Chest Pain Evaluation: Diagnostic Testing.

Chest pain/discomfort (CP) is a common symptom and can be a diagnostic dilemma for many clinicians. The misdiagnosis of an acute or progressive chronic cardiac etiology may carry a significant risk of morbidity and mortality. This review summarizes the different options and modalities for establishing the diagnosis and severity of coronary artery disease. An effective test selection algorithm should be individually tailored to each patient to maximize diagnostic accuracy in a timely fashion, determine short- and long-term prognosis, and permit implementation of evidence-based treatments in a cost-effective manner. Through collaboration, a decision algorithm was developed (www.chowmd.ca/cadtesting) that could be adopted widely into clinical practice.

La douleur ou la gêne thoracique sont des symptômes fréquents qui peuvent poser un dilemme diagnostique pour de nombreux médecins. Les erreurs de diagnostic d'une cause aiguë ou chronique progressive d'origine cardiaque peuvent d'ailleurs entraîner un risque considérable de morbidité et de mortalité. La présente synthèse porte sur les différentes options et modalités d'établissement du diagnostic et de la gravité d'une coronaropathie. Un algorithme efficace pour le choix des tests doit être adapté à chaque patient afin de maximiser l'exactitude diagnostique dans les plus brefs délais, de déterminer le pronostic à court et à long terme, et de permettre une mise en œuvre de traitements fondés sur des données probantes tout en tenant compte des coûts. Un algorithme décisionnel a donc été conjointement mis au point (www.chowmd.ca/cadtesting) et pourrait être largement adopté dans la pratique clinique.

Right ventricular strain: measurement and clinical application.

PURPOSE OF REVIEW: Right ventricular (RV) assessment has long been challenging and technically difficult using echocardiography. This is mainly the result of the asymmetrical shape of the RV making it difficult to visualize on one-or-two dedicated views, thus requiring multiple integrated views and subjective assessment. Measurement of tricuspid annular systolic plane excursion and RV tissue Doppler velocity have become relied-upon methods of objective assessments; however, have limitations for characterizing true RV physiology. RECENT FINDINGS: Studies suggest that two-dimensional RV free wall longitudinal systolic strain (RVFWS) using speckle-tracking echocardiography has emerged as a reproducible, feasible and highly prognostic technique for quantifying RV function. This has been demonstrated for patients with heart failure, ischemic heart disease, pulmonary hypertension, infiltrative disease and many other types of cardiovascular disease. SUMMARY: The current review outlines the clinical use of RVFWS, and its integration with other commonly used echocardiographic measurements to more accurately assess RV function, cause and prognosis to guide and improve patient care decision making.

End of life decisions in heart failure: to turn off the intracardiac device or not?

PURPOSE OF REVIEW: Heart failure is a significant public health concern around the world. Implantable cardioverter defibrillators with or without cardiac resynchronization therapy (CRT-D) have proven survival benefit. As patients progress to end-stage disease, management shifts to palliative care, and cardiologists are often confronted with how to best manage these devices. RECENT FINDINGS: Studies suggest that up to one-third of patients with an implantable cardioverter defibrillator receive painful shocks in the last 24 h of life. Disabling pacing or resynchronization devices may further weaken the heart function and expedite death, particularly if the patient has no underlying ventricular rhythm. Is it ethical or legal to discontinue functions of the implantable device? The discussion and the decision to be made are whether to continue both pacing and tachyarrhythmia therapies, disable tachyarrhythmia therapies while maintaining pacing, or discontinue both. SUMMARY: The decision to disable all or parts of the device function is ultimately up to the patient. To avoid painful shocks near the end of life, it is recommended that tachyarrhythmia therapies be turned off when the patient is being treated palliatively. After informed discussion, withdrawing the resynchronization or pacing device option is also acceptable if requested by the patient regardless of the potential outcomes.

Type 2 diabetes epidemic in First Nations people of Canada.

Diabetes is a chronic condition that results in the body's inability to either produce or respond to insulin. Abnormal insulin production and sensitivity lead to improper blood glucose levels and energy storage required for homeostatic organ maintenance. Over 151 million people worldwide, including 7% of the US and 5% of Canadian populations have been diagnosed with diabetes, and the prevalence varies greatly by race and ethnicity. However, since the end of World War II, the people with the greatest risk include First Nations people, including Canada's aboriginal, Inuit and Native Indian populations with up to a 5-fold greater prevalence than the general population. Prevalence can vary from 8% to 48% among the sexes and tribes. Understanding the prevalence and causes of this epidemic is immediately needed as diabetes precedes various other endocrine and cardiovascular diseases. Here we review the current understanding of diabetes risk in Canada's First Nations people in the hope to bring greater awareness among healthcare professionals and implementation of measures to prevent spread of this disease.

