Inhibition of HINT1 Modulates Spinal Nociception and NMDA Evoked Behavior in Mice.

The interactions between the mu-opioid (MOR) and N-methyl-d-aspartate receptor (NMDAR) constitute an area of intense investigation because of their contributions to maladaptive neuroplasticity. Recent evidence suggests that their association requires the involvement of histidine triad nucleotide-binding protein (HINT1) with the enzyme's active site being critical in its regulatory role. Since it is known that spinal blockade of NMDA receptors prevents the development of opioid analgesic tolerance, we hypothesized that spinal inhibition of the HINT1 enzyme may similarly inhibit opioid tolerance. To address these questions, we evaluated novel HINT1 active-site inhibitors in two models of NMDAR and MOR interaction, namely, MOR inhibition of spinal NMDA activation and acute endomorphin-2 tolerance. These studies revealed that while the tryptamine carbamate of guanosine inhibitor, TrpGc, blocked both the development of opioid tolerance and the inhibitory effect of opioids on NMDA activation of the NMDA receptor, acyl-sulfamate analogues could only block the latter. Thermodynamic binding and X-ray crystallographic studies suggested that there are key differences between the bound HINT1-inhibitor surfaces that may be responsible for their differential ability to probe the ability of HINT1 to regulate cross talk between the mu-opioid receptor and NMDA receptor in the spinal cord.

Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia.

Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.

Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Via Radial Access Anticoagulated With Bivalirudin Versus Heparin: A Report From the National Cardiovascular Data Registry.

OBJECTIVES: The aim of this study was to compare bivalirudin with heparin as anticoagulant agents in patients with ST-segment elevation myocardial infarction treated with radial primary percutaneous coronary intervention (PCI). BACKGROUND: Recent studies in which PCI was performed predominantly via radial access did not show bivalirudin to be superior to heparin. METHODS: Outcomes were compared in patients with STEMI included in the National Cardiovascular Data Registry CathPCI database from 2009 to 2015 who underwent primary PCI via radial access and who were anticoagulated with bivalirudin or heparin. RESULTS: The sample included 67,368 patients, of whom 29,660 received bivalirudin and 37,708 received heparin. The 2 groups of patients did not differ significantly in their mean age or percentage of men. The unadjusted comparison showed no significant difference in the rate of the composite endpoint of death, myocardial infarction, or stroke (4.6% vs. 4.7%; p = 0.47) and a significantly higher rate of acute stent thrombosis (1.00% vs. 0.60%; p < 0.001) with bivalirudin compared with heparin. After adjusting for multiple variables, including a propensity score reflecting the probability of receiving bivalirudin, the odds ratio of the composite endpoint of death, myocardial infarction, or stroke for bivalirudin versus heparin was 0.95 (95% confidence interval: 0.87 to 1.05; p = 0.152), and the odds ratio for acute stent thrombosis was 2.11 (95% confidence interval: 1.73 to 2.57) for bivalirudin versus heparin. Major bleeding rates were not significantly different. CONCLUSIONS: In patients undergoing primary PCI via transradial access anticoagulated with bivalirudin or heparin, there was no difference in the composite endpoint of death, myocardial infarction, or stroke.

Use and Effectiveness of Bivalirudin Versus Unfractionated Heparin for Percutaneous Coronary Intervention Among Patients With ST-Segment Elevation Myocardial Infarction in the United States.

OBJECTIVES: The purpose of this study was to describe temporal trends and determine the comparative effectiveness of bivalirudin versus unfractionated heparin (UFH) during percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Several clinical trials have compared the safety and effectiveness of bivalirudin versus UFH during PCI for STEMI, but results have been conflicting. METHODS: Trends in anticoagulant use were examined among 513,775 PCIs for STEMI from July 2009 through December 2014 within the National Cardiovascular Data Registry CathPCI Registry. We conducted an instrumental variable analysis comparing bivalirudin with UFH, using operator preference for bivalirudin as the instrument. We used a test of mediation to determine the extent to which differences in outcomes between anticoagulants were due to differences in use of glycoprotein IIb/IIIa inhibitors (GPI). Primary outcomes were in-hospital bleeding and mortality. RESULTS: Bivalirudin use increased from 2009 through 2013, followed by a new decline. GPIs were used in 74.7% of UFH PCIs versus 26.5% of bivalirudin PCIs. In unadjusted analyses, bivalirudin was associated with decreased bleeding (risk difference [RD]: -4.2%; p < 0.001) and mortality (RD: -0.84%; p < 0.001). After instrumental variable analyses, bivalirudin remained associated with less bleeding (RD: -3.75%; p < 0.001), but not mortality (RD: -0.10%; p = 0.280). The higher rate of GPI use with UFH was responsible for more than one-half of bivalrudin's bleeding reduction (GPI-adjusted RD: -1.57%; p < 0.001). Bleeding reductions were negligible for transradial PCI (RD: -0.11%; p = 0.842). CONCLUSIONS: The use of bivalirudin during STEMI has decreased. Bivalirudin was associated with reduced bleeding and no mortality difference. The bleeding reduction with bivalirudin was largely explained by the greater use of GPIs with UFH.

