Efficacy of Blended Collaborative Care for Patients With Heart Failure and Comorbid Depression: A Randomized Clinical Trial.

Importance: Depression is often comorbid in patients with heart failure (HF) and is associated with worse clinical outcomes. However, depression generally goes unrecognized and untreated in this population. Objective: To determine whether a blended collaborative care program for treating both HF and depression can improve clinical outcomes more than collaborative care for HF only and physicians' usual care (UC). Design, Setting, and Participants: This 3-arm, single-blind, randomized effectiveness trial recruited 756 participants with HF with reduced left ventricular ejection fraction (<45%) from 8 university-based and community hospitals in southwestern Pennsylvania between March 2014 and October 2017 and observed them until November 2018. Participants included 629 who screened positive for depression during hospitalization and 2 weeks postdischarge and 127 randomly sampled participants without depression to facilitate further comparisons. Key analyses were performed November 2018 to March 2019. Interventions: Separate physician-supervised nurse teams provided either 12 months of collaborative care for HF and depression ("blended" care) or collaborative care for HF only (enhanced UC [eUC]). Main Outcomes and Measures: The primary outcome was mental health-related quality of life (mHRQOL) as measured by the Mental Component Summary of the 12-item Short Form Health Survey (MCS-12). Secondary outcomes included mood, physical function, HF pharmacotherapy use, rehospitalizations, and mortality. Results: Of the 756 participants (mean [SD] age, 64.0 [13.0] years; 425 [56%] male), those with depression reported worse mHRQOL, mood, and physical function but were otherwise similar to those without depression (eg, mean left ventricular ejection fraction, 28%). At 12 months, blended care participants reported a 4.47-point improvement on the MCS-12 vs UC (95% CI, 1.65 to 7.28; P = .002), but similar scores as the eUC arm (1.12; 95% CI, -1.15 to 3.40; P = .33). Blended care participants also reported better mood than UC participants (Patient-Reported Outcomes Measurement Information System-Depression effect size, 0.47; 95% CI, 0.28 to 0.67) and eUC participants (0.24; 95% CI, 0.07 to 0.41), but physical function, HF pharmacotherapy use, rehospitalizations, and mortality were similar by both baseline depression and randomization status. Conclusions and Relevance: In this randomized clinical trial of patients with HF and depression, telephone-delivered blended collaborative care produced modest improvements in mHRQOL, the primary outcome, on the MCS-12 vs UC but not eUC. Although blended care did not differentially affect rehospitalization and mortality, it improved mood better than eUC and UC and thus may enable organized health care systems to provide effective first-line depression care to medically complex patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02044211.

The Preimplantation Psychosocial Evaluation and Prediction of Clinical Outcomes During Mechanical Circulatory Support: What Information Is Most Prognostic?

BACKGROUND: Psychosocial evaluations are required for long-term mechanical circulatory support (MCS) candidates, no matter whether MCS will be destination therapy (DT) or a bridge to heart transplantation. Although guidelines specify psychosocial contraindications to MCS, there is no comprehensive examination of which psychosocial evaluation domains are most prognostic for clinical outcomes. We evaluated whether overall psychosocial risk, determined across all psychosocial domains, predicted outcomes, and which specific domains appeared responsible for any effects. METHODS: A single-site retrospective analysis was performed for adults receiving MCS between April 2004 and December 2017. Using an established rating system, we coded psychosocial evaluations to identify patients at low, moderate, or high overall risk. We similarly determined risk within each of 10 individual psychosocial domains. Multivariable analyses evaluated whether psychosocial risk predicted clinical decisions about MCS use (DT versus bridge), and postimplantation mortality, transplantation, rehospitalization, MCS pump exchange, and standardly defined adverse medical events (AEs). RESULTS: In 241 MCS recipients, greater overall psychosocial risk increased the likelihood of a DT decision (odds ratio, 1.76; P = 0.017); and postimplantation pump exchange and occurrence of AEs (hazard ratios [HRs] ≥ 1.25; P ≤ 0.042). The individual AEs most strongly predicted were cardiac arrhythmias and device malfunctions (HRs ≥ 1.39; P ≤ 0.032). The specific psychosocial domains predicting at least 1 study outcome were mental health problem severity, poorer medical adherence, and substance use (odds ratios and HRs ≥ 1.32; P ≤ 0.010). CONCLUSIONS: The psychosocial evaluation predicts not only clinical decisions about MCS use (DT versus bridge) but important postimplantation outcomes. Strategies to address psychosocial risk factors before or soon after implantation may help to reduce postimplantation clinical risks.

