Effects of active commuting on health-related quality of life and sickness-related absence.

Increased physical activity is associated with numerous health benefits. This study investigated the effect of active commuting (walking and cycling to work) on health-related quality of life (HRQoL) and absence days from work due to sickness in healthy working adults. In total, 73 participants (age: 46 ± 9 years), all working at a tertiary university hospital in Salzburg, Austria, were randomized into an intervention group (IG, n = 51) and a control group (CG, n = 22). The IG was asked to commute actively for twelve months, whereas the CG did not have to change their usual commuting behavior. IG was divided into two subgroups: IG-C (cycling, n = 26) was asked to commute by bicycle and IG-PT (public transport, n = 25) partially using public transportation and walked the remaining distance to work. Significant positive changes in IG were observed in four subcomponents of the SF-36 (physical functioning (95 [10] to 100 [8.8], P = .023), mental health (82 [15] to 86 [15], P = .036), vitality (65 [20] to 70 [14], P = .005), and general health (70 [19] to 80 [24], P = .004)) as well as the physical component summary score (56.5 [9] to 59.2 [6.3], P = .002). IG-C showed greater and more statistically significant changes regarding HRQoL compared to IG-PT. Associations between active commuting and sick-leave days were only observed in IG-PT (7.5 [14.8] to 4.0 [11.3] days, P = .038). In conclusion, active commuting improves various components of HRQoL and might therefore be a possible strategy to increase quality of life in the workforce.

Impact of clinical presentation and presence of coronary sclerosis on long-term outcome of patients with non-obstructive coronary artery disease.

BACKGROUND: Non-obstructive coronary artery disease (NOCAD) is a common finding on coronary angiography. Our goal was to evaluate the long-term prognosis of NOCAD patients with stable angina (SA). METHODS: The study cohort consisted of 7478 NOCAD patients with normal EF (≥ 50%), and SA who underwent coronary angiography between 1995 and 2012. We compared NOCAD patients (stenosis< 50%) with 10,906 patients with stable obstructive CAD (≥ 50%). The primary endpoint was all-cause mortality. Secondary endpoints included repeat angiography, progressive CAD, and PCI. A second comparison group consisted of 7344 patients with NOCAD presenting with an ACS. Rates of all-cause mortality of NOCAD ACS patients were compared to NOCAD SA patients. RESULTS: Median follow-up time was 6.5 years. NOCAD patients had a lower risk of all-cause mortality compared to CAD patients (HR CAD vs. NOCAD 1.33 (1.19-1.49); p < 0.001). This was driven by patients with normal coronary arteries (HR CAD vs. normal 1.63 (1.36-1.94), p < 0.001), whereas patients with minimal disease (> 0% and < 50%) were at similar risk as CAD patients (HR CAD vs. minimal 1.08 (0.99-1.29), p = 0.06). In NOCAD patients, the strongest predictors of all-cause mortality were age and minimal disease. SA patients with NOCAD had low rates of repeat angiography (7.3%), future CAD (2.3%) and PCI (1.7%). NOCAD ACS patients had a 41% increase in all-cause mortality risk compared to NOCAD SA patients (HR 1.41 (1.25-1.6), p < 0.001). CONCLUSIONS: This study underlines the importance of minimal CAD, as it is not a benign disease entity and portends a similar risk as stable obstructive CAD.

Benefits and outcomes of a new multidisciplinary approach for the management and financing of sudden unexplained death cases in a forensic setting in Switzerland.

