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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.

Fibrosis is the outcome of excess deposition of extracellular matrix components and underlies diastolic and systolic heart failure. Metalloproteinases (MMPs and ADAMs) and their inhibitors (TIMPs) are critical regulators of ECM turnover and fibrosis. TIMP3 is a potent inhibitor of MMPs and ADAMs, whereby it regulates tissue proteolysis and cytokine bioavailability. TIMP3 levels are reduced in human heart disease, and we found that mice lacking Timp3 (KO) exhibit severe dilated cardiomyopathy (DCM), extensive interstitial fibrosis and early heart failure (HF) following pressure overload compared to wild type (WT) mice. We showed upregulated TNF signaling within 6 hrs of aortic banding (AB) which when blocked, significantly improved DCM and prevented HF. We then investigated the mechanism underlying the extensive fibrosis despite the increased MMP activity in the TIMP3KO mice. Comparative microarray analyses show a significant upregulation of the TGFβ1 signaling pathway within 6 hrs of AB in KO vs WT hearts. In vivo treatment of KO-AB mice with a TGFβ1-neutralizing antibody (1D11) completely abolishes fibrosis, markedly improves left ventricular dilation, systolic and diastolic heart function (LVEDD(mm): 4.3 ± 0.1 in WT, 5.4 ± 0.1 in KO, 4.7 ± 0.1 in KO+ 1D11; fractional shortening(%): 40.2 ± 1.7 in WT, 19.6 ± 2.2 in KO, 36.2 ± 0.7 in KO+ 1D11; E/Ac ratio: 2.5 ± 0.3 in WT, 1.8 ± 0.3 in KO, 2.4 ± 0.2 in KO + 1D11; n = 22, P < 0.05). Interestingly, blocking TGFβ1 also prevented the early rise in TNF in KO hearts. Using primary neonatal culture systems, we found that cardiomyocyte-fibroblast interaction is essential for a fibrotic response to agonists (Ang II, PE). Further, KO co-cultures generate a 5-fold greater fibrosis (P < 0.05) through activation of Smad2/3 pathway compared to WT. TGFβ also regulates TNF transcription more potently in KO cells since a 3-fold higher TNF induction occurred in response to recombinant TGFβ1 in KO vs WT co-cultures (P < 0.05). In conclusion, TIMP3 is a critical regulator of TGFβ1 and TNF, and its deficiency induces parallel dysregulations in the signaling of these cytokines very early after pressure overload, leading to severe interstitial fibrosis and DCM, hence, TIMP3-based therapies can simultaneously impact fibrosis and DCM.

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene–targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload–induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin −/y and Apelin +/y mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.

Most common cardiovascular disorders, including atherosclerosis, heart failure, hypertension, and arrhythmias, are multigenic or complex disorders. Dilated cardiomyopathies are most commonly associated with mutations of the cytoskeletal proteins, including dystrophin complex that binds cell cytoskeleton to the extracellular matrix, such as desmin, etc. The long QT syndromes can be subclassified based on genotypes, such that IKs (the slowly activating delayed rectifier potassium current) potassium channel mutations account for the majority of LQT1/5 and the JLN1/2 phenotypes. The IKr (the rapidly activating delayed rectifier potassium current) potassium channel mutations may account for the LQT2/6 syndromes and the sodium channel mutations account for LQT3. Some candidate genes for susceptibility to myocardial infarction include thrombospondin-1,4, lymphotoxin-α, and 5-lipoxygenase, but others are being reported presently. Single nucleotide polymorphism (SNP) variations are being linked to cardiovascular disease, including the apolipoprotein E-ɛ4 4 polymorphism, which predisposes individuals to coronary artery disease, and variations in the β2-adrenergic receptor polymorphism, which predispose individuals to heart failure.

Cardiomyopathies are diseases of the heart resulting in impaired cardiac muscle function, which can lead to heart dilation or overt heart failure. These diseases represent a major cause of global morbidity and death. Innovative preventive and therapeutic measures are urgently needed for early detection, categorization, and treatment of patients at risk of cardiomyopathy. These developments will require a more complete understanding of the molecular effects of impaired cardiac function, even prior to overt disease. The use of gel-free expression proteomics in the detailed analysis of cardiac tissues should yield significant insight into the pathophysiology of these diseases.

Left ventricular (LV) dysfunction and/or heart failure (HF) are frequent complications of hypertension and myocardial infarction (MI), placing affected patients at increased risk of significant morbidity and premature death. Given that the renin-angiotensin-aldosterone system (RAAS) is activated and of pathophysiological importance in such patients, a strong therapeutic rationale exists to target the main effector mechanism (that is, angiotensin II [Ang II]) in order to lessen the associated morbidity and mortality burden.Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality and LV dysfunction and to slow disease progression in patients with HF, including high-risk, post-MI patients. However, ACE inhibitors (ACE-Is) may not provide optimal long-term RAAS blockade (a finding that is associated with a worse prognosis) such and many patients are unable to tolerate such therapy (because of troublesome dry cough, for example). In contrast, Ang II receptor blockers (ARBs) may block the RAAS more completely than ACE-Is and appear to be better tolerated. Several large-scale trials have evaluated the efficacy of ARBs in patients with LV dysfunction and/or HF (including high-risk, post-MI patients), and have confirmed their utility as an R efficacious and well-tolerated alternative to ACE-Is in this setting.

Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.

The importance of heart failure with preserved ejection fraction is increasingly recognized. We conducted a study to evaluate the epidemiologic features and outcomes of patients with heart failure with preserved ejection fraction and to compare the findings with those from patients who had heart failure with reduced ejection fraction.From April 1, 1999, through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized in three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction), and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure.Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups.Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction.

