Abstract Background Ischaemic heart disease (IHD) is the leading cause of death worldwide. The World Health Organisation (WHO) collects mortality data coded using the International Statistical Classification of Diseases (ICD) code. Methods We analysed IHD deaths world-wide between 1995 and 2009 and used the UN population database to calculate age-specific and directly and indirectly age-standardised IHD mortality rates by country and region. Results IHD is the single largest cause of death worldwide, causing 7,249,000 deaths in 2008, 12.7% of total global mortality. There is more than 20-fold variation in IHD mortality rates between countries. Highest IHD mortality rates are in Eastern Europe and Central Asian countries; lowest rates in high income countries. For the working-age population, IHD mortality rates are markedly higher in low-and-middle income countries than in high income countries. Over the last 25 years, age-standardised IHD mortality has fallen by more than half in high income countries, but the trend is flat or increasing in some low-and-middle income countries. Low-and-middle income countries now account for more than 80% of global IHD deaths. Conclusions The global burden of IHD deaths has shifted to low-and-middle income countries as lifestyles approach those of high income countries. In high income countries, population ageing maintains IHD as the leading cause of death. Nevertheless, the progressive decline in age-standardised IHD mortality in high income countries shows that increasing IHD mortality is not inevitable. The 20-fold mortality difference between countries, and the temporal trends, may hold vital clues for handling IHD epidemic which is migratory, and still burgeoning.
Abstract All authors to papers in the International Journal of Cardiology must adhere to the following principles: 1 That the corresponding author has the approval of all other listed authors for the submission and publication of all versions of the manuscript. 2. That all people who have a right to be recognised as authors have been included on the list of authors and everyone listed as an author has made an independent material contribution to the manuscript. 3. That the work submitted in the manuscript is original and has not been published elsewhere and is not presently under consideration of publication by any other journal other than in oral, poster or abstract format. 4. That the material in the manuscript has been acquired according to modern ethical standards and has been approved by the legally appropriate ethical committee. 5. That the article does not contain material copied from anyone else without their written permission. 6. That all material which derives from prior work, including from the same authors, is properly attributed to the prior publication by proper citation. 7. That the manuscript will be maintained on the servers of the Journal and held to be a valid publication by the Journal only as long as all statements in these principles remain true. 8. That if any of the statements above ceases to be true the authors have a duty to notify the Journal as soon as possible so that the manuscript can be withdrawn.
Abstract Principles of Ethical Publishing in the International Journal of Cardiology: 1. That the corresponding author has the approval of all other listed authors for the submission and publication of all versions of the manuscript. 2. That all people who have a right to be recognised as authors have been included on the list of authors and everyone listed as an author has made an independent material contribution to the manuscript 3. That the work submitted in the manuscript is original and has not been published elsewhere and is not presently under consideration of publication by any other journal. The oral or poster presentation of parts of the work and its publishing as a single page abstract does not count as prior publication for this purpose. 4. That the material in the manuscript has been acquired according to modern ethical standards and does not contain material copied from anyone else without their written permission 5. That all material which derives from prior work, including from the same authors, is properly attributed to the prior publication by proper citation 6. That the manuscript will be maintained on the servers of the Journal and held to be a valid publication by the Journal only as long as all statements in these principles remain true 7. That if any of the statements above ceases to be true the authors have a duty to notify the journal as soon as possible so that the manuscript can be withdrawn.
Abstract Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. The understanding of the risk factors for CVD may yield important insights into the prevention, etiology, course, and treatment of this major public health concern. Autonomic imbalance, characterized by a hyperactive sympathetic system and a hypoactive parasympathetic system, is associated with various pathological conditions. Over time, excessive energy demands on the system can lead to premature aging and diseases. Therefore, autonomic imbalance may be a final common pathway to increased morbidity and mortality from a host of conditions and diseases, including cardiovascular disease. Heart rate variability (HRV) may be used to assess autonomic imbalances, diseases and mortality. Parasympathetic activity and HRV have been associated with a wide range of conditions including CVD. Here we review the evidence linking HRV to established and emerging modifiable and non-modifiable CVD risk factors such as hypertension, obesity, family history and work stress. Substantial evidence exists to support the notion that decreased HRV precedes the development of a number of risk factors and that lowering risk profiles is associated with increased HRV. We close with a suggestion that a model of autonomic imbalance may provide a unifying framework within which to investigate the impact of risk factors, including psychosocial factors and work stress, on cardiovascular disease.