Direct injection of kit ligand-2 lentivirus improves cardiac repair and rescues mice post-myocardial infarction.

Myocardial infarction (MI) and subsequent adverse remodeling cause heart failure. Previously we demonstrated a role for Kit ligand (KL) in improving cardiac function post-MI. KL has two major isoforms; KL-1 is secreted whereas KL-2 is predominantly membrane bound. We demonstrate here first that KL-2-deficient mice have worse survival and an increased heart/bodyweight ratio post-MI compared to mice with reduced c-Kit receptor expression. Next we synthesized recombinant lentiviral vectors (LVs) that engineered functional expression of murine KL-1 and KL-2. For in vivo analyses, we directly injected these LVs into the left ventricle of membrane-bound KL-deficient Sl/Sl(d) or wild-type (WT) mice undergoing MI. Control LV/enGFP injection led to measurable reporter gene expression in hearts. Injection of LV/KL-2 attenuated adverse left ventricular remodeling and dramatically improved survival post-MI in both Sl/Sl(d) and WT mice (from 12 to 71% and 35 to 73%, respectively, versus controls). With regard toward beginning to understand the possible salutary mechanisms involved in this effect, differential staining patterns of Sca-1 and Ly49 on peripheral blood (PB) cells from therapeutically treated animals was found. Our data show that LV/KL-2 gene therapy is a promising treatment for MI.

Chlamydophila pneumoniae inhibits differentiation of progenitor adipose cells and impairs insulin signaling.

BACKGROUND: Recent clinical studies have shown Chlamydophila pneumoniae seropositivity to be related to overweight status and inversely related to insulin sensitivity. The present study was performed to investigate the potential effects of C. pneumoniae infection of adipocytes. METHODS: 3T3-L1 cells and primary epididymal preadipocytes were infected with C. pneumoniae either before or after induction of differentiation, and the effects on adipogenesis and insulin signaling were determined. Tumor necrosis factor (TNF)-alpha signaling was examined by assessing the effects of C. pneumoniae infection in preadipocytes isolated from epididymal adipose tissue of both wild-type and TNF-alpha(-/-) mice. RESULTS: C. pneumoniae successfully infected both undifferentiated and differentiated 3T3-L1 cells in vitro. The bacteria were also detected in adipose tissue of infected low-density lipoprotein receptor-deficient mice. TNF-alpha protein levels were significantly increased in cells infected with either live or heat-killed C. pneumoniae or treated with lipopolysaccharide or heat-shock protein 65; this increase was associated with inhibition of adipocyte differentiation and down-regulation of insulin-stimulated tyrosine-phosphorylated insulin receptor and its substrate. In contrast, C. pneumoniae infection in TNF-alpha(-/-) adipocytes produced no apparent changes, but addition of recombinant TNF-alpha reversed this effect. CONCLUSIONS: We demonstrate for the first time that C. pneumoniae can infect murine pre- and postdifferentiated adipocytes and, through a TNF-alpha-mediated inflammatory mechanism, can impair differentiation and insulin signaling.

Correction of cardiac abnormalities in fabry mice by direct intraventricular injection of a recombinant lentiviral vector that engineers expression of alpha-galactosidase A.

BACKGROUND: Recombinant lentiviral vectors (LVs) offer the possibility of stable, long-term expression of transgenes even in non-dividing cells. In the present study this vector system was applied to a clinically relevant cardiovascular problem. METHODS AND RESULTS: Fabry disease results from deficient activity of alpha-galactosidase A (alpha-gal A) and cardiac abnormalities are a common and an important cause of death in patients with the disease. A therapeutic LV that delivers the alpha-gal A cDNA has been synthesized. In vitro studies established efficient transduction of the H9c2 rat cardiomyocytes and showed overexpression of enGFP (control) and alpha-gal A. In in vivo studies, the enGFP cDNA was transferred into C57BL/6 mouse hearts by direct intraventricular injection. Next, in a mouse model of Fabry disease, the recombinant therapeutic construct was delivered analogously. In cardiac tissue, alpha-gal A activity rose to 23% of normal levels at day 7 after LV injection, which is encouraging because levels of correction approximating 5% of normal may be curative for this disorder. There was also a corresponding reduction in globotriaosylceramide accumulation. Other organs assayed showed no detectable changes in alpha-gal A activity levels in injected animals. CONCLUSION: A localized benefit of directly injecting a therapeutic LV into the heart has been shown, confirming the utility of this delivery system for research and therapy for a variety of cardiovascular disorders.

Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction.