Remote monitoring for heart failure: Assessing the risks of readmission and mortality.

Study objective: Remote monitoring (RM) can help patients with heart failure (HF) remain free of hospitalization. Our objective was to implement a patient-centered RM program that ensured timely clinical response, which would be associated with reduced mortality. Design: This was a retrospective, observational, propensity-matched study. Setting: A large regional health system between 9/1/2016-1/31/2018. Participants: Patients admitted with acute HF exacerbation were matched on key variables. Up to two comparison patients were selected for each RM user. Interventions: We used an algorithmic approach to assess daily physiologic data, assess symptoms, provide patient education, encourage patient self-management, and triage medical problems. Main outcome measures: We assessed all-cause mortality using Kaplan-Meier and log rank analysis. We used Cox proportional hazards to compare risk of death. Results: Our cohort of 680 RM users and 1198 comparisons were similar across baseline characteristics except age (74.7 years versus 76.6 years, p < 0.001, respectively). Having one or more admissions in the preceding 120 days was more prevalent in the RM group (35.9% versus 29.8%, p = 0.013). The 30- and 90-day all-cause readmission rates were each higher among the RM users compared with the comparison patients (p = 0.013 and p < 0.001 for 30 and 90 days, respectively). Mortality was lower in the RM group at 30 and 90 days post-discharge (p < 0.001). Conclusions: RM that responds to biometric data and encourages patient self-management can be used in a large hospital system and is associated with decreased all-cause mortality. Our findings underscore RM technology as a method to improve HF care.

Left ventricular assist device implant and subsequent orthotopic heart transplant after chronic type B aortic dissection.

The criteria for being placed on the list of the International Society for Heart and Lung Transplantation for an orthotopic heart transplant mention nothing about patients with aortic dissection. Nor are there any guidelines pertaining to the patient with type B aortic dissection. Herein, we report the case of a patient with chronic type B aortic dissection for whom we successfully performed a left ventricular assist device implant followed by an orthotopic heart transplant.

Blended Collaborative Care to Treat Heart Failure and Comorbid Depression: Rationale and Study Design of the Hopeful Heart Trial.

OBJECTIVE: Despite numerous improvements in care, morbidity from heart failure (HF) has remained essentially unchanged in recent years. One potential reason is that depression, which is comorbid in approximately 40% of hospitalized HF patients and associated with adverse HF outcomes, often goes unrecognized and untreated. The Hopeful Heart Trial is the first study to evaluate whether a widely generalizable telephone-delivered collaborative care program for treating depression in HF patients improves clinical outcomes. METHODS: The Hopeful Heart Trial aimed to enroll 750 patients with reduced ejection fraction (HFrEF) (ejection fraction ≤ 45%) including the following: (A) 625 patients who screened positive for depression both during their hospitalization (Patient Health Questionnaire [PHQ-2]) and two weeks following discharge (PHQ-9 ≥ 10); and (B) 125 non-depressed control patients (PHQ-2(-)/PHQ-9 < 5). We randomized depressed patients to either their primary care physician's "usual care" (UC) or to one of two nurse-delivered 12-month collaborative care programs for (a) depression and HFrEF ("blended") or (b) HrEFF alone (enhanced UC). Our co-primary hypotheses will test whether "blended" care can improve mental health-related quality of life versus UC and versus enhanced UC, respectively, on the Mental Component Summary of the Short-Form 12 Health Survey. Secondary hypotheses will evaluate the effectiveness of our interventions on mood, functional status, hospital readmissions, deaths, provision of evidence-based care for HFrEF, and treatment costs. RESULTS: Not applicable. CONCLUSIONS: The Hopeful Heart Trial will determine whether "blended" collaborative care for depression and HFrEF is more effective at improving patient-relevant outcomes than collaborative care for HFrEF alone or doctors' UC for HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02044211.