Abstract Background Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy. Methods In a Phase 3, randomized, double-blind, double-dummy study ( NCT01644474 ), patients (low-density lipoprotein cholesterol [LDL-C] 100–190 mg/dL, 10-year risk of fatal cardiovascular events ≥ 1%–<5% [systemic coronary risk estimation]) were randomized to ezetimibe 10 mg/day ( n = 51) or alirocumab 75 mg subcutaneously (via 1mL autoinjector) every 2 weeks (Q2W) ( n = 52), with dose up-titrated to 150 mg Q2W (also 1 mL) at week 12 if week 8 LDL-C was ≥ 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks, analyzed using all available data (intent-to-treat approach, ITT). Analyses using on-treatment LDL-C values were also conducted. Results Mean (SD) baseline LDL-C levels were 141.1 (27.1) mg/dL (alirocumab) and 138.3 (24.5) mg/dL (ezetimibe). The 24-week treatment period was completed by 85% of alirocumab and 86% of ezetimibe patients. Least squares mean (SE) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe (ITT; p < 0.0001) and 54 (2)% versus 17 (2)% (on-treatment; p < 0.0001). At week 12, before up-titration, alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% (on-treatment). Injection site reactions were infrequent (< 2% and < 4% of alirocumab and ezetimibe patients, respectively). Conclusions Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide ≥ 50% LDL-C reduction in the majority of the patients. Adverse events were comparable between groups.
Abstract Background Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial function and has shown to have prognostic value for future cardiovascular disease (CVD). The predictive strength of FMD in CVD patients compared to populations not diagnosed for CVD warrants further investigation. We systematically reviewed prospective studies that investigated the association between brachial FMD and future cardiovascular events, with particular focus on the role of underlying health status. Methods To obtain eligible studies, several literature databases were systematically searched through March 2011. Pooled overall risk estimates were calculated separately for continuous risk estimates for CVD (per 1% higher FMD) and for categorical risk estimates for CVD (having high vs. low FMD), based on random-effects models. Results A total of 23 studies including 14,753 subjects were eligible for inclusion in the meta-analysis. For studies reporting continuous risk estimates, the pooled overall CVD risk was 0.92 (95%CI: 0.88; 0.95) per 1% higher FMD. The observed association seemed stronger (P-value < 0.01) in diseased populations than in asymptomatic populations (0.87 (95%CI: 0.83; 0.92) and 0.96 (95%CI: 0.92; 1.00) per 1% higher FMD, respectively). For studies reporting categorical risk estimates, the pooled overall CVD risk for high vs. low FMD was similar in both types of populations, on average 0.49 (95%CI: 0.39; 0.62). Conclusions Our findings show that brachial FMD is inversely associated with future CVD events, with some indications for a stronger relation in diseased populations. Endothelial dysfunction may be considered relevant for classifying subjects in terms of CVD risk.
Abstract Background Heart failure (HF) imposes both direct costs to healthcare systems and indirect costs to society through morbidity, unpaid care costs, premature mortality and lost productivity. The global economic burden of HF is not known. Methods We estimated the overall cost of heart failure in 2012, in both direct and indirect terms, across the globe. Existing country-specific heart failure costs analyses were expressed as a proportion of gross domestic product and total healthcare spend. Using World Bank data, these proportional values were used to interpolate the economic cost of HF for countries of the world where no published data exists. Countries were categorized according to their level of economic development to investigate global patterns of spending. Results 197 countries were included in the analysis, covering 98.7% of the world's population. The overall economic cost of HF in 2012 was estimated at $108 billion per annum. Direct costs accounted for ~ 60% ($65 billion) and indirect costs accounted for ~ 40% ($43 billion) of the overall spend. Heart failure spending varied widely between high-income and middle and low-income countries. High-income countries spend a greater proportion on direct costs: a pattern reversed for middle and low-income countries. Conclusions Heart failure imposes a huge economic burden, estimated at $108 billion per annum. With an aging, rapidly expanding and industrializing global population this value will continue to rise.
Abstract Background/objectives Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. Methods Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. Results We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (− 14 to − 15 mV at 23 °C vs − 24 mV at 37 °C). The uptake of iPS-exo protects H9C2 cells against H2 O2 -induced oxidative stress by inhibiting caspase 3/7 activation (P < 0.05, n = 6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardial injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. Conclusions Exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represents novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an “off-the-shelf” therapy to rescue ischemic cardiomyocytes in conditions such as MIR.
