts and strongly correlates with left ventricular remodeling. Progerin might be involved in progression of heart failure and myocardial aging.

An ordinal prediction model of the diagnosis of non-obstructive coronary artery and multi-vessel disease in the CARDIIGAN cohort

Abstract Background The extent of coronary artery disease (CAD) is relevant for the evaluation and the choice of treatment of patients and consists of the severity of stenoses and their distribution within the coronary tree. Diagnosis is not easy and severe CAD should not be missed. For low-risk patients one wants to avoid the invasive angiography. We aim to propose a diagnostic prediction model of CAD respecting the degree of disease severity. Methods We included 4888 patients from the Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort. An ordinal regression model was applied to estimate the probabilities of five incrementally disease categories: no CAD, non-obstructive stenosis, and one-, two- and three-vessel disease. We included 11 predictors in the model: age, sex, chest pain, diabetes, hypertension, dyslipidaemia, smoking, HDL and LDL cholesterol, fibrinogen, and C-reactive protein. Bootstrapping was used to validate model performance (discrimination and calibration). Results Age, sex, and three laboratory measures had a large predictive effect. The model poorly separated most adjacent disease categories, but performed well for categories far apart, with little optimism. The overall discrimination added up to a c statistic of 0.71 (95% CI 0.69 to 0.73). The model enables the estimation of individual patient probabilities of disease severity categories. Conclusions The proposed ordinal diagnostic risk model, employing routinely obtainable variables, allows distinguishing the extent of CAD and can especially discriminate between non-obstructive stenosis and multi-vessel disease in our CARDIIGAN patients. This can help to decide on treatment strategy and thereby reduce the number of unnecessary angiographies.