Acute heart failure management in the USA and Japan: overview of practice patterns and review of evidence.

Globally, acute heart failure (AHF) remains an ongoing public health issue with its prevalence and mortality increasing in the east and the west. Effective treatment strategies to stabilize AHF are important to alleviate clinical symptoms and to improve clinical outcomes. However, despite the progress in the management of stable and chronic heart failure, no single agent has been proven to play a definitive role in the management of AHF. As a consequence, contemporary treatment strategies for patients with AHF vary greatly by region. This manuscript reviews the medical treatment options for AHF, with an emphasis on the differences between the treatment strategies in the USA and Japan. This information would provide a framework for clinicians to evaluate and manage patients with AHF and highlight the remaining questions to improve clinical outcomes.

Outcomes of Heart Failure Admissions Under Observation Versus Short Inpatient Stay.

BACKGROUND: Patients with heart failure (HF) are admitted either under observation (OBS) or inpatient stays; however, there is little data on whether this designation reflects the clinical status of a patient, with significant logistical and financial implications. We sought to compare the outcomes of patients with HF admitted OBS versus inpatient stay (≤2 days; INPT). METHODS AND RESULTS: From January 1, 2008 to September 30, 2015, our multisite health system saw 21 339 unique patients totaling 52 493 hospital admissions with a primary diagnosis of HF. Patients were excluded if they underwent cardiac surgery (n=611), heart transplantation (n=187), or left ventricular assist device insertion (n=198), or if they died during hospitalization (n=1839). Of the remaining 50 654 discharges, 2 groups were identified: INPT group and OBS group. Outcomes were HF readmission, all-cause readmission, and all-cause mortality within 1 year of discharge. Hazard ratios were computed using the Andersen-Gill method in the Cox proportional-hazards model. A total of 8709 admissions (17%) occurred in the INPT group and 2648 admissions (5%) occurred in the OBS group. HF readmission rate at 1 year was 55.3% in INPT versus 66.5% in OBS (hazard ratio, 0.75; 95% confidence interval, 0.71-0.80; P<0.01). All-cause readmission rate at 1 year was 70.7% in INPT versus 82.5% in OBS (hazard ratio, 0.74; 95% confidence interval, 0.70-0.78; P<0.01). All-cause mortality at 1 year occurred in 25.2% of INPT versus 24.2% of OBS (hazard ratio, 1.03; 95% confidence interval, 0.95-1.12; P=0.46). CONCLUSIONS: HF admissions designated INPTs were associated with lower readmission rates and equivalent mortality to those designated OBS.

Radiofrequency ablation of post-incisional atrial flutter and high-output heart failure in a patient with interrupted inferior vena cava and hereditary hemorrhagic telangiectasia.

A 61-year-old female with a history of secundum atrial septal defect repair and hereditary hemorrhagic telangiectasia presented with epistaxis. She was found to have atypical atrial flutter with 2:1 atrioventricular conduction. Radiofrequency ablation was planned, but inferior vena cava interruption precluded right atrial (RA) access. The RA was then accessed through both subclavian veins, and activation mapping revealed a dense atriotomy scar in the posterolateral inferior RA. Wavefront propagation proceeded caudally through an area of slow conduction confined by the atriotomy scar. Atypical atrial flutter terminated during a second radiofrequency application to an isthmus confined by 2 regions of dense scar. The arrhythmia did not recur, although the patient later experienced typical atrial flutter and atrial fibrillation. High-output heart failure due to systemic arteriovenous shunt was confirmed by cardiac catheterization and improved markedly with bevacizumab therapy.

Noninvasive assessment of acute dyspnea in the ED.