Inappropriate cardiac remodeling and repair after myocardial infarction (MI) predisposes to heart failure. Studies have reported on the potential for lineage negative, steel factor positive (c-kit+) bone marrow-derived hematopoetic stem/progenitor cells (HSPCs) to repair damaged myocardium through neovascularization and myogenesis. However, the precise contribution of the c-kit signaling pathway to the cardiac repair process has yet to be determined. In this study, we sought to directly elucidate the mechanistic contributions of c-kit+ bone marrow-derived hematopoetic stem/progenitor cells in the maintenance and repair of damaged myocardium after MI. Using c-kit-deficient mice, we demonstrate the importance of c-kit signaling in preventing ventricular dilation and hypertrophy, and the maintenance of cardiac function after MI in c-kit-deficient mice. Furthermore, we show phenotypic rescue of cardiac repair after MI of c-kit-deficient mice by bone marrow transplantation of wild-type HSPCs. The transplanted group also had reduced apoptosis and collagen deposition, along with an increase in neovascularization. To better understand the mechanisms underlying this phenotypic rescue, we investigated the gene expression pattern within the infarcted region by using microarray analysis. This analysis suggested activation of inflammatory pathways, specifically natural killer (NK) cell-mediated mobilization after MI in rescued hearts. This finding was confirmed by immunohistology and by using an NK blocker. Thus, our investigation revealed a previously uncharacterized role for c-kit signaling after infarction by mediating bone marrow-derived NK and angiogenic cell mobilization, which contributes to improved remodeling and cardiac function after MI.

Dissecting mechanisms of innate and acquired immunity in myocarditis.

Inflammation underlies the pathogenesis of some of the most common cardiovascular diseases. Myocarditis is a relevant clinical cause of heart failure, but also provides an excellent laboratory model to study the mechanisms of inflammation leading to heart failure. The availability of different inbred mouse strains for inducing myocarditis using viral or myosin as triggers provides an excellent platform for investigation. The recent use of genetically manipulated mouse models of transgenic overexpression or knockout or knockin targets have provided opportunity to pinpoint specific pathways underlying myocarditis. These pathways include the involvement of both innate and acquired immunity, as well as the role of viral receptors in disease phenotype. These different models also permit the evaluation of therapeutic strategies of candidates for clinical development.

Effects of benazepril, an angiotensin-converting enzyme inhibitor, combined with CGS 35066, a selective endothelin-converting enzyme inhibitor, on arterial blood pressure in normotensive and spontaneously hypertensive rats.

Continuous intra-arterial administration of a selective endothelin-converting enzyme (ECE) inhibitor CGS 35066 at a dose of 30 mg/kg decreased the mean arterial blood pressure (MABP) in conscious unrestrained normotensive rats and spontaneously hypertensive rats (SHRs). At that dose, the magnitude of the antihypertensive effects was greater in SHRs than in normotensive rats. Additional administration of an angiotensin-converting enzyme (ACE) inhibitor benazapril (lotensin) further reduced MABP in normotensive rats and completely blocked hypertension in SHRs. However, when the selective ECE inhibitor was subsequently removed, blood pressure was less inhibited in normotenive rats whereas it remained strongly inhibited in SHRs by the ACE inhibitor alone. These results imply that simultaneous treatment with benazepril and CGS 35066 gave additive antihypertensive effects in normotensive rats but not in SHRs, when both compounds were administered at a dose of 30 mg/kg. Our results suggest that: (i) the endothelin (ET) system together with the renin-angiotensin system contribute to the maintenance of blood pressure in normal healthy rats; (ii) while an ECE inhibitor acts as an antihypertensive agent on its own, the sole efficacy of ACE inhibitor at that dose is sufficient to block MABP without the participation of the ET system in SHR.

Effects of a selective endothelin A receptor antagonist, ABT-627, in healthy normotensive anaesthetized rats developing acute pulmonary air embolism.

Acute pulmonary air embolism (APAE) injures the vascular endothelium in the lung and results in pulmonary hypertension (PH). Endothelins (ETs), a family of potent vasoactive peptides, are known to be associated with PH of various aetiologies. We evaluated the effects of ABT-627, a selective ET(A) receptor (ET(A)-R) antagonist in a rat model of APAE over 3 h. APAE rats developed a higher right ventricular systolic pressure (RVSP), lower mean arterial blood pressure (MABP), and had lower PaO(2). At 3 h, arterial plasma levels of ET-1 were increased. ABT-627-treated controls showed no effects. However, ABT-627 significantly lowered RVSP during APAE, abolished the short recovery phase (within 10-25 min) of MABP without affecting the subsequent lowering of MABP, and improved oxygen saturation in APAE rats. These results show that ET(A)-R subtype is involved in the pathogenesis of APAE since a blockade of this receptor subtype attenuated the cardiopulmonary deterioration and improved blood gas exchanges in rats with this disease.