Proteomics is the new systems biological approach to the study of proteins and protein variation on a large scale as a result of biological processes and perturbations. The field is undergoing a dramatic transformation, owing to the completion and annotation of the human genome as well as technological advances to study proteins on a large scale. The new science of proteomics can potentially yield novel biomarkers reflecting cardiovascular disease, establish earlier detection strategies, and monitor responses to therapy. Technological advances permit the unprecedented large-scale identification of peptide sequences in a biological sample with mass spectrometry, whereas gel-based techniques provide further refinement on the status of post-translational modification. The application of high throughput protein evaluation with a subset of predefined targets, identified through proteomics, microarray profiling, and pathway analysis in animal models and human tissues, is gaining momentum in research and clinical applications. Proteomic analysis has provided important insights into ischemic heart disease, heart failure, and cardiovascular pathophysiology. The combination of proteomic biomarkers with clinical phenotypes and genetic haplotype information can lead to a more precise diagnosis and therapy on an individual basis--the fundamental premise of "personalized medicine."

Cardiovascular diseases remain the major cause of mortality and morbidity in the Western world. Heart failure is the most rapidly rising cardiovascular condition and is associated with high mortality. The etiology of heart failure is multiple, ranging from genetic cardiomyopathies to structural modifications to the heart following myocardial infarction or long-standing high blood pressure. Molecular system biology techniques (microarrays and proteomics) in combination with bioinformatics can now provide unique insights into the molecular mechanisms leading to heart failure. Both gene-gene and gene-environment interactions determine the specific phenotype and outcomes in this condition. The identification of these pathways also provides opportunities for the discovery of novel diagnostic and/or prognostic markers, and important therapeutic targets. How recent applications of genomics technologies depict a more complete portrait of molecular events in heart failure is summarized.

Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3 −/− mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNFα converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-α (TNFα) processing. In addition, TNFα production increased in timp-3 −/− -AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3 −/− -AB myocardium. Timp-3 −/− /tnfα −/− mice were generated and subjected to AB for comparative analyses with timp-3 −/− -AB mice. This revealed the critical role of TNFα in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNFα, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNFα, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3 −/− -AB mice. Notably, combining TNFα ablation with MMP inhibition completely rescued heart disease in timp-3 −/− -AB mice. This study provides a basis for anti-TNFα and MMP inhibitor combination therapy in heart disease.

Although pentoxifylline (PTXF), a phosphodiesterase inhibitor, has been reported to exert beneficial effects in cardiac bypass surgery, its effect and mechanisms against ischemia-reperfusion (I/R) injury in heart are poorly understood. Because I/R is known to increase the level of tumor necrosis factor (TNF)-alpha in myocardium and PTXF has been shown to depress the production of TNF-alpha in failing heart, this study examined the hypothesis that PTXF may attenuate cardiac dysfunction and reduce TNF-alpha content in I/R heart. For this purpose, isolated rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 2-30 min. Although cardiac dysfunction due to ischemia was not affected, the recovery of heart function upon reperfusion was markedly improved by PTXF treatment. This cardioprotective effect of PTXF was dose dependent; maximal effect was seen at a concentration of 125 microM. TNF-alpha, nuclear factor-kappaB (NF-kappaB), and phosphorylated NF-kappaB contents were decreased in ischemic heart but were markedly increased within 2 min of starting reperfusion. The ratio of cytosolic-to-homogenate NF-kappaB was decreased, whereas the ratio of particulate-to-homogenate NF-kappaB was increased in I/R hearts. These changes in TNF-alpha and NF-kappaB protein contents as well as in NF-kappaB redistribution due to I/R were significantly attenuated by PTXF treatment. The results of this study indicate that the cardioprotective effects of PTXF against I/R injury may be due to reductions in the activation of NF-kappaB and the production of TNF-alpha content.

Background— S100B, a 20-kDa, Ca 2+ -binding dimer, is a putative intrinsic negative regulator of myocardial hypertrophy expressed after myocardial infarction. S100B-overexpressing transgenic (TG) and S100B-knockout (KO) mice have been generated to assess the consequences of S100B expression and altered hypertrophy after infarction. Methods and Results— We compared 21 wild-type (WT), 20 TG, and 24 KO mice over 35 days after experimental myocardial infarction with sham-operated controls (n=56). Of those, 4 WT-infarcted mice, 7 TG-infarcted mice, and 1 KO-infarcted mouse and no sham-operated mice died during the observation period. Among survivors, echocardiography, hemodynamic studies, and postmortem examination indicated that the WT and KO groups of infarcted mice mounted a hypertrophic response that was augmented in KO mice. The S100B-overexpressing TG group did not develop hypertrophy but demonstrated increased apoptosis. The postinfarct end-diastolic pressure was lower in KO mice than in WT mice, in accordance with other structural, hemodynamic, and functional parameters, which suggests that abrogation of S100B expression augmented hypertrophy, decreased apoptosis, and was beneficial to preservation of cardiac function within this time frame. Conclusions— S100B regulates the hypertrophic response and remodeling in the early postinfarct period and represents a potential novel therapeutic target.

Heart failure is an important cause of morbidity and mortality. Clinical trials over the past 2 decades have revolutionized the care of patients with systolic heart failure, and substantial data support the use of angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin-receptor blockers, and aldosterone blockers in the management of this serious condition. This article reviews the evidence on the pharmacologic treatment of heart failure, with a focus on recent clinical trials.