BACKGROUND: We compared the ability of noninvasive measurements of cardiac output (CO) and thoracic fluid content (TFC) and their change in response to orthostatic challenges to diagnose acute decompensate heart failure (ADHF) from non-ADHF causes of acute dyspnea in patients in the ED. METHODS: Forty-five patients > 44 years old presenting in the ED with dyspnea were studied. CO and TFC were monitored with a NICOM bioreactance device. CO and TFC were measured continuously while each patient was sitting, supine, and during a passive leg-raising maneuver (3 min each); the maximal values during each maneuver were reported. Orthostatic challenges were repeated 2 h into treatment. One patient was excluded because of intolerance to the supine position. Diagnoses obtained with the hemodynamic measurements were compared with ED diagnoses and with two expert physicians by chart review (used as gold standard diagnosis); both groups were blinded to CO and TFC values. Patient's treatment, ED disposition, hospital length of stay, and subjective dyspnea (Borg scale) were also recorded. RESULTS: Sixteen of 44 patients received a diagnosis of ADHF and 28 received a diagnosis of non-ADHF by the experts. Baseline TFC was higher in patients with ADHF (P = .001). Fifteen patients were treated for ADHF, and their Borg scale values decreased at 2 h (P < .05). TFC threshold of 78.8 had a receiver operator characteristic area under the curve of 0.81 (76% sensitivity, 71% specificity) for ADHF. Both ADHF and non-ADHF groups were similar in their increased CO from baseline to PLR and supine. Pre- and posttreatment measurements were similar. CONCLUSIONS: Baseline TFC can discriminate patients with ADHF from non-ADHF dyspnea in the ED.

Heart transplantation for adults with congenital heart disease: results in the modern era.

BACKGROUND: Heart transplantation in adults with congenital heart disease (CHD) has historically been associated with sub-optimal survival compared with other indications for transplantation. The purpose of this study was to evaluate survival outcomes after heart transplantation in a contemporary cohort of adults with CHD and to identify risk factors for mortality that may help guide recipient and donor selection. METHODS: We performed a retrospective analysis of our adult heart transplant database, from January 2001 to February 2011, identifying 19 patients who underwent transplantation for CHD. These patients were compared with a control group of 428 patients who underwent transplantation for indications other than CHD. Kaplan-Meier survival analysis and Cox regression modeling were performed. RESULTS: The mean age for the CHD group was 39.4 ± 13 years vs 54.7 ± 12 years (p < 0.001). There was no significant difference in survival (CHD vs control) at 30 days (89% vs 92%, p = 0.5567), 1 year (84% vs 86%, p = 0.6976) or 5 years (70% vs 72%, p = 0.8478). The only significant predictor of death in the CHD group was donor organ ischemic time >4 hours (HR 13.26, 95% CI 1.3 to 132.2, p = 0.028). There was no significant correlation with recipient age, history of failed Fontan surgery, pre-operative ventilator use, donor:recipient weight ratio <0.8, donor:recipient CMV mismatch, model for end-stage liver disease (MELD) score or percent reactive antibody >10%. CONCLUSIONS: In the modern era, with careful donor and recipient selection, adults with CHD have excellent early and mid-term survival after heart transplantation, rivaling that of recipients with other indications for transplantation.

The methionine 196 arginine polymorphism of the TNF receptor 2 gene (TNFRSF1B) is not associated with worse outcomes in heart failure.

Tumor necrosis factor α (TNFα) may contribute to the pathologic process of congestive heart failure (CHF). TNFα signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region. The 587G allele is associated with greater severity and/or prevalence of some inflammatory diseases, but its role in CHF in unknown. This study sought to test the hypothesis that the 587G allele is associated with a worse outcome or more severe phenotype in CHF. Peripheral blood DNA was isolated and genotyped from 379 heart failure patients enrolled in a genetic outcome study (GRACE); (44.7% ischemic, 70.4% male, 8.5% black race, age 55.6 ± 11.7 yr (SD), LVEF 24.5 ± 8.3%, NYHA 2.53 ± 0.64). Genotyping was performed by PCR-RFLP. Cardiac function was assessed from medical records at study entry. The distribution of genotypes in this population was 54% T/T, 38.4% G/T and 7.7% G/G. Mean LV ejection fraction (T/T 24.4 ± 8.2, T/G 25.0 ± 8.4, G/G 23.3 ± 8.6, n=352, p=ns) and LV end-diastolic dimensions (T/T 6.57 ± 0.93, T/G 6.53 ± 1.0, G/G 6.57 ± 0.78, n=211, p=ns) were comparable in all groups. Transplant-free survival (median 23 months (range 1-62 months) did not vary by genotype (p=0.95). A lack of effect (p=0.74) on transplant-free survival was also observed in a subset of patients with ischemic heart failure (n=169). The TNFRSF1B 587G allele is not associated with the severity of heart failure phenotype or clinical outcomes in patients with chronic CHF.

