Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction

New Findings What is the central question of this study? Type 2 diabetes is associated with a higher rate of ventricular arrhythmias compared with the non‐diabetic population, but the associated myocardial gene expression changes are unknown; furthermore, it is also unknown whether any changes are attributable to chronic hyperglycaemia or are a consequence of structural changes. What is the main finding and its importance? We found downregulation of left ventricular ERG gene expression and increased NCX1 gene expression in humans with type 2 diabetes compared with control patients with comparable left ventricular hypertrophy and possible myocardial fibrosis. This was associated with QT interval prolongation. Diabetes and associated chronic hyperglycaemia may therefore promote ventricular arrhythmogenesis independently of structural changes. Type 2 diabetes is associated with a higher rate of ventricular arrhythmias, and this is hypothesized to be independent of coronary artery disease or hypertension. To investigate further, we compared changes in left ventricular myocardial gene expression in type 2 diabetes patients with patients in a control group with left ventricular hypertrophy. Nine control patients and seven patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal‐averaged ECGs and echocardiograms before surgery. During surgery, a left ventricular biopsy was taken, and mRNA expressions for genes relevant to the cardiac action potential were estimated by RT‐PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara–Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal‐averaged ECGs between groups, but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of KCNH2 and KCNJ3 were lower in the diabetes group, whereas KCNJ2 , KCNJ5 and SLC8A1 expression were higher. Modelling suggested that these changes would lead to prolongation of the action potential duration with generation of early after‐depolarizations secondary to a reduction in density of the rapid delayed rectifier K+ current and increased Na+–Ca2+ exchange current. These data suggest that diabetes leads to pro‐arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population

Myocardial Infarction as a Presentation of Clinical In-Stent Restenosis

Abstract Background In-stent restenosis is considered to be a gradual and progressive condition and there is scant data on myocardial infarction (MI) as a clinical presentation. Methods and Results Of 2,462 consecutive patients who underwent percutaneous coronary intervention between June 2001 and December 2002, clinical in-stent restenosis occurred in 212 (8.6%), who were classified into 3 groups: ST elevation MI (STEMI), non-ST elevation MI (NSTEMI) and non-MI. Of the 212 patients presenting with clinical in-stent restenosis, 22 (10.4%) had MI (creatine kinase (CK) ≥2 × baseline with elevated CKMB). The remaining 190 (89.6%) patients had stable angina or evidence of ischemia by stress test without elevation of cardiac enzymes. Median interval between previous intervention and presentation for clinical in-stent restenosis was shorter for patients with MI than for non-MI patients (STEMI, 90 days; NSTEMI, 79 days; non-MI, 125 days; p=0.07). Diffuse in-stent restenosis was more frequent in MI patients than in non-MI patients (72.7% vs 56.3%; p<0.005). Renal failure was more prevalent in patients with MI than in those without MI (31.8% vs 6.3%, p=0.001). Compared with the non-MI group, patients with MI were more likely to have acute coronary syndromes at the time of index procedure (81.8% vs 56.8%, p=0.02). Conclusion Clinical in-stent restenosis can frequently present as MI and such patients are more likely to have an aggressive angiographic pattern of restenosis. Renal failure and acute coronary syndromes at the initial procedure are associated with MI. (Circ J 2006; 70: 1026 - 1029

Clinical pre-test probability for obstructive coronary artery disease: insights from the European DISCHARGE pilot study.

To test the accuracy of clinical pre-test probability (PTP) for prediction of obstructive coronary artery disease (CAD) in a pan-European setting. Patients with suspected CAD and stable chest pain who were clinically referred for invasive coronary angiography (ICA) or computed tomography (CT) were included by clinical sites participating in the pilot study of the European multi-centre DISCHARGE trial. PTP of CAD was determined using the Diamond-Forrester (D+F) prediction model initially introduced in 1979 and the updated D+F model from 2011. Obstructive coronary artery disease (CAD) was defined by one at least 50% diameter coronary stenosis by both CT and ICA. In total, 1440 patients (654 female, 786 male) were included at 25 clinical sites from May 2014 until July 2017. Of these patients, 725 underwent CT, while 715 underwent ICA. Both prediction models overestimated the prevalence of obstructive CAD (31.7%, 456 of 1440 patients, PTP: initial D+F 58.9% (28.1-90.6%), updated D+F 47.3% (34.2-59.9%), both p < 0.001), but overestimation of disease prevalence was higher for the initial D+F (p < 0.001). The discriminative ability was higher for the updated D+F 2011 (AUC of 0.73 95% confidence interval [CI] 0.70-0.76 versus AUC of 0.70 CI 0.67-0.73 for the initial D+F; p < 0.001; odds ratio (or) 1.55 CI 1.29-1.86, net reclassification index 0.11 CI 0.05-0.16, p < 0.001). Clinical PTP calculation using the initial and updated D+F prediction models relevantly overestimates the actual prevalence of obstructive CAD in patients with stable chest pain clinically referred for ICA and CT suggesting that further refinements to improve clinical decision-making are needed. https://www.clinicaltrials.gov/ct2/show/NCT02400229 KEY POINTS: • Clinical pre-test probability calculation using the initial and updated D+F model overestimates the prevalence of obstructive CAD identified by ICA and CT. • Overestimation of disease prevalence is higher for the initial D+F compared with the updated D+F. • Diagnostic accuracy of PTP assessment varies strongly between different clinical sites throughout Europe