Guideline-Appropriate Care and In-Hospital Outcomes in Patients With Heart Failure in Teaching and Nonteaching Hospitals: Findings From Get With The Guidelines-Heart Failure.

BACKGROUND: Despite increasing awareness regarding evidence-based guidelines, considerable gaps exist for heart failure (HF) quality of care at teaching hospitals (TH) and nonteaching hospitals (NTH). We analyzed data from Get With The Guidelines (GWTG)-HF to compare the rates and trends of guideline-recommended care at TH and NTH for patients with HF. METHOD AND RESULTS: Baseline patient characteristics, performance measures, and in-hospital outcomes were compared between 197 187 HF patients admitted to TH and 106 924 patients admitted to NTH between 2005 and 2014. Patients treated in TH were younger and were more likely to be black and uninsured. Defect-free care (defined as 100% compliance with performance measures) was similar in both group of hospitals (crude rates: 88% at TH versus 86% at NTH, adjusted odds ratio 0.99, 95% confidence interval 0.73-1.34) as were individual performance measures: discharge instruction, documentation of ejection fraction, use of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists, use of ß-blocker, and smoking cessation counseling. During the study period, there was improvement in adherence with performance measures over time, with no significant difference at TH (adjusted odds ratio 1.20, 95% confidence interval 1.11-1.30; P<0.01) and NTH (adjusted odds ratio 1.09, 95% confidence interval 1.02-1.17; P=0.01; interaction P value 0.07). CONCLUSIONS: Data from the GWTG-HF program suggest that there was improving and comparable adherence with HF performance measures and use of guideline-recommended therapies irrespective of hospital teaching status.

Comparison of transradial coronary procedures via right radial versus left radial artery approach: A meta-analysis.

INTRODUCTION: Coronary angiography and angioplasty via transradial approach is shown to be associated with significant reduction in access site complications. Due to a lack of sufficient data, the use of the right or left radial approach is still operator-dependent. We performed a meta-analysis of prospective randomized studies to compare right versus left radial artery approach for coronary procedures. METHODS: We found 12 randomized studies meeting the predetermined inclusion criteria. A total of 6,450 patients were included in the meta-analysis of which 3,217 patients underwent coronary procedures via right radial approach and 3,233 patients via left radial approach. The primary endpoint was the comparison of fluoroscopy time, procedure time, contrast use and cross-over rates between two radial approaches. RESULTS: Pooled analysis of the included studies showed a similar rate of cross-over events (4.2% for right radial approach vs. 4.1% for left radial approach, odds ratio (OR)=1.08, P = 0.68), and similar total procedure times (18.8 ± 10.3 min vs. 18.1 ± 10.0 min, standard difference (SD) of the mean = 0.09, P = 0.162) between the two radial approaches. However, the right radial approach was found to be associated with minimally longer fluoroscopy times (5.8 ± 4.4 min vs. 5.3 ± 4.2 min, SD of the mean = 0.157, P < 0.001) and greater contrast use (84 ± 35 mL vs. 82 ± 34 mL, SD of the mean = 0.082, P = 0.003). Access site complications and the incidence of stroke were similar between two radial approaches. CONCLUSION: Our meta-analysis suggests a small but statistically significant difference in terms of contrast use and fluoroscopy time in favor of coronary procedures performed via left radial approach in comparison to right radial approach without any significant difference in access site or other procedural complications between the two radial approaches. © 2016 Wiley Periodicals, Inc.

Cardiac-resynchronization therapy in patients with systolic heart failure and QRS interval ≤130 ms: insights from a meta-analysis.

