Ischemic Arrhythmias Research Articles

Early Detection of Chemotherapy- Induced Cardiotoxicity in Hematological Patients: A Prospective Study

Introduction: Chemotherapy-induced cardiotoxicity is an important concern in the long-term survivors era, especially in those younger patients who may suffer excess cardiovascular morbidity and worse outcomes. There is no consensus on monitoring criteria for this phenomenon and prompt therapy has not been yet properly established. We aim to evaluate prospectively early detection of cardiotoxicity, incidence, timing of occurrence and pre-existing factors during two years.Methods: This prospective study is being conducted at La Paz University Hospital in the period 2012-2013 (n=80) (age 18-84) based on anthracycline chemotherapy. A second phase of the study is ongoing, pending completion of the two year follow-up. Patients’ levels of analytical biomarkers cardiac troponin (cTnl) and B type natriuretic peptid (NT pro BNP), echocardiogram parameters left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured before starting chemotherapy, 3 weeks and 3 months afterwards, and then every six months during 2 years. In the first visit different clinical variables were also measured, including age, sex, body mass index, cardiovascular risk factors and previous treatments with chemotherapy and radiotherapy. Cardiotoxicity was defined as a reduction in LVEF <50% or >10% with basal >50%. Another cardiotoxicity conditions such as ischemic cardiomyopathy, arrhythmia, pericarditis and valvular heart disease were also considered. The cumulative dose of chemotherapy was measured in every visit.Results: Eighty patients were included; 49% women; 53.75% non-Hodgkin lymphoma, 22.5% Hodgkin lymphoma and 23.75% acute myeloid leukemia. Fifteen patients died (18.75%), 100% due to tumour related causes. Nine patients did not attend follow-up (11.25%). A total of 14 cardiotoxicity events occurred (17.5%): the most frequent event was reduction in LVEF (78,5%). Ischemic events and valvular disease were also observed. No hospitalization was needed in any of the events. Two of them recovered LVEF-levels spontaneously in the next visit. The other 9 were treated with heart failure therapy: 8 with ACE (angiotensin converting enzyme) inhibitors and beta- blockers and 1 with ACE inhibitors. Six (66.6%) of those who received specific treatment recovered basal LVEF-levels, 2 maintained LVEF dysfunction, and 1 died during follow-up due to tumour-related causes. In 85.7% of patients, cardiotoxicity occurred within the first year of follow-up. Basal LVEF and previous treatment with chemotherapy were significant predictors of subsequent cardiotoxicity (Cox regression model).Conclusions: early detection of cardiotoxic events provides an opportunity to start heart failure therapy on time to prevent progression to established heart failure. Previous chemotherapy treatment points to an increased risk of cardiotoxicity, so more intensive surveillance is necessary. Extended analysis of patients being included in the ongoing study will extend the information about cumulative anthracycline dose and cardiotoxicity induced by non-anthracycline chemotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cardiac Events in Real-World Multiple Myeloma Patients Treated with Carfilzomib: A Retrospective Claims Database Analysis