Despite the potential usefulness of administrative databases for evaluating outcomes, coding of heart failure and associated comorbidities have not been definitively compared with clinical data.To compare the predictive value of heart failure diagnoses and secondary conditions identified in a large administrative database with chart-based records.The authors studied 1808 patient records sampled from 14 acute care hospitals and compared clinically recorded data with administrative records from the Canadian Institute for Health Information. The impact of comorbidity coding in the administrative data set according to the Charlson classification was examined in models of 30-day mortality.The positive predictive value (PPV) of a primary diagnosis ICD-9 428 was 94.3% using the Framingham criteria and 88.6% using criteria previously validated with pulmonary capillary wedge pressure. There was reduced prevalence of secondary comorbid conditions in administrative data in comparison with clinical chart data. The specificities and PPV/negative predictive values of administratively identified index comorbidities were high. The sensitivities of index comorbidities were low, but were enhanced by examination of hospitalizations within 1 year prior to the index heart failure admission. Using information from prior hospitalizations modestly enhanced 30-day mortality model performance; however, the odds ratio point estimates of the index and enhanced administrative data sets were consistent with the clinical model.The ICD-9 428 primary diagnosis is highly predictive of heart failure using clinical criteria. Examination of hospitalization data up to 1 year prior to the index admission improves comorbidity detection and may provide enhancements to future studies of heart failure mortality.

The Canadian Hypertension Education Program (CHEP) has alerted Canadian clinicians to the importance of treating hypertension, and they have responded by improving the awareness, treatment, and control of hypertension. A significant fraction of patients with hypertension still have not achieved blood pressure control, particularly younger men, who are often unaware and therefore untreated, and older women, who are often treated but uncontrolled. The article by McAlister in this issue demonstrates the importance of hypertension as a marker of treatable cardiovascular risk. The data are reassuring on one hand, demonstrating relatively high rates of blood pressure control in both Canada and the United States. On the other hand, the study shows that the vast majority of hypertensive patients have a high calculated Framingham global cardiovascular risk score. McAlister’s team was able to link up institutional data sets in both Canada and in the United States. Data were extracted from the 2007-2009 cycle of the Canadian Health Measures Survey or the 2005-2008 US National Health and Nutrition Examination Survey. These surveys randomly sampled people living in the community and included face-to-face questionnaires to obtain a medical history and a list of current medications. They also included physical measures such as body mass index, blood pressure, and laboratory samples for blood and urine in a subgroup of participants. Having laboratory values and medication reviews available permitted more accurate case definitions for disease states than can be obtained with self-reports alone. As an example, the presence of chronic kidney disease had a self-reported sensitivity of only 7%, compared with diabetes at 64% and dyslipidemia at 69%.

TNF-alpha has been shown to be involved in cardiac dysfunction during ischemia/reperfusion injury; however, no information regarding the status of TNF-alpha production in myocardial injury due to intracellular Ca2+-overload is available in the literature. The intracellular Ca2+-overload was induced in the isolated rat hearts subjected to 5 min Ca2+-depletion and 30 min Ca2+-repletion (Ca2+-paradox). The Ca2+-paradox hearts exhibited a dramatic depression in left ventricular developed pressure, a marked elevation in left ventricular end diastolic pressure, and more than a 4-fold increase in TNF-alpha content. The ratio of cytosolic to homogenate nuclear factor-kappaB (NFkappaB) was decreased whereas the ratio of phospho-NFkappaB to total NFkappaB was increased in the Ca2+-paradox hearts. All these changes due to Ca2+-paradox were significantly attenuated upon treating the hearts with 100 microM pentoxifylline. These results suggest that activation of NFkappaB and increased production of TNF-alpha may play an important role in cardiac injury due to intracellular Ca2+-overload.

Background— We investigated the potential contributions of tumor necrosis factor-α (TNF-α) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF −/− ) mice compared with C57/BL wild-type (WT) mice. Methods and Results— Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (n=120) of WT mice died of cardiac rupture, in contrast to 2.5% (n=80) of TNF −/− mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF −/− mice on day 3; (3) matrix metalloproteinase-9 and -2 activity in the infarcted myocardium was significantly higher in WT than in TNF −/− mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and ±dP/dt max (68.3%/65.3%) in WT mice but a less significant decrease in ±dP/dt max (25.8%/28.8%) in TNF −/− mice; (5) cardiac collagen volume fraction was lower in WT than in TNF −/− mice on days 3 and 7 but higher on day 28 compared with TNF −/− mice; and (6) a reduction in myocyte apoptosis in TNF −/− mice occurred on day 28 compared with WT mice. Conclusions— Elevated local TNF-α in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.

Background— It is not known whether subspecialty care by cardiologists improves outcomes in heart failure patients from the community over care by other physicians. Methods and Results— Using administrative data, we monitored 38 702 consecutive patients with first-time hospitalization for heart failure in Ontario, Canada, between April 1994 and March 1996 and examined differences in processes of care and clinical outcomes between patients attended by physicians of different disciplines. We found that patients attended by cardiologists had lower 1-year risk-adjusted mortality than those attended by general internists, family practitioners, and other physicians (28.5% versus 31.7%, 34.9%, and 35.9%, respectively; all pairwise comparisons, P P P P =0.39, respectively). Multivariable hierarchical modeling demonstrated a significant physician-level effect for both outcomes in favor of the cardiologists, particularly against non-general internists. Cardiologist care was associated with higher adjusted rates of invasive interventions and postdischarge prescriptions of heart failure medications. Conclusions— In this population-based cohort, heart failure patients attended by cardiologists in hospital had lower risk of death as well as the composite risk of death or readmission than patients attended by noncardiologists. These data raise the need to identify specialty-driven differences in processes of care for heart failure patients, which may explain the observed disparity in clinical outcomes that presently favor cardiologist care.

Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.