AIMS: Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in patients with chronic systolic heart failure (SHF) and a wide QRS complex. It is unclear whether the same benefit extends to patients with QRS duration (QRSd) <130 ms. METHODS AND RESULTS: Our aim was to perform a meta-analysis of all randomized controlled trial (RCTs) and to evaluate the effect of implantable CRT defibrillator(CRTD) on all-cause mortality, HF mortality, and HF hospitalization in patients with QRSd <130 ms. We performed a systematic literature search to identify all RCTs, comparing CRTD therapy with implantable cardiac defibrillator (ICD) therapy in patients with SHF (ejection fraction <35%) and QRS ≤130 ms, published in Pubmed, Medline, EMBASE, Cochrane library, and Google scholar from June 1980 through June 2013. The search terms included CRT, QRS duration, narrow QRS, clinical trial, RCT, biventricular pacing, heart failure, systolic dysfunction, dyssynchrony, left ventricular remodelling, readmission, mortality, survival, and various combinations of these terms. We studied the trends of overall mortality, SHF mortality, and hospitalizations due to SHF between the two groups. Heterogeneity of the studies was analysed by Q statistic. A fixed-effect model was used to compute the relative risk (RR) of mortality due to SHF, while a random-effects model was used to compare hospitalization due to SHF. Out of a total of 12 100 citations, four RCTs comparing CRTD vs. ICD therapy in patients with SHF and QRS ≤130 ms fulfilled the inclusion criteria. The median follow-up was 12 months and the cumulative number of patients was 1177. Relative Risk for all-cause mortality in patients treated with CRTD was 1.66 with a 95% CI of 1.096-2.515 (P = 0.017) while for SHF mortality was 1.29 with 95% CI of 0.68-2.45 (P = 0.42). Relative risk for HF hospitalization in patients treated with CRTD was 0.94 with 95% CI of 0.50-1.74 (P = 0.84) in comparison to the ICD group. CONCLUSION: Cardiac-resynchronization therapy defibrillator has no impact on SHF mortality and SHF hospitalization in patients with systolic HF with QRS duration ≤130 ms and is associated with higher all-cause mortality in comparison with ICD therapy.

Favorable effects of vasodilators on left ventricular remodeling in asymptomatic patients with chronic moderate-severe aortic regurgitation and normal ejection fraction: a meta-analysis of clinical trials.

BACKGROUND: The role of vasodilator therapy in asymptomatic patients with chronic moderate to severe aortic regurgitation (AR) and normal left ventricular (LV) function is uncertain. We assessed the effects of vasodilator therapy (hydralazine, calcium channel blockers, and angiotensin-converting enzyme inhibitors) in this subgroup of patient population. HYPOTHESIS: Vasodilators have favorable effects on LV remodelling in asymptomatic patients with chronic moderate to severe aortic regurgitation and normal LV function. METHODS: We performed a systematic literature search for randomized clinical trials using long-term vasodilator therapy in asymptomatic patients with chronic severe AR and normal LV function. The magnitude of difference between the vasodilator and nonvasodilator groups was assessed by computing the mean difference (MD). Heterogeneity of the studies was analyzed by Cochran Q statistics. The MD for LV ejection fraction, LV end systolic volume index, and LV end diastolic volume index were computed by random effects model. The MD for LV end-systolic diameter and LV end-diastolic diameter were computed by fixed effects model. A 2-sided alpha error <0.05 was considered to be statistically significant. RESULTS: Seven studies with 460 patients were included. Meta-analysis of the studies revealed a significant increase in LVEF (MD: 5.32, 95% confidence interval [CI]: 0.37 to 10.26, P = 0.035), a significant decrease in LV end diastolic volume index (MD: -16.282, 95% CI: -23.684 to -8.881, P < 0.001), and a significant decrease in LV end diastolic diameter (MD: -2.343, 95% CI: -3.397 to -1.288, P < 0.001) in the vasodilator group compared with the nonvasodilator group. However, there was no significant decrease in LV end systolic volume index (MD: -6.105, 95% CI: -12.478 to 0.267, P = 0.060) or in LV end systolic diameter (MD: 0.00, 95% CI: -0.986 to 0.986, P = 1.0) in the vasodilator group compared with the nonvasodilator group. CONCLUSIONS: In asymptomatic patients with chronic severe AR and normal LV function, vasodilators have favorable effects on LV remodeling.

Fixing the "broken heart": pharmacologic implications.

Broken-heart syndrome also known as Left ventricular apical ballooning syndrome or Stress-induced cardiomyopathy or Takotsubo cardiomyopathy is an important clinical entity, which presents clinically, similar to acute coronary syndrome with an acute onset of chest pain, ST-T changes in electrocardiogram, and moderate cardiac enzyme elevation. Recent studies have shown that it accounts for 1%-2% of cases of ST-elevation infarction. An episode of intense emotional or physiologic stress has been reported before its presentation and is presumed to be the triggering factor in the pathogenesis. The pathophysiology of this syndrome still remains unclear, and management is mostly empiric and supportive. In this review, we have discussed various pathophysiologic mechanisms underlying this cardiomyopathy and their pharmacological implications and role of medications such as aspirin, beta blockers, angiotensin-converting enzyme inhibitors, and statins for patients presenting with this syndrome in treatment and prevention.