Introduction: Multiple myeloma (MM) is a hematologic cancer that mostly affects elderly patients who are at increased risk for development of cardiac-related comorbidities due to age-, disease-, and treatment-related factors. In real world data, approximately 25-30% of MM patients are hospitalized for a cardiac event after MM diagnosis (Kistler et al. American Society Hematology 2012 Annual Meeting, poster 2916). The proteasome inhibitor, carfilzomib, is approved for treatment of patients with relapsed or refractory MM. In carfilzomib clinical trials, grade 3 or higher cardiac failure was reported for ~4% of patients (Stewart et al. NEJM 2015;372:142-52, Dimopoulos et al. Lancet Oncol 2016;17:27-38). In this retrospective analysis, we sought to evaluate the incidence rate (IR) of cardiac events in MM patients treated with carfilzomib in a real-world setting in the US and to describe differences in baseline characteristics between carfilzomib-treated MM patients who do and do not have cardiac events.Methods: Newly-diagnosed MM patients with symptomatic disease were identified in the Truven MarketScan claims database from 1/1/05 to 6/30/15 using an algorithm validated for ascertainment of MM patients in claims data (Princic et al. Blood 2015;126:4521). All carfilzomib-treated patients were included in the analysis. The first dose of carfilzomib was the index date. The baseline period was 12 months prior to the MM diagnosis date to the index date. Cardiac events (hypertension, heart failure, ischemic heart disease, arrhythmias and conduction disorders, and cardiomyopathy) were identified during baseline by inpatient (IP) or outpatient (OP) claims and after index date by primary diagnosis on IP claims (hospitalized events). Logistic regression was used to estimate baseline covariates associated with any cardiac event. Due to sample size constraints, multivariate regression was not performed. The incidence rate (IR) per 1000 patient-years (PYRs) and associated 95% confidence interval (CI) of hospitalized cardiac events during carfilzomib treatment which included 30 days after the last carfilzomib dose were calculated among patients without a history of the corresponding hospitalized event during the baseline period.Results: The cohort included 498 MM patients treated with carfilzomib; 108 (22%) patients had ≥1 cardiac event identified by both IP and OP claims and 24 (5%) had ≥1 hospitalized cardiac event. Of the 24 hospitalized patients, 14 were hospitalized during carfilzomib treatment (median days to onset = 104) and 8 were hospitalized after carfilzomib treatment (>30 days post dosing; median days to onset = 284). The median age (range) of the 24 patients with hospitalized cardiac events and those with no hospitalized cardiac claims (n=474) was 62 (37, 79) and 61 (36, 96) years, respectively (Table). Baseline medical history of any cardiac event was evident for 92% of hospitalized patients and 84% of non-hospitalized patients. Among hospitalized patients, 25% were over 75 years as compared with 13% of non-hospitalized patients. In univariate analysis, patients with baseline amyloidosis, hypertensive chronic kidney disease, and chronic kidney disease had higher odds of having a hospitalized cardiac event. No significant differences were seen in the proportion of patients with or without a hospitalized cardiac event when evaluated by line of therapy or by carfilzomib treatment regimen (monotherapy or combination). Among patients aged 75+ years, 8.7% were hospitalized, while 2.5% and 4.9% of 65-74 and 18-64 year old patients were hospitalized, respectively (Table). IR per 1000 PYRs [95% CI] among the 14 carfilzomib-treated MM patients hospitalized for any cardiac event during the carfilzomib treatment period was 89.7 (49.0; 150.5) - see Figure for IRs of specific cardiac events.Conclusions: Among carfilzomib-treated patients in a US claims database, hospitalization for a cardiac event was uncommon (~5%) and does not exceed what has been observed in MM patients. Patients at highest risk for cardiac hospitalizations had a history of amyloidosis or chronic renal failure. Additional analyses in much larger populations are needed to better understand risk factors for these events. [Display omitted] [Display omitted] DisclosuresChari:Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding. Aggarwal:Amgen: Employment, Equity Ownership. Mezzi:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Zhu:Amgen Inc.: Consultancy. Braunlin:Amgen Inc.: Employment, Equity Ownership. Werther:Amgen Inc.: Employment, Equity Ownership. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding.

Efficacy of β-blocker therapy for secondary prevention for patients undergoing coronary artery bypass grafting surgery.

The efficacy and safety of β-blockers in the treatment of cardiovascular diseases, such as ischemic heart disease, cardiac arrhythmias, and heart failure, have been well established for decades. In this article, we review the current opinions on the application of β-blockers for secondary prevention in patients undergoing coronary artery bypass grafting (CABG) surgery. As the average age of patients treated surgically for coronary artery disease (CAD) is increasing, it is not uncommon to have candidates for CABG presenting with concomitant atrial fibrillation, heart failure or hypertension, most of which were caused by excessive activation of the adrenergic nervous system. In a recent decade, a number of national quality-improvement efforts using a variety of techniques have been made to increase the use of β-blocker therapy before or following the CABG. Results from recent large observational studies among patients with CAD showed that β-blockers were associated with a lower risk of cardiac events only among those with heart failure or recent myocardial infarction. However, the consistent use of β-blockers could benefit those with or without prior myocardial infarction who underwent CABG and discharged alive. In real-world clinical practice, β-blockers are effective and safe to control heart rate and symptoms in patients with CAD, especially for those concomitant with left ventricular systolic dysfunction or prior myocardial infarction. Current evidence supports the preoperative use of β-blocker therapy for patients undergoing CABG as a prevention of new-onset atrial fibrillation. It is reasonable to continue β-blockers as chronic therapy in all CABG patients without contraindications after hospital discharge. Further strategies should be developed to understand and improve discharge prescription of β-blockers and long-term patient adherence.

Effects of insulin-induced hypoglycaemia on lipolysis rate, lipid oxidation and adipose tissue signalling in human volunteers: a randomised clinical study.

