John J. Warner

Histone Deacetylase Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy

Background— Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. Methods and Results— Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA’s cardioprotective effects. Conclusions— The US Food and Drug Administration–approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.

Inhaled Nitric Oxide Selectively Dilates Pulmonary Vasculature in Adult Patients With Pulmonary Hypertension, Irrespective of Etiology

OBJECTIVES We sought to compare the responses of patients with pulmonary hypertension from primary and secondary causes (PPH and SPH, respectively) to inhaled nitric oxide (iNO) in the cardiac catheterization laboratory. BACKGROUND Pulmonary hypertension can lead to right ventricular pressure overload and failure. Although vasodilators are effective as therapy in patients with PPH, less is known about their role in adults with SPH. Inhaled nitric oxide can accurately predict the response to other vasodilators in PPH and could be similarly utilized in SPH. METHODS Forty-two patients (26 to 77 years old) with pulmonary hypertension during cardiac catheterization received iNO. Demographic and hemodynamic data were collected. Their response to iNO was defined by a decrease of > or =20% in mean pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). RESULTS Mean PA pressures and PVR were lower during nitric oxide (NO) inhalation in all patients with pulmonary hypertension. Seventy-eight percent of patients with PPH and 83% of patients with SPH were responders to iNO. A trend was seen toward a greater response with larger doses of NO in patients with SPH. Nitric oxide was a more sensitive predictor of response (79%), compared with inhaled oxygen (64%), and was well tolerated, with no evidence of systemic effects. Elevation in right ventricular end-diastolic pressure appeared to predict poor vasodilatory response to iNO. CONCLUSIONS Nitric oxide is a safe and effective screening agent for pulmonary vasoreactivity. Regardless of etiology of pulmonary hypertension, pulmonary vasoreactivity is frequently demonstrated with the use of NO. Right ventricular diastolic dysfunction may predict a poor vasodilator response.

Changes in Right Ventricular Structure and Function Assessed Using Cardiac Magnetic Resonance Imaging in Bosentan-Treated Patients With Pulmonary Arterial Hypertension

Patients with pulmonary arterial hypertension (PAH) usually show improvements in symptoms, exercise capacity, and hemodynamics after treatment with approved medical therapies. This study sought to determine whether improvement in right-sided cardiac function measured using cardiac magnetic resonance imaging would also be seen and whether these changes would correlate with improvement in exercise capacity. Sixteen patients with PAH underwent evaluation at baseline and after 12 months of treatment with bosentan. After treatment, cardiac index, pulmonary vascular resistance, and 6-minute walk distance improved, and there was a trend toward improvement in right ventricular (RV) stroke volume (70 +/- 27 to 81 +/- 30 ml; p = 0.08), but no change in RV ejection fraction (RVEF) or RV end-diastolic volume. Six-minute walk distance improved by 59 m (p <0.05) in the overall cohort and improved more in patients in whom RVEF increased compared with those with stable or decreased RVEF (+98 vs -37 m, respectively; p = 0.01). Three patients died during follow-up, and these patients had significantly lower RVEF and left ventricular end-diastolic volume indexes than surviving patients. In conclusion, these results suggest that cardiac magnetic resonance imaging may have value in determining response to therapy and prognosis in patients with PAH.

Serial echocardiographic evaluation of restenosis after successful percutaneous mitral commissurotomy

OBJECTIVES This study was designed to determine predictors of restenosis after successful percutaneous mitral commissurotomy (PMC) and its relationship to late clinical outcome. BACKGROUND The restenosis rate after PMC and its relationship to late clinical outcome is poorly defined. METHODS Serial echocardiography was performed in 310 patients who underwent PMC. Restenosis, defined as mitral valve area (MVA) <1.5 cm(2) and > or = 50% loss of initial MVA increase, was determined by both two-dimensional (2D) and Doppler echocardiography. Clinical, echocardiographic and cardiac catheterization variables were evaluated to determine predictors of restenosis. The relationship between restenosis and major adverse clinical events (death, repeat PMC or mitral valve replacement) and functional status was assessed. RESULTS Acute procedural success occurred in 206 patients (66%), who were then followed for restenosis. The cumulative restenosis rate was approximately 40% at six years after successful PMC (44% by 2D and 40% by Doppler MVA). The only independent predictor of restenosis was echocardiographic score (restenosis at five years was 20% for score <8 vs. 61% for score > or = 8, p < 0.001). The decline in MVA and occurrence of restenosis was gradual and progressive during the follow-up period. Procedural results and baseline factors predicted event-free survival. Restenosis by 2D MVA was related to adverse events or New York Heart Association functional class 3 to 4 symptoms, but restenosis was not an independent predictor of clinical outcome by multivariate analysis. CONCLUSIONS Restenosis is a common, gradual and progressive occurrence after successful PMC and is predicted by higher echocardiographic score. Restenosis is related to late adverse clinical outcome, though clinical outcome remains best predicted by the acute procedural results of PMC.