A micro-ribonucleic acid signature associated with recovery from assist device support in 2 groups of patients with severe heart failure.

OBJECTIVES: This study was conducted to test the hypothesis that cardiac micro-ribonucleic acid (miR) profiling in severe heart failure patients at the time of ventricular assist device (VAD) placement would differentiate those who remained VAD-dependent from those with subsequent left ventricular (LV) recovery. BACKGROUND: The relationship of myocardial miR expression to ventricular recovery is unknown. METHODS: We studied 28 patients with nonischemic cardiomyopathy requiring VAD support consisting of test and validation cohorts from 2 institutions: 14 with subsequent LV recovery and VAD removal and 14 clinically matched VAD-dependent patients. Apical core myocardium was studied for expression of 376 miRs by polymerase chain reaction (PCR) array and real-time-PCR methods. Samples from 7 nonfailing hearts were used in confirmatory studies. RESULTS: By PCR array, 10 miRs were differentially expressed between LV recovery and VAD-dependent patients in the test cohort. The real-time PCR confirmed lower expression in LV recovery patients for 4 miRs (15b, -1.5-fold; 23a, -2.2-fold; 26a, -1.4-fold; and 195, -1.8-fold; all p < 0.04 vs. VAD dependent). The validation cohort similarly showed lower miRs expression in LV recovery patients (23a, -1.8-fold; and 195, -1.5-fold; both p < 0.03). Furthermore, miR 23a and 195 expression in nonfailing hearts was similar to LV recovery patients (both p < 0.04 vs. VAD dependent). The LV recovery patients also had significantly smaller cardiomyocytes by quantitative histology in both cohorts. CONCLUSIONS: Lower cardiac expression of miRs 23a and 195 and smaller cardiomyocyte size at the time of VAD placement were associated with subsequent LV functional recovery. Differential expression of miRs at VAD placement may provide markers to assess recovery potential.

Tissue inhibitor of metalloproteinase-2 gene delivery ameliorates postinfarction cardiac remodeling.

HYPOTHESIS: Adenoviral-mediated (AdV-T2) overexpression of TIMP-2 would blunt ventricular remodeling and improve survival in a murine model of chronic ischemic injury. METHODS: Male mice (n = 124) aged 10-14 weeks underwent either (1) left coronary artery ligation to induce myocardial infarction (MI group, n = 36), (2) myocardial injection of 6 × 10¹° viral particles of AdV-T2 immediately post-MI (MI + T2 group, n = 30), (3) myocardial injection of 6 × 10¹° viral particles of a control adenovirus (MI + Ct, n = 38), or 4) received no intervention (controls, n = 20). On post-MI day 7, surviving mice (n = 79) underwent echocardiographic, immunohistochemical, and biochemical analysis. RESULTS: In infarcted animals, the MI + T2 group demonstrated improved survival (p < 0.02), better preservation of developed pressure and ventricular diameter (p < 0.04), and the lowest expression and activity of MMP-2 and MMP-9 (p < 0.04) compared with MI and MI + Ct groups. All infarcted hearts displayed significantly increased inflammatory cell infiltration (p < 0.04 vs. control, MI, or MI + T2), with infiltration highest in the MI + Ct group and lowest in the MI + T2 group (p < 0.04). CONCLUSIONS: Adenoviral mediated myocardial delivery of the TIMP-2 gene improves post-MI survival and limits adverse remodeling in a murine model of MI.

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.

AIMS: Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated. METHODS AND RESULTS: In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis. CONCLUSION: This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.

A PRKAG2 mutation causes biphasic changes in myocardial AMPK activity and does not protect against ischemia.