The aims of this study were to determine the role of lipolysis in hypoglycaemia and define the underlying intracellular mechanisms. Nine healthy volunteers were randomised to treatment order of three different treatments (crossover design). Treatments were: (1) saline control; (2) hyperinsulinaemic hypoglycaemia (HH; i.v. bolus of 0.1U/kg insulin); and (3) hyperinsulinaemic euglycaemia (HE; i.v. bolus of 0.1U/kg insulin and 20% glucose). Inclusion criteria were that volunteers were healthy, aged >18years, had a BMI between 19 and 26kg/m2, and provided both written and oral informed consent. Exclusion criteria were the presence of a known chronic disease (including diabetes mellitus, epilepsy, ischaemic heart disease and cardiac arrhythmias) and regular use of prescription medication. The data was collected at the medical research facilities at Aarhus University Hospital, Denmark. The primary outcome was palmitic acid flux. Participants were blinded to intervention order, but caregivers were not. Adrenaline (epinephrine) and glucagon concentrations were higher during HH than during both HE and control treatments. NEFA levels and lipid oxidation rates (determined by indirect calorimetry) returned to control levels after 105min. Palmitate flux was increased to control levels during HH (p = NS) and was more than twofold higher than during HE (overall mean difference between HH vs HE, 114 [95% CI 64, 165μmol/min]; p < 0.001). In subcutaneous adipose tissue biopsies, we found elevated levels of hormone-sensitive lipase (HSL) and perilipin-1 phosphorylation 30min after insulin injection during HH compared with both control and HE. There were no changes in the levels of adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58) or G0/G1 switch gene 2 (G0S2) proteins. Insulin-stimulated phosphorylation of Akt and mTOR were unaffected by hypoglycaemia. Expression of the G0S2 gene increased during HE and HH compared with control, without changes in ATGL (also known as PNPLA2) or CGI-58 (also known as ABHD5) mRNA levels. These findings suggest that NEFAs become a major fuel source during insulin-induced hypoglycaemia and that lipolysis may be an important component of the counter-regulatory response. These effects appear to be mediated by rapid stimulation of protein kinase A (PKA) and HSL, compatible with activation of the β-adrenergic catecholamine signalling pathway. ClinicalTrials.gov NCT01919788 FUNDING: : The study was funded by Aarhus University, the Novo Nordisk Foundation and the KETO Study Group/Danish Agency for Science Technology and Innovation (grant no. 0603-00479, to NM).

A minor but deadly surgery of colonic polypectomy in an elderly and fragile patient: a case report and the review of literature.

BackgroundEpithelial dysplasia and adenomatous polyps of colorectum are precancerous lesions. Surgical removal is still one of the important treatment approaches for colorectal polyps.Case presentationA male patient over 78 years was admitted due to bloody stool and abdominal pain. Colonoscopic biopsy showed a high-grade epithelial dysplasia in an adenomatous polyp of sigmoid colon. Anemia, COPD, ischemic heart disease (IHD), arrhythmias, and hypoproteinemia were comorbidities. The preoperative preparation was carefully made consisting of oral nutritional supplements (ONS), blood transfusion, cardiorespiratory management, and hemostatic therapy. However, his illness did not improve but deteriorate mainly due to polyp rebleeding during preparative period. The open polypectomy was performed within 60 min under epidural anesthesia. Postoperative treatments included oxygen inhalation, bronchodilation, parenteral and enteral nutrition, human serum albumin, antibiotics, and blood transfusion. Unluckily, these did not significantly facilitate to surgical recovery on account of severe comorbidities and complications. The most serious complications were colonic leakage and secondary abdominal severe infection. The patient finally gave up treatment due to multiple organ dysfunction syndromes.ConclusionsThe polypectomy for colonic polyp is a seemingly minor but potentially deadly surgery for patients with severe comorbidities, and prophylactic ostomy should be considered for the safety.

Cardiovascular side effects of small molecule therapies for cancer.

Targeted therapies such as monoclonal antibodies and small molecule inhibitors of protein kinases, have improved the prognosis for patients with a wide range of cancers. Several of these classes of therapies are associated with cardiovascular and metabolic sequelae. These include heart failure or an asymptomatic decline in ejection fraction, peripheral and cardiac ischemic events, pulmonary hypertension, arrhythmias and QT-prolongation. This review will focus on the following targeted therapies: BCR-Abl tyrosine kinase inhibitors (TKI), vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors as well as mitogen activated protein kinase (MEK) inhibitors and mammalian target of rapamycin complex (mTOR) inhibitors. The HER2/ErbB2 inhibitors trastuzumab and pertuzumab are important targeted therapies used in the treatment of breast cancer that have been reviewed in detail elsewhere and will not be discussed in this review.1 Table 1 summarizes the cardiovascular side effects of small molecule therapies for cancer.2 View this table: Table 1 Cardiovascular Side effects of Small Molecule Therapies for Cancer BCR-Abl tyrosine kinase inhibitors are an important advance in the treatment of chronic myelogenous leukemia (CML) and the cardiovascular side effects have been extensively reviewed by Moslehi et al.3 Imatinib, a first generation TKI was followed by the second generation TKIs nilotinib, dasatinib and bosutinib and the third-generation agent ponatinib. Imatinib has a low incidence of cardiomyopathy and heart failure, with sequential imaging studies demonstrating rates of left ventricular dysfunction comparable to expected population incidence.4 The heart failure and cardiomyopathy rates for dasatinib were similar …