Cachexia is a serious, however underestimated and underrecognised medical consequence of malignant cancer, chronic heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, rheumatoid arthritis, Alzheimer's disease, infectious diseases, and many other chronic illnesses. The prevalence of cachexia is high, ranging from 5% to 15% in CHF or COPD to 60% to 80% in advanced cancer. By population prevalence, the most frequent cachexia subtypes are in order: COPD cachexia, cardiac cachexia (in CHF), cancer cachexia, and CKD cachexia. In industrialized countries (North America, Europe, Japan), the overall prevalence of cachexia (due to any disease) is growing and currently about 1%, i.e., about nine million patients. The relative prevalence of cachexia is somewhat less in Asia, but is a growing problem there as well. In absolute terms, cachexia is, in Asia (due to the larger population), as least as big a problem as in the Western world. Cachexia is also a big medical problem in South America and Africa, but data are scarce. A consensus statement recently proposed to diagnose cachexia in chronic diseases when there is weight loss exceeding 5% within the previous 3–12 months combined with symptoms characteristic for cachexia (e.g., fatigue), loss of skeletal muscle and biochemical abnormalities (e.g., anemia or inflammation). Treatment approaches using anabolics, anti-catabolic therapies, appetite stimulants, and nutritional interventions are under development. A more thorough understanding of the pathophysiology of cachexia development and progression is needed that likely will lead to combination therapies being developed. These efforts are greatly needed as presence of cachexia is always associated with high-mortality and poor-symptom status and dismal quality of life. It is thought that in cancer, more than 30% of patients die due to cachexia and more than 50% of patients with cancer die with cachexia being present. In other chronic illnesses, one can estimate that up to 30% of patients die with some degree of cachexia being present. Mortality rates of patients with cachexia range from 10% to 15% per year (COPD), to 20% to 30% per year (CHF, CKD) to 80% in cancer.
Abstract Background Exosomes play an important role in intercellular signaling and exert regulatory function by carrying bioactive molecules. This study investigated (1) the cardioprotective capabilities of exosomes derived from mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4 ) and (2) its underlying regulatory mechanisms for expression of target proteins in recipient cells. Methods and results Exosomes were isolated and purified from MSCGATA-4 (ExoGATA-4 ) and control MSCs (ExoNull ). Cell injury was investigated in primary cultured rat neonatal cardiomyocytes (CM) and in the rat heart. Exosomes contributed to increased CM survival, reduced CM apoptosis, and preserved mitochondrial membrane potential in CM cultured under a hypoxic environment. Direct intramyocardial transplantation of exosomes at the border of an ischemic region following ligation of the left anterior descending coronary artery significantly restored cardiac contractile function and reduced infarct size. Real-time PCR revealed that several anti-apoptotic miRs were highly expressed in ExoGATA-4 . Rapid internalization of ExoGATA-4 by CM was documented using time-lapse imaging. Subsequent expression of these miRs, particularly miR-19a was higher in CM and in the myocardium treated with ExoGATA-4 compared to those treated with ExoNull . The enhanced protective effects observed in CM were diminished by the inhibition of miR-19a. The expression level of PTEN, a predicted target of miR-19a, was reduced in CM treated with ExoGATA-4 , which resulted in the activation of the Akt and ERK signaling pathways. Conclusions ExoGATA-4 upon transplantation in the damaged tissue mediate protection by releasing multiple miRs responsible for activation of the cell survival signaling pathway.
Abstract Background Sympathetic overactivation, is reduced by renal denervation in drug-resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. Method 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mm Hg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May–July 2011. Patients were admitted for pre-procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. Results No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Δsystolic − 7.1 ± 6.9 mm Hg, p = 0.35; Δdiastolic − 0.6 ± 4.0 mm Hg, p = 0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Δcreatinine − 5.7 ± 8.4 μmol/l, p = 0.52 and Δurea − 1.0 ± 1.0 mmol/l, p = 0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Δ = 27.1 ± 9.7 m, p = 0.03), with each patient showing an increase. Conclusions This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham-controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe.
