Chad E. Darling

Aging Mouse Hearts Are Refractory to Infarct Size Reduction With Post-Conditioning

OBJECTIVES Our aim was to establish whether the efficacy of post-conditioning is maintained in aging hearts. BACKGROUND Post-conditioning, or relief of myocardial ischemia in a stuttered manner, has been shown to reduce infarct size, in part because of up-regulation of survival kinases (extracellular-signal regulated kinase [ERK] 1/2 or PI3-kinase/Akt) during the early min of reperfusion. All of these data have, however, been obtained in adult populations; the question of whether post-conditioning-induced cardioprotection is maintained in aging cohorts is unknown. METHODS Isolated buffer-perfused hearts were obtained from 3- to 4-month-old (adult) and 20- to 24-month-old C57BL/6J mice and subjected to 30 min of ischemia. For each cohort, hearts were randomized to receive standard, abrupt (control) reperfusion, or were post-conditioned with 3 or 6 10-s cycles of stuttered reflow. Primary end points were infarct size, cardiac expression of phospho-Akt, phospho-mitogen-activated protein kinase kinase 1/2 and phospho-ERK 1/2, and expression of mitogen-activated protein kinase-phosphatase-1 (MKP-1: phosphatase purported to play a primary role in ERK dephosphorylation). RESULTS In adult mouse hearts, post-conditioning significantly reduced infarct size via up-regulation of ERK (but not Akt) signaling. In contrast, in the 2-year-old cohort, post-conditioning failed to limit necrosis, possibly a consequence of the deficit in ERK phosphorylation and increased MKP-1 expression seen in old hearts. Indeed, infusion of sodium orthovanadate, a nonspecific MKP inhibitor, attenuated MKP-1 expression and restored the post-conditioned phenotype in old hearts. CONCLUSIONS Old mouse hearts are refractory to infarct size reduction with post-conditioning, possibly because of an age-associated increase in MKP-1 and resultant deficit in ERK phosphorylation.

Cardioprotection 'outside the box'--the evolving paradigm of remote preconditioning.

Abstract. Conventional ischemic preconditioning is the phenomenon whereby brief episodes of myocardial ischemia render the ischemic territory resistant to a subsequent, sustained ischemic insult. A growing body of evidence further indicates that brief ischemia applied in distant organs and tissues can also protect naïve, virgin myocardium from ischemic injury. In this review, we describe the initial observations that provided the impetus for the study of ‘remote preconditioning’, and summarize our current knowledge of the three facets of ‘preconditioning at a distance’ – intra-cardiac, inter-organ and transferred inter-cardiac preconditioning.

’Postconditioning’ the human heart: Multiple balloon inflations during primary angioplasty may confer cardioprotection

Growing evidence from experimental models suggests that relief of myocardial ischemia in a stuttering manner (i.e., ’postconditioning’ [PostC] with brief cycles of reperfusion-reocclusion) limits infarct size. However, the potential clinical efficacy of PostC has, to date,been largely unexplored. Using a retrospective study design, our aim was to test the hypothesis that creatine kinase release (CK: clinical surrogate of infarct size) would be attenuated in ST-segment elevation myocardial infarction (STEMI) patients requiring multiple balloon inflations-deflations during primary angioplasty versus STEMI patients who received minimal balloon inflations and/or direct stenting. To investigate this concept, we reviewed the records of all STEMI patients with single vessel occlusion who presented to our institution from November 2004 – April 2006 for primary angioplasty. Exclusion criteria were: previous MI, cardiogenic shock, patients resuscitated from cardiac arrest, or pre-infarct angina. Patients were prospectively divided into two subsets: those receiving 1–3 balloon inflations (considered the minimum range to achieve patency and stent placement) versus those in whom 4 or more inflations were applied. Peak CK release was significantly lower in patients requiring ≥4 versus 1–3 inflations (1655 versus 2272 IU/L; p<0.05), an outcome consistent with the concept that relief of sustained ischemia in a stuttered manner (analogous to postconditioning) may evoke cardioprotection in the clinical setting.

Improved Survival after Heart Failure: A Community-based Perspective

Background Heart failure is a highly prevalent, morbid, and costly disease with a poor long‐term prognosis. Evidence‐based therapies utilized over the past 2 decades hold the promise of improved outcomes, yet few contemporary studies have examined survival trends in patients with acute heart failure. The primary objective of this population‐based study was to describe trends in short‐ and long‐term survival in patients hospitalized with acute decompensated heart failure (ADHF). A secondary objective was to examine patient characteristics associated with decreased long‐term survival. Methods and Results We reviewed the medical records of 9748 patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004. Patients hospitalized with ADHF were more likely to be elderly and to have been diagnosed with multiple comorbidities in 2004 compared with 1995. Over this period, survival was significantly improved in‐hospital, and at 1, 2, and 5 years postdischarge. Five‐year survival rates increased from 20% in 1995 to 29% in 2004. Although survival improved substantially over time, older patients and patients with chronic kidney disease, chronic obstructive pulmonary disease, anemia, low body mass index, and low blood pressures had consistently lower postdischarge survival rates than patients without these comorbidities. Conclusion Between 1995 and 2004, patients hospitalized with ADHF have become older and increasingly comorbid. Although there has been a significant improvement in survival among these patients, their long‐term prognosis remains poor, as fewer than 1 in 3 patients hospitalized with ADHF in 2004 survived more than 5 years.

Clinical Features, Treatment Practices, and Hospital and Long-term Outcomes of Older Patients Hospitalized with Decompensated Heart Failure: The Worcester Heart Failure Study

OBJECTIVES: To examine age‐specific differences in clinical presentation, receipt of therapeutic practices and lifestyle recommendations, and hospital and long‐term survival in patients hospitalized for acute heart failure HF.