Anticoagulant selection in relation to the SAMe-TT₂R₂ score in patients with atrial fibrillation:The GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores &gt;2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores &gt;2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score &gt;2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores &gt;2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores &gt;2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.</p

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Gene polymorphism influences response to angiotensin blockade

Researchers have been examining the role of the angiotensin converting enzyme (ACE) gene insertion/delection polymorphism and the role of the gene DD genotype in different cardiovascular diseases. Specifically, a limited number of small studies have examined the effects of these genetic variants in response to treatment with drugs that affect the renin angiotensin system. Since recent research has concluded that the angiotensin converting enzyme DD genotype may be associated with a poor response to ACE inhibitor treatment, a pilot study was undertaken to determine the effect of the angiotensin II receptor blocker losartan on the hypotensive response in patients with different ACE genetic variants.</p

Stroke complicating cardiac catheterization: A preventable and treatable complication

Stroke is a rare but serious complication of cardiac catheterization. Due to the low incidence of stroke complicating catheterization of the left heart, there is no clearly defined optimal treatment. With increasing numbers of diagnostic and interventional cardiac procedures being performed, definitive management pathways for periprocedural neurological complications need to be defined. Many studies have shown excellent results with both thrombolytic and catheter-based neurovascular rescue, but equal attention should be paid to identify measures to prevent this iatrogenic complication. It is also imperative that management decisions be taken jointly by the cardiologist and stroke physician. We review the literature regarding the features of ischemic stroke complicating cardiac catheterization, the various management modalities and suggest a management protocol.</p

NICE recommendations for the assessment of stable chest pain:Assessing the early economic and service impact in the rapid-access chest pain service

Background In 2010, guidelines published by the National Institute for Clinical Excellence (NICE) suggested a change in the way patients with stable chest pain of suspected cardiac origin were investigated. These guidelines removed exercise treadmill testing from routine use and introduced cardiac CT to regular use. Objective To investigate whether these guidelines had improved our service provision by reducing the number of further investigations required to make a diagnosis, and to see if our costs had increased now that the less expensive exercise treadmill tests were not recommended. Methods Clinic letters were used to assess patients pretest likelihood of coronary artery disease for two six-month cohorts of consecutive patients seen in the rapid access chest pain clinic (January-June 2010 and July-December 2011) using NICE published methodology, and to ascertain which investigations patients had. Using NICE modelled costs, we generated comparative hypothetical costs for each cohort and an average cost per patient. Results In the January-June 2010 cohort, 435 patients with chest pain were seen, and in July-December 2011, 334 patients were seen. In the pre-NICE guidelines cohort, 23% of patients required two investigations as compared with 11.4% in the post-NICE guidelines cohort, with no patient requiring three investigations as compared with 3% in the original cohort. There was no significant increase in costs per patient in the post-NICE guidance group. Conclusions Implementing NICE guidance reduced the number of investigations needed per patient, and did not prove more expensive for our department in the short term.</p

Endocarditis in a large district general hospital:A study of the microbiological spectrum between 2000 and 2011

Infective endocarditis is one of three common cardiac infections in the United Kingdom, in addition to myocarditis and pericarditis, with a reported incidence of 1.7 to 6.2 cases per 100,000 patient years. Infective endocarditis can often have serious consequences and a wide variety of organisms may be the causative pathogen. There are little published data regarding the exact spectrum of organisms that cause endocarditis in the United Kingdom and whether organisms such as streptococci still dominate. In the present study, all cases of endocarditis at the authors' institution, representing a typical nontertiary centre, were retrospectively examined and audited to provide a snapshot of the organism spectrum in these patients. The cases of more than 120 patients who were coded as having endocarditis by the institution's clinical coding department during the period between December 2000 and January 2011 were examined. Microbiological tests and clinical case notes of all patients were reviewed. Of the 101 patients diagnosed with and treated for endocarditis, 64 were male, with a mean age of 60.57 years. The most common organisms identified were Streptococcus species (31%), Staphylococcus aureus (27%) and Enterococcus faecalis (21%). The organisms with the highest associated mortality rate were S aureus and the 'other organism' group, which included non-HACEK group (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella species) pathogens such as Candida albicans. Streptococcus species and S aureus remain the main cause of endocarditis in a typical hospital setting in the United Kingdom, although in a smaller proportion of cases than historical data suggests. Overall, mortality remains high, and the clinician should remain vigilant to endocarditis in any patient with a positive blood culture because the number of cases of endocarditis caused by less typical organisms are increasing.</p