Dominant mutations in the gamma2 regulatory subunit of AMP-activated protein kinase (AMPK), encoded by the gene PRKAG2, cause glycogen storage cardiomyopathy. We sought to elucidate the effect of the Thr400Asn (T400N) human mutation in a transgenic mouse (TGT400N) on AMPK activity, and its ability to protect the heart against ischemia-reperfusion injury. TGT400N hearts had markedly vacuolated myocytes, excessive accumulation of glycogen, hypertrophy, and preexcitation. Early activation of myocardial AMPK, followed by depression, and then recovery to wild-type levels was observed. AMPK activity correlated inversely with glycogen content. Partial rescue of the phenotype was observed when TGT400N mice were crossbred with TGalpha2DN mice, which overexpress a dominant negative mutant of the AMPK alpha2 catalytic subunit. TGT400N hearts had greater infarct sizes and apoptosis when subjected to ischemia-reperfusion. Increased AMPK activity is responsible for glycogen storage cardiomyopathy. Despite high glycogen content, the TGT400N heart is not protected against ischemia-reperfusion injury.

Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling.

The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-alpha receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One hundred and ninety-four wild-type (WT) and TNFR1 gene-deleted (TNFR1KO) mice underwent left coronary artery ligation to induce myocardial infarction. On days 1, 3, 7, and 42, mice underwent transesophageal echocardiography. Hearts were weighed, and the left ventricle (LV) was assayed for matrix metalloproteinase (MMP)-2 and -9 activity and for tissue inhibitor of MMP (TIMP)-1 and -2 expression. Deletion of the TNFR1 gene substantially improved survival because no deaths were observed in TNFR1KO mice versus 56.4% and 18.2% in WT males and females, respectively (P < 0.002). At 42 days, LV remodeling, assessed by LV function (fractional area change of 31.9 +/- 7.9%, 32.2 +/- 7.7%, and 21.6 +/- 7.1% in TNFR1KO males, TNFR1KO females, and WT females, respectively, P < 0.04), and hypertrophy (heart weight-to-body weight ratios of 5.435 +/- 0.986, 5.485 +/- 0.677, and 6.726 +/- 0.704 mg/g, P < 0.04) were ameliorated in TNFR1KO mice. MMP-9 activity was highest at 3 days postinfarction and was highest in WT males (1.9 +/- 0.4 4, 3.6 +/- 0.24, 1.15 +/- 0.28, and 1.3 +/- 1.2 ng/100 microg protein, respectively, in TNFR1KO males, WT males, TNFR1KO females, and WT females, respectively, P < 0.002), whereas at 3 days TIMP-1 mRNA fold upregulation compared with type- and sex-matched controls was lowest in WT males (138.32 +/- 13.05, 46.74 +/- 5.43, 186.09 +/- 28.07, and 101.76 +/- 22.48, respectively, P < 0.002). MMP-2 and TIMP-2 increased similarly in all infarcted groups. These findings suggest that the benefits of TNFR1 ablation might be attributable at least in part to the attenuation of cytokine-mediated imbalances in MMP-TIMP activity.

Assessment of infarct size and myocardial function in mice using transesophageal echocardiography.

BACKGROUND: Because transthoracic echocardiography (TTE) has significant limitations in assessing changes consequent to myocardial infarction (MI) in mice, we studied two novel methods to characterize such infarcts. METHODS: Large MIs were produced by proximal left coronary artery ligation, and small MIs by distal left coronary artery ligation. Serum cardiac troponin I levels were measured 24 hours postoperatively. At 2 weeks, mice underwent transesophageal echocardiography (TEE) and TTE. Infarct sizes were determined histologically. RESULTS: Surviving mice were classified according to infarct size. TEE identified all histologically proven large infarcts, and 4 of 5 small infarcts. TTE identified 4 of 5 large infarcts, but only 1 of 5 small infarcts. TEE-derived fractional area change, but not TTE-estimated left ventricular fractional shortening, was significantly different among large, small, and sham infarcts. Cardiac troponin I showed excellent correlation with infarct size and mortality. CONCLUSIONS: Cardiac troponin I was found to predict infarct size and mortality, whereas TEE proved superior to TTE in determining infarct size and/or myocardial function in a murine MI model. These tools should provide more accurate assessments in preclinical studies of ischemic cardiomyopathy.

Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype.

Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of caveolin-3 expression is fundamental for normal muscle functions. Since caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of caveolin-3 on cardiac structure and function by characterizing caveolin-3 transgenic mice. Our results indicate that overexpression of caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of caveolin-3 in the heart. Taken together, these results indicate that overexpression of caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.