Impact of COPD on the Mortality and Treatment of Patients Hospitalized With Acute Decompensated Heart Failure: The Worcester Heart Failure Study

BACKGROUND COPD is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and postdischarge mortality and treatment of patients hospitalized with ADHF according to COPD status. METHODS The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during four study years: 1995, 2000, 2002, and 2004. Patients were followed through 2010 for determination of their vital status. RESULTS Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including β-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable, adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 year (adjusted relative risk [RR], 1.10; 95% CI, 1.06-1.14) and 5 years (adjusted RR, 1.40; 95% CI, 1.28-1.52) after hospital discharge than patients who were not previously diagnosed with COPD. CONCLUSIONS COPD is a common comorbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and ensure that patients with ADHF and COPD receive optimal treatment modalities.

PULSE-SMART: Pulse-Based Arrhythmia Discrimination Using a Novel Smartphone Application

Atrial fibrillation (AF) is a common and dangerous rhythm abnormality. Smartphones are increasingly used for mobile health applications by older patients at risk for AF and may be useful for AF screening.

Recent trends in post-discharge mortality among patients with an initial acute myocardial infarction

The objectives of this study were to describe contemporary postdischarge death rates of patients hospitalized at all Worcester, Massachusetts, hospitals after initial acute myocardial infarctions (AMIs) and to examine factors associated with a poor prognosis. The medical records of patients discharged from 11 central Massachusetts medical centers after initial AMIs during 2001, 2003, 2005, and 2007 were reviewed, identifying 2,452 patients. This population was composed of predominantly older patients, men (58%), and whites. Overall, the 3-month, 1-year, and 2-year all-cause death rates were 8.9%, 16.4%, and 23.4%, respectively. Over time, reductions in postdischarge mortality were observed in crude as well as multivariate-adjusted analyses. In 2001, the 3-month, 1-year, and 2-year all-cause death rates were 11.1%, 17.1%, and 25.6%, respectively, compared to rates of 7.9%, 12.7%, and 18.6% in patients discharged in 2007. Older age, male gender, hospitalization for a non-ST-segment elevation AMI, renal dysfunction, and preexisting heart failure were associated with an increased risk for dying after hospital discharge. These results suggest that the postdischarge prognosis of patients with initial AMIs has improved, likely reflecting enhanced in-hospital and postdischarge management practices. In conclusion, patients with initial AMIs can also be identified who are at increased risk for dying after hospital discharge, in whom increased surveillance and targeted treatment approaches can be directed.

Hypoosmotic stress stimulates growth in HepG2 cells via protein kinase B—dependent activation of activator protein-1

Although hypoosmotic stress-induced cell swelling activates phosphatidylinositol-3-kinase, its impact on the downstream signal protein kinase B and cell growth is unknown. Activator protein-1 is in part phosphatidylinositol-3-kinase dependent, and is important in proliferation. We hypothesized that cell swelling modulates proliferation in HepG2 cells via the protein kinase B-dependent activation of activator protein-1. HepG2 cells pretreated with or without LY294002 were exposed for up to 30 minutes to hypoosmotic medium (160 mOsm/L). Tumor necrosis factor-alpha (1.4 nmol/L) or normoosmolar medium (270 mOsm/L) served as positive and negative controls, respectively. Western immunoblots measured cytoplasmic phosphorylated and total protein kinase B. Electromobility shift assays measured nuclear activator protein-1. Methylene blue assays measured cell proliferation at 24, 48, and 72 hours after stimulation. Hypoosmotic stress phosphorylated protein kinase B by 10 minutes. Subsequently, hypoosmotic exposure stimulated activator protein-1 by 30 minutes. Pulse exposure to hypoosmotic stress potentiated HepG2 proliferation by 72 hours as compared to both negative controls and LY-inhibited cells (n = 4 per group, P = 0.009 and P = 0.004, respectively; P <0.001 analysis of variance. All three activation events were abolished with LY294002 pretreatment. In HepG2 cells, hypoosmotic stress-induced swelling stimulates proliferation via protein kinase B-mediated activation of activator protein-1. These data delineate a possible mechanism linking changes in cell volume to growth in human liver cancer.

Long-term survival for patients with acute decompensated heart failure according to ejection fraction findings.

Limited data exist about the long-term prognosis of patients with acute decompensated heart failure (ADHF) further stratified according to ejection fraction (EF) findings. The primary objective of this population-based observational study was to characterize and compare trends in long-term prognosis after an episode of ADHF across 3 EF strata. Hospital medical records were reviewed for 3,604 residents of the Worcester, Massachusetts, metropolitan area who were discharged after ADHF from all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004 and had EF measurements during their index hospitalizations. The average age of this population was 75 years, most were white, and 44% were men. Approximately 49% of the population had heart failure (HF) with preserved EF (EF ≥ 50%), 37% had HF with reduced EF (EF ≤ 40%), and 14% had HF with borderline EF (EF 41% to 49%). Patients with HF with preserved EF experienced higher postdischarge survival rates than patients with either HF with reduced EF or HF with borderline EF at 1, 2, and 5 years after discharge from all central Massachusetts medical centers. Although prognosis at 1 year after hospital discharge improved for all patient groups during the years under study, especially for those with HF with reduced EF and HF with preserved EF, these encouraging trends decreased with increasing duration of follow-up. In conclusion, although improvements in 1-year postdischarge survival were observed for patients in each of the 3 EF groups examined to varying degrees, the postdischarge prognosis of all patients with ADHF remains guarded.