Quality indicators are measurement tools for assessing the structure, processes and outcomes of care. Although quality indicators have been developed in other countries, Canadian cardiovascular disease indicators do not exist.To develop quality indicators for measuring and improving congestive heart failure (CHF) care in Canada.An 11-member multidisciplinary national expert panel was selected from nominees from national medical organizations. Potential quality indicators were identified by a detailed search of published guidelines, randomized trials and outcomes studies. A two-step modified Delphi process was employed with an initial screening round of indicator ratings, followed by a national quality indicator panel meeting, where definitions of the indicators were developed using consensus methods. Indicators were designed to be measurable, using retrospective chart review and linking existing administrative databases.The case definition criterion was developed based on a discharge diagnosis of CHF (International Classification of Diseases, 9th revision [ICD-9] code 428.x), with diagnostic confirmation using clinical criteria. In total, 29 indicators and five test indicators were recommended. Process indicators included prescription for angiotensin-converting enzyme inhibitors, beta-blockers or warfarin (for atrial fibrillation) at hospital discharge. Nonpharmacological in hospital process indicators included evaluation of left ventricular function, weight measurement and selected patient education counselling instructions. Process indicators in the ambulatory setting included prescription and adherence to drug therapies and physician follow-up. Outcome indicators included mortality, readmissions and emergency visits.A set of Canadian quality indicators for CHF care encompassing organizational attributes, pharmacotherapy, investigations, counselling, continuity of care and disease outcomes has been developed. These quality indicators will serve as a foundation for future studies evaluating the quality of CHF care in Canada.

Mr S. is a 46-year-old East-Indian male with typical manifestations of the cardiovascular dysmetabolic syndrome of insulin resistance (type II diabetes, obesity, dyslipidemia, hypertension, and elevated levels of high-sensitivity C-reactive protein). His medications include ramipril, simvastatin, enteric-coated aspirin, metformin, and glyburide. He has no symptoms of cardiac ischemia or congestive heart failure and has preserved left ventricular function. Over the past few months his glycemic control has been inadequate, and a decision to initiate an insulin sensitizer (glitazone) is made. Treatment is initiated with rosiglitazone 4 mg twice daily, with marked improvement in glycemic control and other components of the cardiovascular dysmetabolic syndrome. Approximately 6 months after initiation of therapy, your junior resident receives a phone call from Mr S, who is extremely anxious and distraught about the possibility of developing heart failure on glitazone therapy. The resident and the patient request your expert opinion about the effects of glitazones on cardiac function and associated hemodynamics. Insulin resistance has been increasingly recognized as a central metabolic disturbance predisposing a patient to hypertension, hyperlipidemia, premature atherosclerosis, left ventricular hypertrophy, and endothelial dysfunction.1 In addition to being a powerful risk marker for the development of cardiovascular disease, insulin resistance is also closely related to cardiac dysfunction and heart failure.2 Thiazolidinediones (TZD; glitazones) are peroxisome proliferator-activated receptor (PPAR) agonists that specifically augment insulin sensitivity and counter insulin resistance in patients with the cardiovascular dysmetabolic syndrome. Currently, there are 2 commercially available glitazones, rosiglitazone and pioglitazone. Troglitazone was withdrawn from the market because of hepatic side effects. The PPAR family is composed of 3 subtypes. TZDs bind with high affinity to the PPARγ isoform. The PPARγ isoform is found in the heart,3–6 endothelium, vascular smooth muscle (including atherosclerotic lesions and neointima formed after angioplasty), liver, skeletal muscle, monocytes/macrophages, and many other …

Most patients with homozygous β-thalassemia require red-cell transfusions to survive beyond the first decade of life. Although this intervention clearly prolongs survival,1 it also results in the accumulation of iron in tissue, which is itself fatal without iron-chelating therapy2. Before the introduction of deferoxamine, iron-induced cardiac dysfunction was a predictable outcome in thalassemia,3 and it is still the leading cause of death, followed in incidence by hepatic disease1. Despite the successes with deferoxamine,4–7 many patients still have serious complications, because of either advanced age at the start of therapy or erratic compliance8–14. To date, the . . .

Group B coxsackieviral (CVB) infection commonly causes viral myocarditis. Mice are protected from CVB3 myocarditis by gene-targeted knockout of p56(Lck)(Lck), the Src family kinase (Src) essential for T cell activation. Extracellular signal-regulated kinase 1 and 2 (ERK-1/2) can influence cell function downstream of Lck. Using T cell lines and neonatal cardiac myocytes we investigated the role of ERK-1/2 in CVB3 infection. In Jurkat T cells ERK-1/2 is rapidly activated by CVB3; but, this response is absent in Lck-negative JCaM T cells. Inhibition of ERK-1/2 with UO126 reduced CVB3 titers in Jurkat cells, but not in JCaM cells. In cardiac myocytes CVB3 activation of ERK-1/2 is blocked by the Src inhibitor PP2. In addition, viral production in myocytes is decreased by Src or ERK-1/2 inhibition. In vitro, in both immune and myocardial cells, ERK-1/2 is activated by CVB3 downstream of Lck and other Src's and is necessary for efficient CVB3 replication. In vivo, following CVB3 infection, ERK-1/2 activation is evident in the myocardium. ERK-1/2 activation is intense in the hearts of myocarditis-susceptible A/J mice. In contrast, significantly less ERK-1/2 activation is found in the hearts of myocarditis-resistant C57BL/6 mice. Therefore, the ERK-1/2 response to CVB3 infection may contribute to differential host susceptibility to viral myocarditis.