Sudden cardiac death (SCD) is an important public health issue. In young persons aged between 1 and 40 years, most SCDs are caused by potentially inherited cardiac diseases, often not detectable during conventional medico-legal investigations and therefore termed as sudden unexplained deaths (SUD). In this study, we describe the implementation, feasibility and importance of a standardized procedure to investigate SUD cases within the forensic framework at the Zurich Institute of Forensic Medicine in Switzerland. This new approach involves a multidisciplinary collaboration including forensic autopsy, second pathology expert opinion, post-mortem molecular genetic testing, cardiac counselling of relatives, and a tentative financing. This procedure is in line with the published Swiss and European recommendations on the management of SCDs. During a two-year pilot project, 39 sudden and unexpected death cases were collected, whereof 10 deceased remained without any identifiable cause of death after medico-legal investigation and second expert evaluation. Molecular autopsy, including 393 genes involved in cardio-vascular and metabolic diseases, identified eight pathogenic or likely pathogenic genetic variants in five out of the 10 deceased (50%). Cardio-genetic follow-up investigations in the families of the 10 deceased revealed phenotype-positive relatives in four families and required specific therapies, including an implantable cardioverter defibrillator (ICD) for primary prevention. Multidisciplinary collaboration is crucial for an optimal management of sudden unexplained death cases, to identify additional relatives at risk, and to prevent other tragic deaths within a family.

Myoglobin for Detection of High-Risk Patients with Acute Myocarditis.

There is an unmet need for accurate and practical screening to detect myocarditis. We sought to test the hypothesis that the extent of acute myocarditis, measured by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR), can be estimated based on routine blood markers. A total of 44 patients were diagnosed with acute myocarditis and included in this study. There was strong correlation between myoglobin and LGE (rs = 0.73 [95% CI 0.51; 0.87], p < 0.001), while correlation was weak between LGE and TnT-hs (rs = 0.37 [95% CI 0.09; 0.61], p = 0.01). Receiver operating curve (ROC) analysis determined myoglobin ≥ 87 µg/L as cutoff to identify myocarditis (92% sensitivity, 80% specificity). The data were reproduced in an established model of coxsackievirus B3 myocarditis in mice (n = 26). These data suggest that myoglobin is an accurate marker of acute myocarditis. Graphical Abstract Receiver operating curve analysis determined myoglobin ≥ 87 µg/L as cutoff to identify myocarditis and these data were reproduced in an established model of coxsackievirus B3 myocarditis in mice: CMRI, cardiac magnetic resonance imaging; Mb, myoglobin; LGE, late gadolinium enhancement; ROC, receiver operating curve analysis.

Telomere gap between granulocytes and lymphocytes is a determinant for hematopoetic progenitor cell impairment in patients with previous myocardial infarction.

OBJECTIVE: We have previously demonstrated that ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular remodeling process. METHODS AND RESULTS: With this study, we intended to identify the influence of telomere length on bone marrow functionality in 50 patients with coronary artery disease (CAD) and previous myocardial infarction. Mean telomere length (mTL) was measured simultaneously in peripheral blood leukocytes and mononuclear bone marrow cells (BMC), using the flow-FISH method. Telomere erosion already occurred at the bone marrow level, whereby age (39 bp/yr, P=0.025) and the number of affected vessels (434 bp/vessel, P=0.029) were the only independent predictors. Lymphocytes demonstrated significant TL shortening between BMCs and peripheral blood in CAD patients (-1011+/-897 bp) as opposed to an increase in a young control group (+235+/-459 bp, P<0.001). SDF- and VEGF-specific migration of BMCs correlated with mTL of lymphocytes (r=0.42, P<0.001) and was significantly reduced in CAD patients. Finally, the telomere length difference between granulocytes and lymphocytes was the most determinant for telomere-associated bone marrow impairment (P<0.001). CONCLUSIONS: In patients with CAD, telomere shortening of BMCs is dependent on both age and the extent of CAD and correlates with bone marrow cell functionality.

Non-steroidal anti-inflammatory drug use in acute myopericarditis: 12-month clinical follow-up.