Abstract Objective The aim of this study was to determine the validity of in-hospital mortality records in the National Health Insurance Research Database (NHIRD) by cross-comparing with death records from the electronic medical records (EMR) of a medical center in southern Taiwan. Methods Data on patients admitted to the medical center for acute myocardial infarction (AMI) or stroke during the years 2005 to 2010 were extracted from the two databases and cross-linkages with patients' characteristics (birth date, gender, admission date, and discharge date). While the death record was available in the catastrophic illness registry data files (CIRD), we also estimated the insurance status and death record in the CIRD subset using confirmed death cases. Additionally, agreement in comorbidities between records from the two databases was evaluated. Results A total of 6197 cases were successfully linked, with a linkage rate of 96.56% of cases in the NHIRD when linked to those from the EMR. Among the linked population, 538 of 682 patients retrieved as expired in the NHIRD were also so recorded in the EMR. This yielded a positive predictive value of 0.79 when the EMR was used as the gold standard. Patients having death records in both the CIRD subset and the EMR totaled 364, which yielded a percentage positive agreement rate of 76%. The consistency in comorbidity diagnoses between the two databases was more than 90% among matched cases. Conclusions The accuracy of death records in the NHIRD was high, and appears to be a valid resource for population research in cardiovascular diseases.
Abstract Background Originally reported to occur predominantly in younger women, idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients. We aimed to describe the characteristics of such patients and their survival under clinical practice conditions. Methods Prospective registry in 28 centers in 6 European countries. Demographics, clinical characteristics, hemodynamics, treatment patterns and outcomes of younger (18–65 years) and elderly (> 65 years) patients with newly diagnosed IPAH (incident cases only) were compared. Results A total of 587 patients were eligible for analysis. The median (interquartile, [IQR]) age at diagnosis was 71 (16) years. Younger patients (n = 209; median age, 54  years) showed a female-to-male ratio of 2.3:1 whereas the gender ratio in elderly patients (n = 378; median age, 75  years) was almost even (1.2:1). Combinations of PAH drugs were widely used in both populations, albeit less frequently in older patients. Elderly patients were less likely to reach current treatment targets (6 min walking distance > 400 m, functional class I or II). The survival rates 1, 2, and 3 years after the diagnosis of IPAH were lower in elderly patients, even when adjusted for age- and gender-matched survival tables of the general population (p = 0.006 by log-rank analysis). Conclusions In countries with an aging population, IPAH is now frequently diagnosed in elderly patients. Compared to younger patients, elderly patients present with a balanced gender ratio and different clinical features, respond less well to medical therapy and have a higher age-adjusted mortality. Further characterization of these patients is required. Clinical trials registration: NCT01347216.
Abstract Background The focus of the diagnostic process in chest pain patients at the emergency department is to identify both low and high risk patients for an acute coronary syndrome (ACS). The HEART score was designed to facilitate this process. This study is a prospective validation of the HEART score. Methods A total of 2440 unselected patients presented with chest pain at the cardiac emergency department of ten participating hospitals in The Netherlands. The HEART score was assessed as soon as the first lab results and ECG were obtained. Primary endpoint was the occurrence of major adverse cardiac events (MACE) within 6 weeks. Secondary endpoints were (i) the occurrence of AMI and death, (ii) ACS and (iii) the performance of a coronary angiogram. The performance of the HEART score was compared with the TIMI and GRACE scores. Results Low HEART scores (values 0–3) were calculated in 36.4% of the patients. MACE occurred in 1.7%. In patients with HEART scores 4–6, MACE was diagnosed in 16.6%. In patients with high HEART scores (values 7–10), MACE occurred in 50.1%. The c-statistic of the HEART score (0.83) is significantly higher than the c-statistic of TIMI (0.75)and GRACE (0.70) respectively (p 98% certainty. In these patients one might consider reserved policies. In patients with high HEART scores (7–10) the high risk of MACE may indicate more aggressive policies.