Background — Previous studies suggested a high incidence of congestive heart failure in patients with single and/or systemic right ventricles. The corresponding risk in an adult population is unknown. Methods and Results — A cohort of 188 consecutive adult patients with single or systemic right ventricles was prospectively assessed with gated radionuclide angiography (n=135) or 2D echocardiography (n=188) and followed up clinically. Clinical assessment showed 82.4% of the patients were in New York Heart Association class I or II, 13.3% were in class III, and 4.3% were in class IV. Heart failure occurred in 22.2% of patients with transposition of the great arteries and a Mustard procedure, 32.3% of patients with congenitally corrected transposition of the great arteries, and 40% of Fontan-palliated patients. Symptomatic patients had significantly lower anaerobic thresholds (10.3±2.8 versus 13.2±4.8 mL · kg −1 · min −1 , P =0.006) and peak · V o 2 (15.2±4.8 versus 20.3±6.8 mL · kg −1 · min −1 , P P =0.00001). Mortality was 47.1% among symptomatic patients and 5% among asymptomatic patients at 15.7 years of postoperative follow-up. Seven of 12 patients with potentially correctable surgical lesions died or persisted in heart failure despite surgery. Best predictors for mortality were New York Heart Association class, systemic ejection fraction, and age at operation. Conclusions — Patients with single or systemic right ventricles have significant risk for heart failure accompanied by high mortality. This study suggests the importance of identifying this group of patients who are at risk for heart failure and considering strategies to preserve ventricular function.

Congestive heart failure (CHF) is a serious medical condition frequently associated with sleep-related breathing disorders, which remain underdiagnosed and undertreated. Recent studies have provided important insight into the pathophysiology of sleep apnea syndrome in patients with CHF, with potential therapeutic implications. In addition to abolition of sleep apnea, continuous positive airway pressure (CPAP) treatment can improve cardiac function and relieve symptoms of CHF. Postulated mechanisms include beneficial hemodynamic effects on ventricular remodeling, unloading of fatigued respiratory muscles, and neurohormonal modulation. Although medium-term studies using CPAP to treat sleep-related breathing disorders associated with CHF have been encouraging, more definitive data from ongoing large clinical trials are necessary to clarify its therapeutic role.

Myocarditis is a poorly understood disease because it progresses through stages with distinctly different mechanisms and manifestations. The objective of this article is to better define myocarditis for both clinicians and clinical scientists by setting it in the framework of 3 phases of disease. In phase 1, the viral stage, we review recent discoveries about the way viruses gain access to target tissue and how they trigger immune responses. In the second, autoimmune phase of disease, we examine the roles of autoreactive T cells, cytokines, and cross-reacting antibodies and reconsider the relevance of recent therapy trials. In the third phase of the disease, dilated cardiomyopathy, we consider the remodeling processes. We then offer current recommendations for diagnosis and therapy and conclude with a look to the future. Myocarditis is a continuum of 3 distinct disease processes, one evolving into the other with transitional periods of indistinctness. For each of the 3 processes, pathogenesis, diagnosis, and treatment differ considerably. Without precise knowledge of the point to which an individual patient’s myocarditis has evolved in this continuum, the clinician can only use diagnostic tools and therapeutic interventions haphazardly. It is likely that the majority of cases of myocarditis, except in countries in which Chagas’ disease or diphtheria is common, result from viral infection, which may progress to an autoimmune phase after resolution or reduction of the initial infection, and then finally to progressive dilatation after resolution or reduction of the autoimmune injury (Figure 1). A viral cause can only be proved by direct molecular or indirect methods. Appropriate treatment at the viral stage is eradication of virus and amelioration of viral injury. The autoimmune phase can be diagnosed by endomyocardial biopsy, supplemented by serological markers of immune activation. Immune suppression is probably the most appropriate therapy in this stage, unless significant viral …

Study objectives: To determine the effects of hyperoxia on left ventricular (LV) function in humans with and without congestive heart failure (CHF). Design: An acute physiologic study of the effect of hyperoxia on right-heart hemodynamics, LV contractility (peak positive rate of rise of LV pressure [1dP/dt]), time constant of isovolumic left ventricular relaxation (t), and LV filling pressures. Setting: Bayer Cardiovascular Clinical Research Laboratory at the Mount Sinai Hospital, Toronto, Ontario. Patients: Sixteen patients with stable CHF and 12 subjects with normal LV function received the hyperoxia intervention. Interventions: Patients received 21% O2 by a nonrebreather mask, followed by 100% O2 for 20 min, and 21% O2 for a 10-min recovery period. Results: In response to hyperoxia, there was a 22 6 6% increase in LV end-diastolic pressure (LVEDP) in the CHF group and a similar 29 6 14% increase in LVEDP in the normal LV function group (p < 0.05 for both; mean 6 SEM). Hyperoxia was also associated with a prolongation in t of 10 6 2% in the CHF group (p < 0.05) and 8 6 2% in the normal LV function group (p < 0.05). No changes in 1dP/dt were observed in either group. Conclusions: Hyperoxia was associated with impairment of cardiac relaxation and increased LV filling pressures in patients with and without CHF. These observations indicate that caution should be used in the administration of high inspired O2 fractions to normoxic patients, especially in the setting of CHF. (CHEST 2001; 120:467‐ 473)

A new regimen of 24-hr ambulatory continuous intravenous infusion of deferoxamine (CIV DFO) through central venous ports was instituted in nine patients aged (mean +/- SD) 22.4 +/- 5.8 years over a period of 15.7 +/- 7.3 months. Central venous infusion sites were changed weekly in the clinic, eliminating the necessity for reconstitution of DFO and needle insertion at home. Because CIV DFO could be interrupted only by medical personnel, patient compliance was documented accurately; patients administered 93.0% +/- 3.2% of CIV DFO prescribed. Mean urinary iron excretion on CIV DFO (66.8 +/- 50.4 mg/24 hr) was significantly greater than that quantitated during 12-hr equivalent-dose subcutaneous DFO infusions (23.4 +/- 18.3 mg/24 hr; P less than 0.025). Mean serum ferritin declined by 71% over the treatment period (P less than 0.005). This regimen confers the advantages of uninterrupted exposure to DFO, is associated with excellent patient compliance, and should be considered in any patient with severe iron overload and erratic compliance with DFO.