Percutaneous stenting of right pulmonary artery stenosis in fibrosing mediastinitis

Pulmonary artery stenosis is an uncommon complication of fibrosing mediastinitis. Previous medical and surgical therapies have provided limited clinical efficacy without objective evidence of clinical improvement. With the advantages of limited invasiveness and absent need for prolonged drug therapy, percutaneous stent deployment to relieve pulmonary artery obstruction represents a novel treatment for this rare disorder. Cathet. Cardiovasc. Intervent. 49:321–324, 2000.

Long-term Outcomes with Ambrisentan Monotherapy in Pulmonary Arterial Hypertension

BACKGROUND This study evaluated long-term outcomes in patients with pulmonary arterial hypertension (PAH) undergoing treatment with ambrisentan monotherapy, a selective oral endothelin-1 receptor antagonist. METHODS AND RESULTS Patients who participated in the Ambrisentan in Pulmonary Arterial Hypertension: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy Study (ARIES-1) clinical trial and extension phase at our institution were included. Cardiac catheterization, 6-minute walk distance (6MWD), and cardiac magnetic resonance (MRI) data were retrospectively reviewed. Twelve patients with PAH (11 idiopathic, 1 fenfluramine) had follow-up from 3 to 5.5 years from the initiation of ARIES-1. Patients received ambrisentan therapy throughout the study period and were on ambrisentan monotherapy for the first 2 years. At year 1, improvements in median mean pulmonary arterial pressure (PA), cardiac output, and pulmonary vascular resistance (PVR) were seen (P = .02, P = .03, P < .01), and the improvement in PVR persisted at 2 years. 6MWD also improved significantly between baseline (350 m) and 1 and 2 years (397 m, P < .01 and 393 m, P = .01). Cardiac MRI results were more varied, with an increase in RV ejection fraction from 29% at baseline to 46% at 2 years (P = .02), but other MRI variables did not improve. CONCLUSIONS Ambrisentan monotherapy led to improvements in catheterization, 6MWD, and RV ejection fraction, and shows promise as a long-term treatment for pulmonary arterial hypertension.

Acquisition, Analysis, and Sharing of Data in 2015 and Beyond: A Survey of the Landscape: A Conference Report From the American Heart Association Data Summit 2015

Background A 1.5‐day interactive forum was convened to discuss critical issues in the acquisition, analysis, and sharing of data in the field of cardiovascular and stroke science. The discussion will serve as the foundation for the American Heart Associations (AHAs) near‐term and future strategies in the Big Data area. The concepts evolving from this forum may also inform other fields of medicine and science. Methods and Results A total of 47 participants representing stakeholders from 7 domains (patients, basic scientists, clinical investigators, population researchers, clinicians and healthcare system administrators, industry, and regulatory authorities) participated in the conference. Presentation topics included updates on data as viewed from conventional medical and nonmedical sources, building and using Big Data repositories, articulation of the goals of data sharing, and principles of responsible data sharing. Facilitated breakout sessions were conducted to examine what each of the 7 stakeholder domains wants from Big Data under ideal circumstances and the possible roles that the AHA might play in meeting their needs. Important areas that are high priorities for further study regarding Big Data include a description of the methodology of how to acquire and analyze findings, validation of the veracity of discoveries from such research, and integration into investigative and clinical care aspects of future cardiovascular and stroke medicine. Potential roles that the AHA might consider include facilitating a standards discussion (eg, tools, methodology, and appropriate data use), providing education (eg, healthcare providers, patients, investigators), and helping build an interoperable digital ecosystem in cardiovascular and stroke science. Conclusion There was a consensus across stakeholder domains that Big Data holds great promise for revolutionizing the way cardiovascular and stroke research is conducted and clinical care is delivered; however, there is a clear need for the creation of a vision of how to use it to achieve the desired goals. Potential roles for the AHA center around facilitating a discussion of standards, providing education, and helping establish a cardiovascular digital ecosystem. This ecosystem should be interoperable and needs to interface with the rapidly growing digital object environment of the modern‐day healthcare system.