Objective: Clinical data on the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in myopericarditis are limited. Since NSAIDs are standard therapy in pericarditis, we retrospectively investigated their safety in myopericarditis. Methods: In a retrospective case-control study, we identified 60 patients with myopericarditis from September 2010 to August 2017. Diagnosis was based on clinical criteria, elevated high-sensitivity troponin T and cardiac magnetic resonance imaging (CMR). All patients received standard heart failure therapy if indicated. Twenty-nine patients (62%) received NSAIDs (acetylsalicylic acid: n=7, average daily dose =1300 mg or ibuprofen: n=22, average daily dose =1500 mg) for an average duration of 4 weeks. To create two cohorts with similar baseline conditions, 15 patients were excluded. Three months after diagnosis, 29 patients were re-evaluated by CMR to measure late gadolinium enhancement (LGE). Results: Baseline characteristics of those treated with or without NSAIDs were similar. Mean age was 34 (±13) years, 6 (13%) were women. Mean left ventricular ejection fraction (LVEF) was 56% (±5). 82 % of the patients (14 of 17) treated with NSAIDs experienced a decrease in LGE at 3 months, while it was only 58 % (7 of 12) of those without NSAIDs (p=0.15). At 12-month follow-up, one of the patients treated without NSAIDs experienced polymorphic ventricular tachycardia (VT) with cardiac arrest, while one of the patients with NSAIDs experienced non-sustained VT. Conclusions: This is the first case-control study demonstrating that NSAIDs are safe in patients with myopericarditis and preserved LVEF. Our data suggest that this drug class should be tested prospectively in a large randomised clinical trial.

Cardiac Rehabilitation and Exercise Prescription in Symptomatic Patients with Non-Obstructive Coronary Artery Disease-a Systematic Review.

PURPOSE OF REVIEW: Non-obstructive coronary artery disease (NOCAD) on coronary angiography is a common finding in patients with stable angina. Angina in NOCAD patients is thought to be caused by endothelial dysfunction of the epicardial coronary arteries and/or the microvasculature. Treatment is empiric, and 30% of patients remain symptomatic in spite of therapy. It is well known that physical exercise can improve endothelial function. The goal of this review was to assess the current literature on effects of physical exercise in NOCAD patients with angina. Therefore, a literature search was conducted to March 13, 2018 using the following search terms: syndrome X, microvascular angina, non-obstructive coronary artery disease and exercise training, cardiac rehabilitation, endothelial function. All original publications were included which examined the effect of a cardiac rehabilitation (CR) program or exercise training (ET) on patients with angina and NOCAD. RECENT FINDINGS: Eight studies, of which four were randomized controlled studies, examined 218 participants, 162 in an intervention and 56 in control groups. Most patients were women (97.7%). Exercise programs varied from 8 weeks to 4 months at moderate intensity and some included relaxation therapy. The studies examined the effect of CR on exercise capacity, quality of life (QoL), and perfusion defects. CR increased exercise capacity, oxygen uptake, symptom severity, and QoL. Myocardial perfusion improved. CR appears to be beneficial in symptomatic patients with NOCAD, improving exercise capacity and QoL and reducing severity of symptoms and myocardial perfusion defects. Data is limited to a small number of predominantly female patients. Further larger trials are warranted to determine the optimal rehabilitation protocols and define its long-term benefits.

Cardiac Magnetic Resonance Imaging in Myocarditis Reveals Persistent Disease Activity Despite Normalization of Cardiac Enzymes and Inflammatory Parameters at 3-Month Follow-Up.