OBJECTIVESThe purpose of this study is to evaluate right ventricular (RV) volume and function after pulmonary valve replacement (PVR) and to address the issue of optimal surgical timing in these patients.BACKGROUNDChronic pulmonary regurgitation (PR) following repair of tetralogy of Fallot (TOF) leads to RV dilation and an increased incidence of sudden cardiac death in adult patients.METHODSWe studied 25 consecutive adult patients who underwent PVR for significant PR late after repair of TOF. Radionuclide angiography was performed in all at a mean of 8.2 months (± 8 months) before PVR and repeated at a mean of 28.0 months (± 22.8 months) after the operation. Right ventricular (RV) end-systolic volume (RVESV), RV end-diastolic volume (RVEDV) and RV ejection fraction (RVEF) were measured.RESULTSMean RVEDV, RVESV and RVEF remained unchanged after PVR (227.1 ml versus 214.9 ml, p = 0.74; 157.4 ml versus 155.4 ml, p = 0.94; 35.6% versus 34.7%, p = 0.78, respectively). Of the 10 patients with RVEF ≥ 0.40 before PVR, 5 patients (50%) maintained a RVEF ≥ 0.40 following PVR, whereas only 2 out of 15 patients (13%) with pre-operative values

The effects of continuous positive airway pressure (CPAP) on left (LV) and right ventricular (RV) volumes in patients with congestive heart failure (CHF) have not been studied. We hypothesized that CPAP would cause greater reductions in cardiac volumes in CHF patients with idiopathic dilated cardiomyopathy (IDC) than in those with ischemic cardiomyopathy (IsC), because their ventricles are more compliant. The effects of a 30-min CPAP application at 10 cm H(2)O on RV and LV end-diastolic (EDV) and end-systolic volumes (ESV), determined by radionuclide angiography, were therefore tested in 22 patients with CHF due to IsC (n = 13) or IDC (n = 9). CPAP-induced reductions in LVEDV, LVESV, RVEDV, and RVESV were significantly greater (p0.05) in the IDC than in the IsC group. Whereas in the IsC group CPAP caused no significant changes in LV or RV volumes, in the IDC group it induced significant reductions in RVEDV (527 +/- 77 ml to 354 +/- 50 ml, p = 0.03) and RVESV (400 +/- 78 ml to 272 +/- 54 ml, p = 0.04) that were greater than any reductions in LVEDV and LVESV. We conclude that CPAP causes greater short-term reductions in RV and LV volumes in CHF patients with IDC than in those with IsC, and that among patients with IDC, CPAP causes greater reductions in RV than in LV volumes.

Objectives: To determine the relationship between the total chronic dose of iron administered, ex-vivo cardiac function and the concentrations of cytotoxic aldehydes in heart tissue of a murine model. Methods: In the first experiment, 34 male B6D2F1 mice were randomized to receive intraperitoneal injections of 5, 10 or 20 mg of iron dextran for three weeks, or a placebo control. The mice were subsequently randomized to undergo ex-vivo assessment of cardiac function. In the second experiment, free radical generation, quantified by the presence of 20 separate cytotoxic aldehydes, was assessed in heart tissue of 40 mice that were randomized to receive chronic treatment with various concentrations of iron dextran (100 mg to 300 mg total chronic dose administered), placebo treatment with saline, or no treatment at all (baseline). Results: Iron-loaded groups displayed dose-dependent depressions of heart rate, systolic pressure, developed pressure, coronary pressure, −d P /d t and +d P /d t , and increases in diastolic pressure. Monotonic dose-dependent increases in total heart aldehydes were observed in the iron-treated groups ( r =0.97, p

Acute iron poisoning and chronic iron overload are well-known causes of myocardial failure. Although the exact mechanism is not known, excess iron-catalyzed free radical generation is conjectured to play a role in damaging the myocardium and altering cardiac function. We report here on the effects of acute and chronic iron-loading on the total iron concentration, glutathione peroxidase activity, and cytotoxic aldehyde production in the heart of a murine model (n = 35). Light microscopic examination for the presence of ferrous and ferric iron was undertaken following histochemical staining for these species. In addition, examination of representative samples by transmission electron microscopy was performed. Our findings show that iron-loading can result in significant increases in total iron concentrations, alterations to glutathione peroxidase activity, and increases in cytoxic aldehyde concentrations in the hearts of mice. Furthermore, we observe that iron-loading can significantly alter and damage various cellular constituents (e.g., mitochondria, lysosomes, sarcoplasmic reticulum) and this may have bearing on the mechanism of iron-induced heart failure.

The full length sequence for the human pathogen coxsackievirus B6 (CVB6, Schmitt strain) has been determined. We used long RT-PCR to generate full length DNA amplicon of CVB6, and then directly sequenced the amplicons. One-step cloning of the full length amplicon enabled us to obtain an infectious clone of CVB6. RNA generated from CVB6 amplicon DNA or CVB6 clones, by transcription with T7 RNA polymerase, was demonstrated to be infectious upon transfection into HeLa cells in vitro. The CVB6 genome is characteristic of enteroviruses, with a 5′-non-translated region (743 nucleotides) followed by an open reading frame (encoding a 2184 amino acid polyprotein) and a 3′-non-translated region (100 nucleotides) and polyadenylated tail. The predicted amino acid sequence of CVB6 clustered with the other CVB serotypes and swine vesicular disease virus (SVDV).