MicroRNAs in Valvular Heart Diseases: Potential Role as Markers and Actors of Valvular and Cardiac Remodeling.

miRNAs are a class of over 5000 noncoding RNAs that regulate more than half of the protein-encoding genes by provoking their degradation or preventing their translation. miRNAs are key regulators of complex biological processes underlying several cardiovascular disorders, including left ventricular hypertrophy, ischemic heart disease, heart failure, hypertension and arrhythmias. Moreover, circulating miRNAs herald promise as biomarkers in acute myocardial infarction and heart failure. In this context, this review gives an overview of studies that suggest that miRNAs could also play a role in valvular heart diseases. This area of research is still at its infancy, and further investigations in large patient cohorts and cellular or animal models are needed to provide strong data. Most studies focused on aortic stenosis, one of the most common valvular diseases in developed countries. Profiling and functional analyses indicate that miRNAs could contribute to activation of aortic valve interstitial cells to a myofibroblast phenotype, leading to valvular fibrosis and calcification, and to pressure overload-induced myocardial remodeling and hypertrophy. Data also indicate that specific miRNA signatures, in combination with clinical and functional imaging parameters, could represent useful biomarkers of disease progression or recovery after aortic valve replacement.

Shensong Yangxin capsules prevent ischemic arrhythmias by prolonging action potentials and alleviating Ca2+ overload.

Shensong Yangxin capsules (SSYX) are an effective traditional Chinese medicine that has been used to treat coronary heart disease clinically. The present study aimed to establish whether SSYX prevent ischemic arrhythmias in rats, and to explore the underlying mechanisms. Male rats were pretreated with distilled water, SSYX and amiodarone for one week. Acute myocardial ischemia (AMI) was performed to induce ischemic arrhythmias. The incidence and severity of ischemic arrhythmias were evaluated. The action potential, transient outward K+ current (Ito) and inward rectifier K+ current (IK1) of rat cardiomyocytes were measured using the patch‑clamp technique. The intracellular Ca2+ concentration of the cardiomyocytes was measured using a laser scanning confocal microscope. The results revealed that SSYX lowered the incidence of arrhythmia markedly during AMI. Furthermore, SSYX delayed the appearance, and reduced the severity, of ischemic arrhythmias compared with the control. In addition, SSYX markedly decreased the ratio of the myocardial infarction region to the whole heart. In an invitro study, SSYX prolonged the action potential duration of rat cardiomyocytes, and inhibited Ito and IK1 markedly. Additionally, SSYX inhibited Ca2+ elevation induced by KCl in cardiomyocytes. These results suggested that SSYX prevents ischemic arrhythmia, and the underlying mechanism responsible for this process may include prolonging the action potential and alleviating Ca2+ overload.

0173 : Mechanisms behind the pro-arrhythmogenic state induced by exposure to chronic intermittent hypoxia

Obstructive sleep apnea (OSA) is now recognized as a major risk factor for cardiovascular disorders including ventricular arrhythmias and sudden cardiac death. We have demonstrated that intermittent hypoxia (IH), a major component of OSA, increases the incidence of myocardial ischemiarelated ventricular fibrillation. The aim of the present study was to investigate the mechanisms behind the arrhythmogenic effects of IH. Wistar rats were exposed to IH (60-sec cycles alternating 21 and 5% FiO2, 8h/day) or normoxia (similar air-air cycles) during 14 days. Arterial blood pressure and ECG were recorded for power spectral analysis and ECG interval measurement. Hearts were removed, perfused in Langendorff mode and paced at 300 bpm. Epicardial and endocardial monophasic action potentials were recorded and action potential duration at 50% repolarization (APD50) was measured. Mean arterial blood pressure was significantly increased by IH exposure. Rats exposed to IH exhibited higher low-frequency (LF) power, lower high-frequency (HF) power and higher LF/HF ratio of heart rate and blood pressure variability, indicative of a systemic sympathetic activation. This was corroborated by a significant increase in circulating norepinephine levels. IH exposure also resulted in a significant increase in QTc and Tpeak- Tend intervals, indicative of increased spatial and transmural dispersion of repolarization and associated with an increased vulnerability to ischemic ventricular arrhythmias. The increase in the transmural repolarization gradient was associated with a significantly longer endocardial APD50 in IH-exposed rats (49.07 ± 2.19 ms) compared to normoxia-exposed rats (41.29 ± 0.62 ms, p<0.01) while epicardial APD50 did not differ. Thus, chronic exposure to intermittent hypoxia, such as that occurring during OSA, promotes a pro-arrhythmogenic state characterized by sympathoactivation and alterations in ventricular repolarization. The author hereby declares no conflict of interest