BACKGROUND: There is a major unmet need to identify high-risk patients in myocarditis. Although decreasing cardiac and inflammatory markers are commonly interpreted as resolving myocarditis, this assumption has not been confirmed as of today. We sought to evaluate whether routine laboratory parameters at diagnosis predict dynamic of late gadolinium enhancement (LGE) as persistent LGE has been shown to be a risk marker in myocarditis. METHODS AND RESULTS: Myocarditis was diagnosed based on clinical presentation, high-sensitivity troponin T, and cardiac magnetic resonance imaging, after exclusion of obstructive coronary artery disease by angiography. Cardiac magnetic resonance imaging was repeated at 3 months. LGE extent was analyzed with the software GT Volume. Change in LGE >20% was considered significant. Investigated cardiac and inflammatory markers included high-sensitivity troponin T, creatine kinase, myoglobin, N-terminal B-type natriuretic peptide, C-reactive protein, and leukocyte count. Twenty-four patients were enrolled. Absolute levels of cardiac enzymes and inflammatory markers at baseline did not predict change in LGE at 3 months. Cardiac and inflammatory markers had normalized in 21 patients (88%). LGE significantly improved in 16 patients (67%); however, it persisted to a lesser degree in 17 of them (71%) and increased in a small percentage (21%) despite normalization of cardiac enzymes. CONCLUSIONS: This is the first study reporting that cardiac enzymes and inflammatory parameters do not sufficiently reflect LGE in myocarditis. Although a majority of patients with normalizing laboratory markers experienced improved LGE, in a small percentage LGE worsened. These data suggest that cardiac magnetic resonance imaging might add value to currently existing diagnostic tools for risk assessment in myocarditis.

The altered apoptotic pathways in cisplatin and etoposide-resistant melanoma cells are drug specific.

Apoptotic deficiency is one of the mechanisms leading to chemoresistance due to the potential of many chemotherapeutic drugs to induce apoptosis. We have examined drug-induced apoptosis in the chemosensitive human melanoma cell line MeWo, as well as in its resistant sublines, which were selected by continuous exposure to etoposide (MeWo(Eto1)) and cisplatin (MeWo(Cis1)). In former studies, activation of the mitochondrial pro-apoptotic pathway could not be demonstrated in etoposide-resistant cells after exposure to etoposide. A significant reduction of PARP [poly (ADP-ribose) polymerase] cleavage and caspase activation, but unimpaired DNA fragmentation, was seen in cisplatin-resistant cells after treatment with cisplatin. In the current study, we investigated effects of chemotherapeutic drugs different from the selecting agents cisplatin and etoposide on the observed modulations of the mitochondrial apoptotic pathway. We analysed dose-dependent release of cytochrome c, caspase-9 activation, cleavage of PARP and activation of effector caspases in etoposide and cisplatin-resistant cells after exposure to etoposide, teniposide, cisplatin or fotemustine. In analogy to etoposide exposure, we could not demonstrate any activation of the apoptotic pathway in etoposide-resistant cells after exposure to teniposide, another topoisomerase-II inhibitor. In contrast, exposure to cisplatin and fotemustine led to apoptotic cell death in these cells. This suggests that the deficiency of apoptosis in etoposide-resistant cells is dependent on the trigger by topoisomerase-II inhibitors. Analysis of cisplatin-resistant cells after etoposide and fotemustine exposure revealed an increased activity of the apoptotic pathway when compared with cisplatin exposure at corresponding survival rates in these cells. These results suggest that the observed modulations of the apoptotic pathway in resistant melanoma cell lines are specific for an anti-neoplastic drug and are not fixed at the molecular level, as different chemotherapeutic drugs are capable of overcoming these alterations.

Increased ventilatory response to carbon dioxide in COPD patients following vitamin C administration.

Patients with chronic obstructive pulmonary disease (COPD) have decreased ventilatory and cerebrovascular responses to hypercapnia. Antioxidants increase the ventilatory response to hypercapnia in healthy humans. Cerebral blood flow is an important determinant of carbon dioxide/hydrogen ion concentration at the central chemoreceptors and may be affected by antioxidants. It is unknown whether antioxidants can improve the ventilatory and cerebral blood flow response in individuals in whom these are diminished. Thus, we aimed to determine the effect of vitamin C administration on the ventilatory and cerebrovascular responses to hypercapnia during healthy ageing and in COPD. Using transcranial Doppler ultrasound, we measured the ventilatory and cerebral blood flow responses to hyperoxic hypercapnia before and after an intravenous vitamin C infusion in healthy young (Younger) and older (Older) subjects and in moderate COPD. Vitamin C increased the ventilatory response in COPD patients (mean (95% CI) 1.1 (0.9-1.1) versus 1.5 (1.1-2.0) L·min-1·mmHg-1, p<0.05) but not in Younger (2.5 (1.9-3.1) versus 2.4 (1.9-2.9) L·min-1·mmHg-1, p>0.05) or Older (1.3 (1.0-1.7) versus 1.3 (1.0-1.7) L·min-1·mmHg-1, p>0.05) healthy subjects. Vitamin C did not affect the cerebral blood flow response in the young or older healthy subjects or COPD subjects (p>0.05). Vitamin C increases the ventilatory but not cerebrovascular response to hyperoxic hypercapnia in patients with moderate COPD.