Abstract —Heart failure is the leading cause of mortality in patients with transfusional iron (Fe) overload in which myocardial iron uptake ensues via a transferrin-independent process. We examined the ability of L-type Ca 2+ channel modifiers to alter Fe 2+ uptake by isolated rat hearts and ventricular myocytes. Perfusion of rat hearts with 100 nmol/L 59 Fe 2+ and 5 mmol/L ascorbate resulted in specific 59 Fe 2+ uptake of 20.4±1.9 ng of Fe per gram dry wt. Abolishing myocardial electrical excitability with 20 mmol/L KCl reduced specific 59 Fe 2+ uptake by 60±7% ( P 2+ uptake depends on membrane voltage. Accordingly, 59 Fe 2+ uptake was inhibited by 10 μmol/L nifedipine (45±12%, P 2+ (86±3%; P P P 59 Fe 3+ ) was significantly lower (1.4±0.3 ng Fe per gram dry wt; P 2+ uptake into heart occurs via the L-type Ca 2+ channel in myocytes. To investigate this further, the effects of Fe 2+ on cardiac myocyte L-type Ca 2+ currents were measured. In the absence of Ca 2+ , noninactivating nitrendipine-sensitive Fe 2+ currents were recorded with 15 mmol/L [Fe 2+ ] o . Low concentrations of Fe 2+ enhanced Ca 2+ current amplitude and slowed inactivation rates, which was consistent with Fe 2+ entry into the cell, whereas higher Fe 2+ levels caused dose-dependent decreases in peak current. Fe 3+ had no effect on current amplitude or decay. Combined, our data suggest that myocardial Fe 2+ uptake occurs via L-type Ca 2+ channels and that blockade of these channels might be useful in the treatment of patients with excessive serum iron levels.

PURPOSE: Training adaptations in patients with coronary artery disease (CAD) have been reported previously, but little is known about central and peripheral adaptations in those recovering from coronary artery bypass graft surgery (CABG). The purpose of this study was to examine the effects of 12 weeks of endurance exercise training on exercise performance and left ventricular and peripheral vascular reserve in a group of uncomplicated CABG patients. METHODS: Thirty-one patients were recruited and began training 8 to 10 weeks after uncomplicated CABG. Patients underwent progressive exercise training consisting of walking and jogging, at 75% to 80% maximal oxygen intake (VO2max). Measures of left ventricular function included ejection fraction (EF), ventricular volumes, and the pressure volume ratio, an index of contractility. Peak ischemic exercise calf blood flow and vascular conductance was determined using strain-gauge plethysmography. Maximal oxygen intake and submaximal blood lactate concentration also was determined. RESULTS: A significant improvement in VO2max (1497 +/- 60 mL/min versus 1691 +/- 71 mL/min) was observed after training. This change was accompanied by an increase in the EF during submaximal exercise (60 +/- 3% versus 63 +/- 2% at 40% VO2max; 61 +/- 3% versus 64 +/- 3% at 70% VO2max) (P < 0.05), and the change in EF from rest to exercise (delta EF). No changes were observed for ventricular volumes during exercise, although there was a trend for a higher stroke volume at 70% VO2max. A significant increase (18%) was observed for peak ischemic exercise calf blood flow and vascular conductance. In addition, submaximal blood lactate concentration was lower after training. CONCLUSIONS: These data indicate that exercise training for 12 weeks in patients recovering from CABG can elicit significant improvements in functional capacity that, for the most part, are secondary to peripheral adaptations, with limited support for improvement in left ventricular function.

Breda virus (BRV), a member of the genus torovirus, is an established etiological agent of diarrhea of cattle, which is found as two separate serotypes, BRV-1 and BRV-2. In this study, a 7.5 kb fragment of the BRV-1 genome that bracketed the genes for the structural proteins of BRV was amplified by long RT-PCR and the amplicon purified and sequenced directly. Sequence analysis revealed the presence of four open reading frames (ORF) corresponding to the peplomer (S), envelope (M), and nucleocapsid (N) genes, and an ORF for a novel 1.2 kb gene located between the M and N genes. This new gene was identical in nucleotide sequence to the hemagglutinin-esterase (HE) gene of BRV-2. With the exception of this new ORF, BRV-1 manifests 80% nucleotide sequence identity with the torovirus prototype, Berne virus (BEV) in the 7.5 kb region from the 3′ end of the genome that contains the genes for the structural proteins. A 504 base segment containing the ORF for the BRV-1 N gene was amplified by RT-PCR, and cloned into an Escherichia coli expression system. The resulting protein was purified by SDS-PAGE and used to immunize guinea pigs. Hyperimmune serum was reactive with bovine torovirus (BTV) and human torovirus (HTV) antigens. By immunoelectron microscopy, it was shown to aggregate broken but not intact torovirus particles from BTV-positive fecal specimens. By immunoblot, the hyperimmune serum reacted specifically with the 20 kD N proteins of both BTV and HTV, as well as with the expressed N protein. BRV-1 and BRV-2 immune sera from gnotobiotic calves, but not human convalescent sera from HTV-infected patients, reacted with the expressed N protein by immunoblot. These findings were applied to the design of a dot blot assay that could specifically detect BTV and HTV from fecal specimens.

Objectives. We sought to assess the clinical outcome, functional status and complications of adult patients with congenitally corrected transposition of the great arteries. Background. Congenitally corrected transposition is a rare form of congenital heart disease, although survival into adult life may be expected. Little information is available on the long-term prognosis of these patients once they have reached adulthood. This study focuses exclusively on patients >18 years old followed up at a single tertiary referral center. Methods. The charts of all patients with a diagnosis of congenitally corrected transposition of the great arteries from the Toronto Congenital Cardiac Centre for Adults since 1985 were reviewed. Data were available for 52 patients, 26 of whom had undergone radionuclide angiography. Mortality, clinical and functional status, surgical procedures and complications were reviewed. Results. Thirteen patients (25%) died; age at death was 38.5 ± 12.5 years (mean ± SD). The current age of survivors is 32.7 years (range 18.2 to 54.3). Of the survivors, 17 had palliative procedures, and 25 had definitive repair, 11 of whom required reoperation. Left ventricle to pulmonary artery conduit replacement was necessary in seven patients. Eighteen patients have permanent pacemakers, nine of whom developed complete heart block perioperatively. Nine patients developed progressive atrioventricular (AV) block unrelated to operation. Supraventricular arrhythmias occurred in 15 patients. Progressive systemic AV valve regurgitation developed in 10 patients and endocarditis in 6. Conclusions. Congenitally corrected transposition in the adult patient is not a benign condition. Late complications are common and warrant careful, long-term follow-up.