Sulfur Dioxide Contributes to the Cardiac and Mitochondrial Dysfunction in Rats.

Epidemiological studies have demonstrated an association between sulfur dioxide (SO2) and an increase of morbidity and mortality of cardiovascular diseases, such as ischemic heart disease, heart failure, and arrhythmia. Mitochondrion is the most sensitive organelle in myocardium of animals exposed to SO2 Here we study the molecular characterization of mitochondrial dysfunction in cardiac muscles of rat after SO2 exposure. We found that the cytochrome c oxidase (COX) activity, mitochondrial membrane potential (ΔΨm), ATP contents, mitochondrial DNA (mtDNA) contents, and mRNA expression of complexes IV and V subunits encoded by mtDNA were decreased after NaHSO3 treatment in vitro or SO2 inhalation in vivo The mitochondrial dysfunctions were accompanied by depressions of co-activator of peroxisome proliferator activated receptor gamma (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM) mRNA and protein. We observed swollen mitochondria and lower amounts of cristae in hearts of rats after 3.5 mg/m(3) SO2 inhalation for 30 days. Interestingly, NaHSO3 induced mitochondrial dysfunctions marked by ΔΨm and ATP reduction could be inhibited by an antioxidant N-acetyl-L-cysteine (NALC), accompanied by the restoration of transcriptional factors expressions. The cardiac mitochondrial dysfunctions could also be alleviated by overexpression of TFAM. SO2 induced abnormal left ventricular function was restored by NALC in vivo Our findings demonstrate that SO2 induces cardiac and mitochondrial dysfunction. And inhibition of reactive oxygen species and enhancing the transcriptional network controlling mitochondrial biogenesis can mitigate the SO2-induced mitochondrial dysfunction.

The effect of sex and age on the comorbidity burden of OSA: an observational analysis from a large nationwide US health claims database.

Obstructive sleep apnoea (OSA) is a highly prevalent condition but studies exploring the burden of OSA-associated comorbidities have been limited by small sample sizes with underrepresentation of women.We queried the Truven Health MarketScan Research Databases 2003-2012, which is a collection of health insurance claims for working adults and retirees with employer-sponsored health insurance. Adults with a diagnostic code for OSA with at least 12 months of follow-up from the index date of OSA diagnosis were compared to a matched random sample. Comorbidities were assessed using International Classification of Diseases, Ninth Edition, codes. A logistic regression model was constructed to test the independent association between OSA and comorbidities.Our cohort included 1,704,905 patients with OSA and 1,704,417 matched controls. All comorbidities were significantly more prevalent in OSA patients. Type 2 diabetes and ischaemic heart disease were more prevalent in men but hypertension and depression were more prevalent in women with OSA. In contrast, the sex differences in the prevalence of congestive heart failure, arrhythmias and stroke were less pronounced. The prevalence of comorbidities increased with age but the effect of age varied based on the specific comorbidity. The divergence between OSA and controls was more pronounced after the sixth decade of life for most cardiovascular diseases (i.e.heart failure, ischaemic heart disease, stroke and arrhythmias), while depression exhibited an opposite trend. In a fully adjusted model, the odds of all comorbidities were significantly increased in OSA patients.In a large, nationally representative sample of working and retired people, OSA is strongly associated with significant comorbidities in both men and women with unique sex differences emerging.

Subclinical pulmonary congestion is prevalent in nephrotic syndrome.