Cerebrovascular and ventilatory responses to acute isocapnic hypoxia in healthy aging and lung disease: effect of vitamin C.

Acute hypoxia increases cerebral blood flow (CBF) and ventilation (V̇e). It is unknown if these responses are impacted with normal aging, or in patients with enhanced oxidative stress, such as (COPD). The purpose of the study was to 1) investigate the effects of aging and COPD on the cerebrovascular and ventilatory responses to acute hypoxia, and 2) to assess the effect of vitamin C on these responses during hypoxia. In 12 Younger, 14 Older, and 12 COPD, we measured peak cerebral blood flow velocity (V̄p; index of CBF), and V̇e during two 5-min periods of acute isocapnic hypoxia, under conditions of 1) saline-sham; and 2) intravenous vitamin C. Antioxidants [vitamin C, superoxide dismutase (SOD), glutathione peroxidase, and catalase], oxidative stress [malondialdehyde (MDA) and advanced protein oxidation product], and nitric oxide metabolism end products (NOx) were measured in plasma. Following the administration of vitamin C, vitamin C, SOD, catalase, and MDA increased, while NOx decreased. V̄p and V̇e sensitivity to hypoxia was reduced in Older by ∼60% (P < 0.02). COPD patients exhibited similar V̄p and V̇e responses to Older (P > 0.05). Vitamin C did not have an effect on the hypoxic V̇e response but selectively decreased the V̄p sensitivity in Younger only. These findings suggest a reduced integrative reflex (i.e., cerebrovascular and ventilatory) during acute hypoxemia in healthy older adults. Vitamin C does not appear to have a large influence on the cerebrovascular or ventilatory responses during acute hypoxia.

Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure.

OBJECTIVES: This study investigated whether reduced levels of circulating endothelial progenitors cells (EPCs) in chronic heart failure (CHF) are secondary to an exhaustion of hematopoietic stem cells (HSCs) in the bone marrow or to reduced mobilization. BACKGROUND: Circulating EPCs presumably originate from bone marrow-derived HSC. Persistent mobilization of EPCs was shown to be associated with favorable left ventricular infarct remodeling processes. METHODS: We assessed the number and functional capacity of EPCs in 17 healthy controls, 25 patients with ischemic cardiomyopathy (ICM), and 20 patients with dilated cardiomyopathy (DCM). To document an impairment of HSC function in the bone marrow, the colony-forming unit capacity of bone marrow-derived mononuclear cells and the number of CD34+ HSCs were examined in 6 healthy volunteers, 94 ICM patients, and 25 DCM patients. RESULTS: The number of EPCs was reduced in CHF, irrespective of its etiology. In contrast, the migratory capacity was selectively impaired in EPCs of ICM patients (4.8 +/- 4.0 migrated cells; DCM 9.7 +/- 5.8; p = 0.02). On multivariate analysis, ICM, advanced New York Heart Association functional class, and CHF were independent predictors of functional EPC impairment. The number of bone marrow-derived CD34+ cells did not differ between the CHF populations. However, colony-forming units (CFUs) were selectively reduced in ICM patients (54.4 +/- 24.6; DCM 68.1 +/- 26.9; p < 0.02). Ischemic cardiomyopathy was the only independent predictor of impaired CFU capacity. Impaired CFU capacity was associated with reduced matrix metalloproteinase-9 activity in the bone marrow plasma. CONCLUSIONS: Ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular (LV) remodeling process.