Corrected QT interval as a predictor of mortality in elderly patients with syncope

Background: Prolonged corrected QT interval (QTc) holds independent prognostic importance in predicting mortality in patients with coronary artery disease, diabetes mellitus and congestive heart failure. However, its association with all cause or cardiac mortality in the general population remains unclear. We evaluated the relationship between prolonged QTc and total mortality among patients with syncope. Methods: This was a retrospective study of 348 patients presenting to the emergency department with syncope of any etiology over a period of one year. All patients with atrial fibrillation, left bundle branch block and cardiac devices (pacemaker/defibrillator) were excluded. Prolonged QTc interval was defined as QTc interval ≥ 440 ms. The primary end point for this study was total mortality in patients presenting with syncope. Results: There were 58 (16%) deaths in this population during a mean follow-up of 30 months. Patients with prolonged QTc interval had significantly higher mortality when compared to those with normal QTc interval (22% vs 11%; p = 0.004). This significance was not retained after adjustment for covariates in the Cox regression model, where we found that age ≥ 65 years (hazard ratio [HR] 7.9; 95% confidence interval [CI] 1.9–32.9; p = 0.004) and QTc interval ≥ 500 ms (HR 3.5; 95% CI 1.56–8.12; p = 0.002) were predictors of increased mortality among patients with syncope. Conclusions: In elderly patients presenting to the emergency department with syncope, QTc interval ≥ 500 ms helps identify patients at higher risk of adverse outcomes. (Cardiol J 2011; 18, 4: 395–400

Skorygowany odstęp QT jako czynnik prognostyczny zgonu w grupie osób w podeszłym wieku z omdleniem w wywiadzie

Wstęp: Wydłużony odstęp QT (QTc) jest niezależnym czynnikiem prognostycznym wzmożonej śmiertelności w grupie osób obciążonych chorobą wieńcową, cukrzycą i zastoinową niewydolnością serca. Jego związek z mechanizmami wszystkich zgonów z przyczyn sercowo-naczyniowych w populacji ogólnej pozostaje niejasny. W niniejszej pracy wykazano zależność między wydłużonym odstępem QT a całkowitą śmiertelnością w grupie osób z omdleniami. Metody: Badaniem retrospektywnie objęto grupę 348 pacjentów, którzy zgłosili się na oddział ratunkowy z powodu omdlenia z jakiejkolwiek przyczyny w ciągu ostatniego roku. Wykluczono osoby z migotaniem przedsionków, blokiem lewej odnogi pęczka Hisa oraz pacjentów z implantowanymi urządzeniami, jak stymulator/kardiowerter-defibrylator. Wydłużony odstęp QT zdefiniowano jako trwający co najmniej 440 ms. Pierwszorzędowy punkt końcowy w badanej grupie osób z omdleniami stanowił zgon. Wyniki: W obserwacji 30-miesięcznej odnotowano 58 zgonów (16%). W grupie pacjentów z wydłużonym odstępem QT odsetek zgonów był znacznie wyższy niż w grupie z prawidłowym odstępem (22% v. 11%; p = 0,004). Ta istotność nie została podtrzymana po dodaniu kowariancji w modelu regresji Coxa, gdzie wiek 65 lat i więcej [hazard względny (HR) 7,9; 95-procentowy przedział ufności (CI) 1,9–32,9; p = 0,004] i odstęp QTc wynoszący co najmniej 500 ms (HR 3,5; 95% CI 1,56–8,12; p = 0,002) łącznie były wskaźnikami prognostycznymi zgonu w grupie pacjentów z omdleniami. Wnioski: W grupie starszych osób zgłaszających się na oddział ratunkowy z powodu omdlenia odstęp QT ≥ 500 ms pozwala pomóc zidentyfikować pacjentów z grupy ryzyka wystąpienia nagłego incydentu sercowego. (Folia Cardiologica Excerpta 2011; 6, 4: 211–216