Abstract Background We aimed to evaluate the effect of prophylactic nebivolol use on prevention of antracycline-induced cardiotoxicity in breast cancer patients. Methods In this small, prospective, double-blind study, we randomly assigned 45 consecutive patients with breast cancer and planned chemotheraphy to receive nebivolol 5 mg daily (n = 27) or placebo (n = 18). Echocardiographic measurements and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were obtained at baseline and at 6-month of chemotherapy. Results Both studied groups had comparable echocardiographic variables and NT-pro-BNP levels at baseline. At 6-month, the left ventricular (LV) end-systolic and end-diastolic diameters increased in the placebo group (LVESD: 29.7 ± 3.4 to 33.4 ± 4.5 mm; LVEDD: 47.2 ± 3.8 to 52.0 ± 4.6 mm, p = 0.01 for both) but remained unchanged in the nebivolol group (LVESD: 30.4 ± 3.5 to 31.0 ± 3.6 mm, p = 0.20; LVEDD: 47.0 ± 4.4 to 47.1 ± 4.0 mm, p = 0.93). The placebo group also had lower LVEF than the nebivolol group (57.5 ± 5.6% vs. 63.8 ± 3.9%, p = 0.01) at 6-month. NT-pro-BNP level remained static in the nebivolol group (147 ± 57 to 152 ± 69 pmol/l, p = 0.77) while it increased in the placebo group (144 ± 66 to 204 ± 73 pmol/l, p = 0.01). Conclusions Prophylactic use of nebivolol treatment may protect the myocardium against antracycline-induced cardiotoxicity in breast cancer patients.
Abstract Aim This study aims to evaluate the incremental value of plasma biomarkers to traditional clinical variables for risk stratification of 30-day and one-year mortality in acutely decompensated heart failure (ADHF). Methods and results Through an international collaborative network, individual patient data on 5306 patients hospitalized for ADHF were collected. The all-cause mortality rate was 11.7% at 30 days and 32.9% at one year. The clinical prediction model (age, gender, blood pressure on admission, estimated glomerular filtration rate < 60 mL/min/1.73 m2 , sodium and hemoglobin levels, and heart rate) had a c-statistic of 0.74 for 30-day mortality and 0.73 for one-year mortality. Several biomarkers measured at presentation improved risk stratification when added to the clinical model. At 30 days, the net reclassification improvement (NRI) was 28.7% for mid-regional adrenomedullin (MR-proADM; p < 0.001) and 25.5% for soluble (s)ST2 (p < 0.001). At one year, sST2 (NRI 10.3%), MR-proADM (NRI 9.1%), amino-terminal pro-B-type natriuretic peptide (NT-proBNP; NRI 9.1%), mid-regional proatrial natriuretic peptide (MR-proANP; NRI 7.4%), B-type natriuretic peptide (NRI 5.5%) and C-reactive protein (CRP; NRI 5.3%) reclassified patients with ADHF (p < 0.05 for all). CRP also markedly improved risk stratification of patients with ADHF as a dual biomarker combination with MR-proADM (NRI 36.8% [p < 0.001] for death at 30 days) or with sST2 (NRI 20.3%; [p < 0.001] for one-year mortality). Conclusion In this study, biomarkers provided incremental value for risk stratification of ADHF patients. Biomarkers such as sST2, MR-proADM, natriuretic peptides and CRP, reflecting different pathophysiologic pathways, add prognostic value to clinical risk factors for predicting both short-term and one-year mortality in ADHF.
Abstract Background We sought to compare the prognosis of patients with spontaneous coronary artery dissection (SCAD) and atherosclerosis as the cause of acute myocardial infarction (AMI), especially in young females. Methods and results A total of 20,195 patients with AMI at 20 institutions between 2000 and 2013 were retrospectively studied. Major adverse cardiac event (MACE: cardiac death, AMI or urgent revascularization) was the endpoint. The overall prevalence of SCAD was 0.31% (n = 63; female, 94%). SCAD developed following emotional stress in 29% of patients. Revascularization was performed in 56% (35 of 63 patients), and SCAD recurrence developed in the originally involved vessel in 6 of 35 patients with revascularization, compared to none among 28 patients after conservative therapy (p = 0.002). We compared the clinical characteristics of young female AMI patients aged ≤ 50 years in the SCAD (n = 45) and no-SCAD groups (atherosclerotic AMI, n = 55). During a median follow-up of 50 months, SCAD recurred in 27% of patients, of which 42% was in the first 30 days. Kaplan–Meier analysis showed a significantly higher incidence of MACE in the SCAD group compared to the no-SCAD group (hazard ratio, 6.91; 95% confidence interval, 2.5 to 24.3; p < 0.001), although the rate of successful percutaneous coronary intervention for SCAD was as high as 92%. Conclusions Young female patients with SCAD represent a high-risk subgroup of patients with AMI and require close follow-up.