Systems-Based Improvement in Door-to-Balloon Times at a Large Urban Teaching Hospital A Follow-Up Study From Parkland Health and Hospital System

Background—Timely reperfusion in ST-segment elevation myocardial infarction (STEMI) patients improves clinical outcomes. Implementing strategies to target institutional-specific delays are crucial for improved patient care. Methods and Results—Using a novel strategy to analyze specific components of door-to-balloon time (DBT) at our institution, we previously identified several specific interval delays in our prior STEMI protocol. We then implemented 4 strategies to reduce DBT: (1) emergency department physician activation of the STEMI protocol; (2) “single call” broadcast paging of the STEMI team by the page operator; (3) immediate feedback to the emergency and cardiology departments with joint monthly quality improvement meetings; and (4) transfer of the off-hours STEMI patient directly to the laboratory on activation by an in-hospital team. After implementation of the new protocol, we examined each component time interval from the first 59 consecutive STEMI patients treated with the new protocol between March 2007 and June 2008 and compared time intervals with the previous 184 STEMI patients. Compared with the previous 184 STEMI patients, the median DBT of the subsequent 59 STEMI patients significantly improved from 125 to 86 minutes (P<0.0001). This improvement was largely driven by a decrease in the interval from the initial 12-lead ECG to activation of the on-call catheterization team (from 40 to 11 minutes, P<0.0001). Conclusions—After examining specific component delays in our institution’s DBT, we were able to successfully use quality improvement strategies to focus on specific sources of delay in our institution. This dramatically improved our median DBT toward the goal of achieving a guideline-recommended <90 minutes for all patients.

Comparison of coronary artery dynamics pre- and post-stenting

Stents have dramatically improved the treatment of coronary artery disease. Since the implantation of stents changes the geometry and dynamics of the coronary artery, it is reasonable to hypothesize that some of these changes may have an important effect on the development of atherosclerosis by modulating the mechanical environment. In this paper, we presented a method to compare the geometric dynamics of the coronary artery before and after stenting using biplane angiography. Two cases are reviewed and a number of parameters are proposed to describe the longitudinal change of the vessel before and after stenting. This analysis technique has the potential to identify some aspects of stent design and procedure that might improve the success rate with this therapeutic approach.

Developing an ST-elevation myocardial infarction system of care in Dallas County

BACKGROUND The American Heart Association Caruth Initiative (AHACI) is a multiyear project to increase the speed of coronary reperfusion and create an integrated system of care for patients with ST-elevation myocardial infarction (STEMI) in Dallas County, TX. The purpose of this study was to determine if the AHACI improved key performance metrics, that is, door-to-balloon (D2B) and symptom-onset-to-balloon times, for nontransfer patients with STEMI. METHODS Hospital patient data were obtained through the National Cardiovascular Data Registry Action Registry-Get With The Guidelines, and prehospital data came from emergency medical services (EMS) agencies through their electronic Patient Care Record systems. Initial D2B and symptom-onset-to-balloon times for nontransfer primary percutaneous coronary intervention (PCI) STEMI care were explored using descriptive statistics, generalized linear models, and logistic regression. RESULTS Data were collected by 15 PCI-capable Dallas hospitals and 24 EMS agencies. In the first 18 months, there were 3,853 cases of myocardial infarction, of which 926 (24%) were nontransfer patients with STEMI undergoing primary PCI. D2B time decreased significantly (P < .001), from a median time of 74 to 64 minutes. Symptom-onset-to-balloon time decreased significantly (P < .001), from a median time of 195 to 162 minutes. CONCLUSION The AHACI has improved the system of STEMI care for one of the largest counties in the United States, and it demonstrates the benefits of integrating EMS and hospital data, implementing standardized training and protocols, and providing benchmarking data to hospitals and EMS agencies.