Patients with congestive heart failure (CHF) suffer from respiratory muscle weakness which may contribute to dyspnea. Nasal continuous positive airway pressure (NCPAP) can improve left ventricular ejection fraction (LVEF) and reduce dyspnea in patients with CHF and Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) but its effects on respiratory muscle strength are not known. We therefore studied the effects of NCPAP on maximal inspiratory and expiratory pressures (MIP and MEP, respectively), LVEF, dyspnea, and fatigue in patients with chronic CHF and CSR-CSA over 3 mo. Eight patients were randomized to control and nine to nightly NCPAP. There were no significant changes in any of these factors in the control group during the study. In contrast, among the NCPAP group, MIP increased from 79.3 +/- 8.1 to 90.7 +/- 10.4 cm H2O (mean +/- SEM; p < 0.02), LVEF increased from 24.0 +/- 4.0 to 32.6 +/- 6.6% (p < 0.02) and symptoms of dyspnea and fatigue were alleviated. However, MEP did not change. In addition, the number of apneas and hypopneas decreased from 49 +/- 11 to 17 +/- 7 per hour of sleep (p < 0.001) and mean low Sao2 during sleep increased from 87.9 +/- 1.0 to 93.0 +/- 1.0% (p < 0.01). Our data indicate that nightly application of NCPAP in patients with CHF and CSR-CSA improves inspiratory muscle strength and LVEF, and relieves dyspnea and fatigue.

ContextA predictive model of mortality in heart failure may be useful for clinicians to improve communication with and care of hospitalized patients.ObjectivesTo identify predictors of mortality and to develop and to validate a model using information available at hospital presentation.Design, Setting, and ParticipantsRetrospective study of 4031 community-based patients presenting with heart failure at multiple hospitals in Ontario, Canada (2624 patients in the derivation cohort from 1999-2001 and 1407 patients in the validation cohort from 1997-1999), who had been identitifed as part of the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study.Main Outcome MeasuresAll-cause 30-day and 1-year mortality.ResultsThe mortality rates for the derivation cohort and validation cohort, respectively, were 8.9% and 8.2% in hospital, 10.7% and 10.4% at 30 days, and 32.9% and 30.5% at 1 year. Multivariable predictors of mortality at both 30 days and 1 year included older age, lower systolic blood pressure, higher respiratory rate, higher urea nitrogen level (all P150) had a mortality rate of 59.0% at 30 days and 78.8% at 1 year. Patients with higher 1-year risk scores had reduced survival at all times up to 1 year (log-rank, P

We hypothesized that (1) patients with congestive heart failure (CHF) and Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) would have greater nocturnal urinary and daytime plasma norepinephrine concentrations (UNE and PNE, respectively) than those without CSR-CSA because of apneas, hypoxia and arousals from sleep and (2) attenuation of CSR-CSA by nasal continuous positive airway pressure (NCPAP) would reduce UNE and PNE concentrations. Eighteen patients with and 17 without CSR-CSA (Non-CSR-CSA group) were studied. Left ventricular ejection fraction was similar in the two groups, but overnight UNE and awake PNE concentrations were greater in the CSR-CSA group (30.2 +/- 2.5 nmol/mmol creatinine and 3.32 +/- 0.29 nmol/L) than in the Non-CSR-CSA group (15.8 +/- 2.1 nmol/mmol creatinine, p < 0.005, and 2.06 +/- 0.56 nmol/L, p < 0.05, respectively). Patients with CSR-CSA were randomized to a control group or to nightly NCPAP for 1 mo. CSR-CSA was attenuated in the NCPAP but not in the control group. The NCPAP group experienced greater reductions in UNE and PNE concentrations (-12.5 +/- 3.3 nmol/mmol creatinine and -0.74 +/- 0.40 nmol/L) than did the control group (-1.3 +/- 2.8 nmol/mmol creatinine, p < 0.025 and 1.16 +/- 0.66 nmol/L, p < 0.025, respectively). In conclusion, in patients with CHF, CSR-CSA is associated with elevated sympathoneural activity, which can be reduced by NCPAP.

Continued adverse remodeling of myocardium after infarction may lead to progressive ventricular dilation and heart failure. We tested the hypothesis that exercise training in a healed myocardial infarction-dysfunction rat model can favorably modify the adverse effects of ventricular remodeling including attenuation of abnormal myosin gene expression. Sprague-Dawley rats were subjected to either proximal LAD ligation or sham operation. At 5 wk after the operation, animals were randomly assigned to sedentary conditions or 6 wk of graduated swim training, creating four experimental groups: infarct sedentary (IS), infarct exercise (IE), sham sedentary (SS), and sham exercise (SE). At 11 wk all rats were sacrificed and analyzed. Compared to sedentary infarct controls, exercise training attenuated left ventricular (LV) dilation and allowed more hypertrophy of the non infarct wall. The exercise-trained hearts also showed a reduction in the estimated peak wall tension. Northern blot analysis showed an increase in beta-myosin heavy chain expression in the hearts of the sedentary infarction group soon after infarction when compared to sham controls. However, with exercise training, there was a significant attenuation of the beta-myosin heavy chain expression in the myocardium. Exercise training in a model of left ventricular dysfunction after healed myocardial infarction can improve the adverse remodeling process by attenuating ventricular dilation and reducing wall tension. The abnormal beta-myosin expression was also attenuated in the exercise trained group. This is evidence that abnormal gene expression following severe myocardial infarction dysfunction can be favorably modified by an intervention.