Azithromycin Therapy Reduces Cardiac Inflammation and Mitigates Adverse Cardiac Remodeling After Myocardial Infarction: Potential Therapeutic Targets in Ischemic Heart Disease

Introduction Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery. Methods and results Male WT mice (C57BL/6, 6–8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45+/Ly6G-/F4-80+/CD86+) and increase in anti-inflammatory (CD45+/Ly6G-/F4-80+/CD206+) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti-inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis. Conclusion Azithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM

Rad GTPase Deletion Atenuates Post-Ischemic Cardiac Dysfunction and Remodeling

The protein Rad interacts with the L-type calcium channel complex to modulate trigger Ca2+ and hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction. Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad and testing the efficacy of Rad deletion in cardioprotection relative to the time of onset of acute myocardial infarction

Adult Spiny Mice (\u3ci\u3eAcomys\u3c/i\u3e) Exhibit Endogenous Cardiac Recovery in Response to Myocardial Infarction

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). While Acomys species exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baseline Acomys cardiac anatomy and function in comparison with commonly used inbred and outbred laboratory Mus strains (C57BL6 and CFW). While our results demonstrated comparable cardiac anatomy and function between Acomys and Mus, Acomys exhibited a higher percentage of cardiomyocytes displaying distinct characteristics. In response to myocardial infarction, all animals experienced a comparable level of initial cardiac damage. However, Acomys demonstrated superior ischemic tolerance and cytoprotection in response to injury as evidenced by cardiac functional stabilization, higher survival rate, and smaller scar size 50 days after injury compared to the inbred and outbred mouse strains. This phenomenon correlated with enhanced endothelial cell proliferation, increased angiogenesis, and medium vessel maturation in the peri-infarct and infarct regions. Overall, these findings demonstrate augmented myocardial preservation in spiny mice post-MI and establish Acomys as a new adult mammalian model for cardiac research

Liposomal Delivery of Azithromycin Enhances Its Immunotherapeutic Efficacy and Reduces Toxicity in Myocardial Infarction

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug\u27s efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans

Loss of Rad-GTPase Produces a Novel Adaptive Cardiac Phenotype Resistant to Systolic Decline with Aging

Rad-GTPase is a regulator of L-type calcium current (LTCC), with increased calcium current observed in Rad knockout models. While mouse models that result in elevated LTCC have been associated with heart failure, our laboratory and others observe a hypercontractile phenotype with enhanced calcium homeostasis in Rad-/-. It is currently unclear whether this observation represents an early time point in a decompensatory progression towards heart failure or whether Rad loss drives a novel phenotype with stable enhanced function. We test the hypothesis that Rad-/- drives a stable nonfailing hypercontractile phenotype in adult hearts, and we examine compensatory regulation of sarcoplasmic reticulum (SR) loading and protein changes. Heart function was measured in vivo with echocardiography. In vivo heart function was significantly improved in adult Rad-/- hearts compared with wild type. Heart wall dimensions were significantly increased, while heart size was decreased, and cardiac output was not changed. Cardiac function was maintained through 18 mo of age with no decompensation. SR releasable Ca2+ was increased in isolated Rad-/- ventricular myocytes. Higher Ca2+ load was accompanied by sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein elevation as determined by immunoblotting and a rightward shift in the thapsigargan inhibitor-response curve. Rad-/- promotes morphological changes accompanied by a stable increase in contractility with aging and preserved cardiac output. The Rad-/- phenotype is marked by enhanced systolic and diastolic function with increased SR uptake, which is consistent with a model that does not progress into heart failure

Azithromycin therapy reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction: Potential therapeutic targets in ischemic heart disease

<div><p>Introduction</p><p>Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery.</p><p>Methods and results</p><p>Male WT mice (C57BL/6, 6–8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45⁺/Ly6G^-/F4-80⁺/CD86⁺) and increase in anti-inflammatory (CD45⁺/Ly6G^-/F4-80⁺/CD206⁺) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti-inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis.</p><p>Conclusion</p><p>Azithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM.</p></div