In patients with nephrotic syndrome (NS), the lung is considered an organ protected from the risk of edema. However, data on objectively measured lung water in NS patients is lacking. Here we measured lung water by an ultrasound (US) technique as well as by transthoracic impedance in 42 asymptomatic patients with active NS, in 14 stage G5D CKD patients on chronic hemodialysis, and in 21 healthy individuals. In patients with active NS, the median number of US-B lines (a metric of lung water) after 5 min in a supine position was significantly higher (12; interquartile range: 7-25) compared with that in healthy individuals (4; 2-9) but similar to that in hemodialysis patients (23; 10-39). The difference between NS patients and healthy individuals was significantly amplified (16; 10-35 vs. 4; 2-9) after 60 min of supine resting and significantly attenuated after 5 min of standing (10; 7-25 vs. 3; 1-6). Posture-dependent changes in lung water in patients with active NS were significantly accentuated compared with both hemodialysis patients and healthy individuals. After NS remission, the number of US-B lines was significantly reduced to 5 (4-18) at 5 min and to 6 (5-22) at 60 min approaching the normal range. Lung congestion in patients with active NS was confirmed by transthoracic impedance. Thus, asymptomatic pulmonary congestion is pervasive in patients with NS. A clinical trial is needed to assess the utility of lung US for the management of patients with NS.

ANTIARRHYTHMIC ACTION OF CARDIOCYTOPROTECTORS IN TREATMENT OF ISCHEMIC HEART DISEASE WITH VENTRICULAR ARRHYTHMIAS

It is known that ventricular dysrhythmias in patients with ischemic heart diasease can be of various origin. Hence selection of antiarrhythmic tactics in such patients should be individual and pathogenetically proved. Aim. To check antiarrhythmic abilities of metabolic therapy for ischemic heart disease combined with variety of ventricular arrhythmias of III-IV grades (by Myerburg RJ). Material and methods. for 42 patients with ventricular arrhythmias of high grade and stable ischemic heart disease with saved ejection fraction of the left ventricle, before and after treatment were done the following: Holter monitoring, treadmill test, and as indicated — coronary arteriography, radionuclide methods of perfusion assessment and metabolism of myocardium, non-invasive topical diagnostics. To individually selected antianginal and antihypertension therapy for all patients was added ethylmethylhydroxypyridine succinate (es) in daily dosage 300 mg, for 2 months. Results. During the study, according to relationship of ventricular arrhythmia with transient ischemia, patients were selected to 2 groups. In the 1 group, with ischemic arrhythmias, in 2 months after start of es, there was significant antiarrhythmic effect: number of single ventricular premature beats decreased by 55%, couplets — by 90%, and episodes of non-sustained ventricular tachicardia — by 100%. At control positrone-emisson tomography in the areas of myocardial ischemia there was significant increase of 11C-buthirate sodium excretion, which witness on the increase of efficacy of energetic metabolism in zones of hypoxia. In the II group, with non-ischemic ventricular arrhythmias — antiarrhythmic effect was not achieved. Conclusion. es should be regarded as pathogenetic chain in complex antiarrhythmic treatment of ventricular arrhythmias in patients with stable ischemic heart disease.

MiR-223-3p as a Novel MicroRNA Regulator of Expression of Voltage-Gated K+ Channel Kv4.2 in Acute Myocardial Infarction

Background/Aims: Acute myocardial infarction (AMI) is a devastating cardiovascular disease with a high rate of morbidity and mortality, partly due to enhanced arrhythmogenicity. MicroRNAs (miRNAs) have been shown to participate in the regulation of cardiac ion channels and the associated arrhythmias. The purpose of this study was to test our hypothesis that miR-223-3p contributes to the electrical disorders in AMI via modulating KCND2, the gene encoding voltage-gated channel Kv4.2 that carries transient outward K⁺ current I_to. Methods: AMI model was established in male Sprague-Dawley (SD) rats by left anterior descending artery (LAD) ligation. Evans blue and TTC staining was used to measure infarct area. I_to was recorded in isolated ventricular cardiomyocytes or cultured neonatal rat ventricular cells (NRVCs) by whole-cell patch-clamp techniques. Western blot analysis was employed to detect the protein level of Kv4.2 and real-time RT-PCR to determine the transcript level of miR-223-3p. Luciferase assay was used to examine the interaction between miR-223-3p and KCND2 in cultured NRVCs. Results: Expression of miR-223-3p was remarkably upregulated in AMI relative to sham control rats. On the contrary, the protein level of Kv4.2 and I_to density were significantly decreased in AMI. Consistently, transfection of miR-223-3p mimic markedly reduced Kv4.2 protein level and Ito current in cultured NRVCs. Co-transfection of AMO-223-3p (an antisense inhibitor of miR-223-3p) reversed the repressive effect of miR-223-3p. Luciferase assay showed that miR-223-3p, but not the negative control, substantially suppressed the luciferase activity, confirming the direct binding of miR-223-3p to the seed site within the KCND2 sequence. Finally, direct intramuscular injection of AMO-223-3p into the ischemic myocardium to knockdown endogenous miR-223-3p decreased the propensity of ischemic arrhythmias. Conclusions: Upregulation of miR-223-3p in AMI repressed the expression of KCND2/Kv4.2 resulting in reduction of I_to density that can cause APD prolongation and promote arrhythmias in AMI, and therefore knockdown of endogenous miR-223-3p might be considered a new approach for antiarrhythmic therapy of ischemic arrhythmias.

