Cardioversion (CV) and radiofrequency catheter ablation (RFA) are often used to restore sinus rhythm in patients with atrial fibrillation (AF). These procedures are associated with a risk for stroke. ...The use of transesophageal echocardiography (TEE) to guide the management of AF is a validated strategy for patients in whom CV is planned, as well patients before RFA. For patients in whom the initial procedure fails, repeat TEE is often performed before repeat CV or RFA. The aim of this study was to test the hypothesis that patients with initial negative results on TEE would be unlikely to have thrombi detected on subsequent TEE and thus may avoid repeat procedures.
A total of 2,999 patients with AF were identified via retrospective review who had undergone TEE before CV or RFA, and 418 of these individuals underwent repeat TEE. After excluding patients who underwent repeat TEE >365 days from the initial study (n = 135) and those with thrombi on initial TEE (n = 20), 263 patients who had underwent two or more examinations were identified and analyzed.
Of 263 eligible patients, two (0.8%; 95% confidence interval, 0.21-2.7%) had thrombi on subsequent TEE.
Fewer than 1% of patients with AF with negative results on baseline TEE had thrombi detected on repeat TEE before subsequent CV or RFA. Thus, it may be possible to selectively screen patients to identify those at low risk for developing thrombi subsequent to negative results on initial TEE, especially if patients are in sinus rhythm. These results suggest the need for a prospective trial to definitively answer the question regarding repeat TEE in low-risk patients.
Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism the gene encoding cytochrome P450, family 3, subfamily A, ...polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3 and transport the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.
Nitric oxide functions as a signaling molecule with a well-established role in vascular homeostasis. It is synthesized from the oxidation of L-arginine by the enzyme, endothelial nitric oxide ...synthase (eNOS). The eNOS gene has a number of polymorphic sites, including SNPs, dinucleotide repeats and variable number tandem repeat sequences, and the opportunity exists to investigate polymorphic functional correlates as well as disease-specific associations, especially in cardiovascular disease, including coronary artery disease, and its most severe consequence, myocardial infarction. A number of clinical and functional correlative studies involving eNOS polymorphisms have been reported and are presented. The promise and complexity of pharmacogenetics is illustrated using eNOS as an example because of its relationship with cardiovascular biology and pathology. In this review, we will discuss the impact of nitric oxide, eNOS, genetic regulation, clinical investigation and, ultimately, prospects for treatment of heart disease.
Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials ...of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S‐metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2–2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25–1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25–1.5 vs. 2–2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (−10.8 ± 5.5) vs. 2–2.25 (−7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25–1.5 (−9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
Aims
Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of ≤35% and CAD amenable to coronary artery bypass grafting (CABG). Patients ...were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM.
Methods and results
The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all‐cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73–1.26. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63–1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing.
Conclusions
Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM.
Background This investigation was designed to identify clinical variables associated with recovery of normal ventricular function in patients with dilated cardiomyopathy treated with medical therapy. ...Recovery of normal ventricular function with medical treatment of patients with dilated cardiomyopathy is observed with increasing frequency. However, the clinical variables associated with such dramatic improvement of ventricular performance are poorly defined. Methods Fifty-three patients with dilated cardiomyopathy and reduced ejection fractions who achieved an increase in ejection fraction to ≥40% with medical therapy were identified during follow-up in a dedicated heart failure clinic. A cohort of patients frequency-matched on baseline ejection fraction who did not recover ventricular systolic function to this magnitude constituted the control group. Clinical variables characterizing the 2 groups were compared by univariable analysis. Variables that significantly differed between the 2 groups were entered in a stepwise logistic regression analysis to identify factors independently associated with recovery of ejection fraction to ≥40%. Results In the final logistic regression model, QRS duration, sex, etiology of cardiomyopathy, diabetes, and systolic blood pressure were significantly associated with improvement of ejection fraction to ≥40%. Conclusions Five clinical variables that are independently associated with improvement of left ventricular ejection fraction to normal or near-normal values with medical therapy alone were identified by this modeling process. These variables may be used to discriminate between patients in whom ventricular function will normalize with medical therapy alone and those who will require more aggressive pharmacologic or device therapy.
Two common genetic polymorphisms in the beta-1 adrenergic receptor (
ADRB1
Ser49Gly rs1801252 and Arg389Gly rs1801253) significantly affect receptor function in vitro. The objective of this study was ...to determine whether
ADRB1
Ser49Gly and Arg389Gly are associated with recovery of left ventricular ejection fraction (LVEF) in patients with heart failure. Patients with heart failure and baseline LVEF ≤ 40% were genotyped (
n
= 98), and retrospective chart review assessed the primary outcome of LVEF recovery to ≥ 40%. Un/adjusted logistic regression models revealed that Ser49Gly, but not Arg389Gly, was significantly associated with LVEF recovery in a dominant genetic model. The adjusted odds ratio for Ser49 was 8.2 (95% CI = 2.1–32.9;
p
= 0.003), and it was the strongest predictor of LVEF recovery among multiple clinical variables. In conclusion, patients with heart failure and reduced ejection fraction that are homozygous for
ADRB1
Ser49 were significantly more likely to experience LVEF recovery than Gly49 carriers.
Effect of Platelet Antigen Polymorphism on Platelet Inhibition by Aspirin, Clopidogrel, or Their Combination
Glen E. Cooke, Yiwen Liu-Stratton, Amy K. Ferketich, Melvin L. Moeschberger, David J. ...Frid, Raymond D. Magorien, Paul Bray, Philip F. Binkley, Pascal J. Goldschmidt-Clermont
Clopidogrel and acetylsalicylic acid (ASA) improve outcomes in patients with acute coronary syndromes. The relative efficacy of these two inhibitors measured in vitro varies according to the agonist used to stimulate platelets. The combination of ASA and clopidogrel appears superior to either inhibitor used alone. PlA2, a polymorphism of glycoprotein IIb/IIIa, functions as an important modifier of the effect of ASA but not of the effect of clopidogrel.
We studied the modifier effect of platelet antigen polymorphism (PlA2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease.
Clopidogrel, when administered with ASA, was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA. We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective.
Thirty PlA1/A1and 30 PlA1/A2patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied.
Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist, and combination therapy resulted in greater inhibition than either inhibitor used alone (p < 0.0001). The use of ASA resulted in greater inhibition compared with clopidogrel with epinephrine (p < 0.0001) and collagen as agonists (p < 0.0001). With collagen as the agonist, platelets from PlA1/A2donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of PlA1/A1and PlA1/A2platelets.
The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. PlA2functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel. These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease.
Background
Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well‐established clinical, ...translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment.
Methods and Results
We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole‐exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase‐like protein‐6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90‐fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse‐rate dependence of augmented Ito.
Conclusions
We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.
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