Tiaogan Qingxin Granule treatment increases myocardial connexin 43 expression in a rat model of arrhythmia.

Myocardial ischemia-induced arrhythmia, especially ventricular arrhythmia, is the main reason for sudden cardiac death. Therefore, ischemic ventricular arrhythmia-targeted treatments are urgently needed. The mechanism of Tiaogan Qingxin Granule in premature ventricular beat (PVB) treatment was explored in arrhythmic rats pretreated with Tiaogan Qingxin Granule. Sprague-Dawley rats (N = 40) were randomly divided into 4 groups: sham-operated, arrhythmia model, Wenxin Granule, and Tiaogan Qingxin Granule. The ischemic arrhythmia model was established by ligating the left anterior descending coronary artery. The Tiaogan Qingxin Granule group was treated intragastrically for 7 days before surgery. Sham-operated rats underwent thoracotomy without coronary artery ligation. Myocardial infarction rate was measured using the triphenyltetrazolium chloride method and Cx43 expression was quantified by western blotting. Compared to the arrhythmia model group, the Tiaogan Qingxin Granule group showed a significant reduction in the myocardial infarct size and myocardial infarction rate (P < 0.01). Cx43 expression in the left ventricular myocardial tissues was significantly lower in the arrhythmia model group than in the sham-operated group (P < 0.01), but significantly higher in the Tiaogan Qingxin Granule group (P < 0.01). Intergroup difference in the relative Cx43 expression between the Tiaogan Qingxin Granule and Wenxin Granule groups was not significant (P > 0.05). Thus, Tiaogan Qingxin Granule reduced the myocardial infarct size, lowered the myocardial infarction rate, and increased Cx43 expression, possibly by increasing blood supply to the cardiac muscles. In conclusion, Tiaogan Qingxin Granule may be useful for treating ischemic PVB.

Long-term risk of cardiovascular and cerebrovascular disease after removal of the colonic microbiota by colectomy: a cohort study based on the Danish National Patient Register from 1996 to 2014

ObjectivesThe hypothesis of the study was that if the gut microbiota is involved in the development of atherosclerotic cardiovascular and cerebrovascular diseases (CVDs), total colectomy may reduce the long-term risk...

Gross anatomical study on the human myocardial bridges with special reference to the spatial relationship among coronary arteries, cardiac veins, and autonomic nerves

Coronary arteries are frequently covered by cardiac muscles. This arrangement is termed a myocardial bridge. Previous studies have shown that myocardial bridges can cause myocardial ischemic diseases or cardiac arrhythmia, but the relevant pathogenic mechanisms remain unknown. We examined 60 hearts from Japanese cadavers macroscopically to clarify the spatial relationships among coronary arteries, cardiac veins and autonomic nerves. We found 86 myocardial bridges in 47 hearts from the 60 cadavers examined (78.3%). Next, we dissected out nine hearts with myocardial bridges in detail under the operating microscope. We found no additional branches of coronary arteries on the myocardial bridge surfaces. However, the cardiac veins, which usually accompany the coronary arteries, ran independently on the myocardial bridge surfaces in the same region. Cardiac autonomic nerves comprised two rami: one was associated with the coronary artery under the myocardial bridge and the other ran on the surface of the bridge. Such spatial relationships among the coronary arteries, cardiac veins and cardiac autonomic nerves at the myocardial bridges are quite similar to those in mouse embryo hearts.

GW26-e2408 Left renal sympathetic stimulation and ablation affect ventricular arrhythmia by modulating left stellate ganglion in a cesium-induced long QT canine model

Our previous study has shown that left renal sympathetic stimulation (LRS) may facilitate ischemic ventricular arrhythmia (VA) by increasing neural activity of left stellate ganglion (LSG). Furthermore, studies have shown that renal sympathetic ablation (LRA) may be anti-arrhythmia. Therefore, we

Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study

SummaryBackgroundVarenicline is an effective pharmacotherapy to aid smoking cessation. However, its use is limited by continuing concerns about possible associated risks of serious adverse cardiovascular and neuropsychiatric events. The aim of this study was to investigate whether use of varenicline is associated with such events.MethodsIn this retrospective cohort study, we used data from patients included in the validated QResearch database, which holds data from 753 National Health Service general practices across England. We identified patients aged 18–100 years (registered for longer than 12 months before data extraction) who received a prescription of nicotine replacement treatment (NRT; reference group), bupropion, or varenicline. We excluded patients if they had used one of the drugs during the 12 months before the start date of the study, had received a prescription of a combination of these drugs during the follow-up period, or were temporary residents. We followed patients up for 6 months to compare incident cardiovascular (ischaemic heart disease, cerebral infarction, heart failure, peripheral vascular disease, and cardiac arrhythmia) and neuropsychiatric (depression and self-harm) events using Cox proportional hazards models, adjusted for potential confounders (primary outcomes).FindingsWe identified 164 766 patients who received a prescription (106 759 for nicotine replacement treatment; 6557 for bupropion; 51 450 for varenicline) between Jan 1, 2007, and June 30, 2012. Neither bupropion nor varenicline showed an increased risk of any cardiovascular or neuropsychiatric event compared with NRT (all hazard ratios [HRs] less than 1. Varenicline was associated with a significantly reduced risk of ischaemic heart disease (HR 0·80 [95%CI 0·72–0·87]), cerebral infarction (0·62 [0·52–0·73]), heart failure (0·61 [0·45–0·83]), arrhythmia (0·73 [0·60–0·88]), depression (0·66 [0·63–0·69]), and self-harm (0·56 [0·46–0·68]).InterpretationVarenicline does not seem to be associated with an increased risk of documented cardiovascular events, depression, or self-harm when compared with NRT. Adverse events that do not come to attention of general practitioners cannot be excluded. These findings suggest an opportunity for physicians to prescribe varenicline more broadly, even for patients with comorbidities, thereby helping more smokers to quit successfully than do at present.FundingEgton Medical Information Systems, University of Nottingham, Ministry of Innovation, Science and Research of the German Federal State of North Rhine-Westphalia, Cancer Research UK, Medical Research Council, Commonwealth Fund.

Cilostazol in peripheral artery disease: Cardiovascular and bleeding events in real-use conditions

e122 Volume 37 Number 8S CiloSTazol iN peripheral arTery diSeaSe: CardioVaSCular aNd bleediNg eVeNTS iN real-uSe CoNdiTioNS J. Real; M. Giner-Soriano; R. Morros; G. Pera; and R. Fores IDIAP Jordi Gol, USR Lleida, Spain; IDIAP Jordi Gol, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain; IDIAP Jordi Gol, USR Metropolitana Nord, Spain; and Institut Catala de la Salut, Catalunya, Spain Background: On 2013, the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) recommended that the use of cilostazol should be restricted. The Spanish Agency for Medicines and Health Products (AEMPS) asked the CHMP to carry out a review following reports of serious suspected side effects such as coronary heart disease (CHD), arrhythmias and haemorrhages. Objectives: To estimate the risk for ischemic events, arrhythmias and haemorrhages in patients with peripheral artery disease treated with cilostazol vs pentoxifylline. Material and Methods: Design: retrospective observational cohort study. Population: ≥ 40 years-old individuals initiating cilostazol or pentoxifylline for peripheral artery disease between 01/04/2009-30/09/2011, not previously treated. End of follow-up: 31/12/2013. Data Sources: SIDIAP database; contains anonymized clinical information from electronic clinical records in Primary Care of 5.8 million people from Catalonia on sociodemographic data, comorbidities, medical procedures, clinical parameters, laboratory data and pharmacy invoicing data. Diagnoses of CHD events, arrhythmias and haemorrhages were linked from hospital discharge database. Statistical Analysis: Two cohorts (cilostazol and pentoxifylline) were matched 1:1 using propensity-score methods to ensure comparability among groups and then followed-up from treatment initiation until event, end of follow-up or death. Survival analysis was performed and cumulative incidence rates of events were obtained for each cohort. Cox proportional-hazards regression models were performed to estimate hazard ratios and 95% confidence intervals (HR; 95% CI). Results: We included 2,953 patients per cohort. They were 68.9 years-old, 76.1% were men. Median follow-up were 1217 days. Preliminary analysis showed no statistically significant differences in the cumulative incidence rates between cohorts: 10.5% vs 11.0% CHD events with cilostazol and pentoxifylline respectively (HR= 0.97; 95% CI: 0.83–1.13), 7.1% vs 8.1% arrhythmias (HR= 0.88; 95% CI: 0.73–1.06), 0.7% cerebral haemorrhages in both cohorts (HR= 1.1; 95% CI: 0.63–2.15) and 3.6% vs 3.4% digestive haemorrhages (HR= 1.07; 95% CI: 0.81–1.40). Conclusions: We found no differences between our cilostazol and pentoxifylline patients in CHD, arrhythmias and bleeding events.