Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.

Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance.

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3(-/-)) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2',7'-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3(-/-) mice than in SD-fed WT mice. In contrast, HFD-fed NOS3(-/-) developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3(-/-) than in those from HFD-fed WT. N(ω)-nitro-L-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3(-/-) mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

Ventricular remodeling and function: insights using murine echocardiography.

Extracellular matrix disturbances play an important role in the development of ventricular remodeling and failure. Genetically modified mice with abnormalities in the synthesis and degradation of extracellular matrix have been generated, in particular mice with deletion or overexpression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). Echocardiography is ideally suited to serially evaluate left ventricular (LV) size and function, thus defining the progression of LV remodeling and failure. This Review describes the echocardiographic parameters that may provide insights into the development of ventricular remodeling and heart failure. The application of echocardiography to study LV remodeling and function after myocardial infarction and LV pressure-overload in wild-type mice and mice deficient or overexpressing MMPs or TIMPs is then detailed. Finally, using the example of mice deficient in nitric oxide synthase 3, a cautionary example is given illustrating discrepancies between the cardiac echocardiographic phenotype and modifications of the extracellular matrix.

Effectiveness of screening for abdominal aortic aneurysm during echocardiography.

Screening patients with abdominal aortic aneurysm (AAA) is associated with reduced AAA-related mortality, but population screening is poorly implemented. Opportunistic screening during imaging for other indications might be efficient. Single-center series reported AAA rates of 0.8% to 6.5% in patients undergoing transthoracic echocardiography (TTE), with disparities due to selection bias. In this first multicenter study, we aimed to assess the feasibility and criteria for screening AAA during TTE in real-life practice. During a week of May 2011, 79 centers participated in a nationwide survey. All patients aged ≥65 years requiring TTE for any indication were eligible, except for those with operated abdominal aorta. We defined AAA by an anteroposterior diameter of the infrarenal aorta≥30 mm. Of 1,382 consecutive patients, abdominal aorta imaging was feasible in 96.7%, with a median delay of 1.7 minutes (>3 minutes in 3.6% of cases). We found AAA in 50 patients (3.7%). Unknown AAA (2.7%) was more frequent in men than women (3.7% vs 1.3%, respectively, p=0.007) and increased by age at 2.2%, 2.5%, and 5.8% in age bands of 65 to 74, 75 to 84, and 85+ years, respectively. None of the female participants aged <75 years had AAA. Smoking status and family history of AAA were significantly more frequent among patients with AAA. The ascending aorta was larger in those with AAA (36.2±4.7 vs 34.0±5.2 mm, p=0.006), and bicuspid aortic valve and/or major aortic regurgitation were also more frequent (8% vs 2.6%, p=0.017). In conclusion, rapid AAA screening during TTE is feasible and should be limited to men ≥65 years and women≥75 years.

Incidental papillary fibroelastoma multimodal: imaging and surgical decisions in 2 patients.

Papillary fibroelastoma is a rare, benign cardiac tumor typically found on the heart valves. It is usually discovered incidentally on echocardiography. The clinical presentation of cardiac papillary fibroelastoma varies from no symptoms to severe embolic sequelae. We report the incidental finding of papillary fibroelastoma in 2 patients. In each, we chose to excise the tumor. The relevant medical literature provides little guidance regarding whether to excise a small papillary fibroelastoma in an asymptomatic patient. Multimodal imaging, which we discuss in the context of our patients' cases, aids the cardiologist and cardiovascular surgeon in more accurately evaluating papillary fibroelastoma preoperatively.

[Selection of patients for transcatheter aortic valve implantation]. / Implantation de valve aortique percutanée : sélection des patients.

A good selection of patients is a crucial step before transcatheter aortic valve implantation (TAVI) in order to select the good indications and choose the access route. TAVI should be considered only in patients with symptomatic severe aortic stenosis and either contraindication or high surgical risk. Indication for TAVI should be discussed in a multidisciplinary team meeting. Echocardiography and/or CT scan are mandatory to evaluate the aortic annulus size and select the good prosthesis size. The possibility of transfemoral implantation is evaluated by angiography and CT scan, and based on the arterial diameters, but also on the presence of tortuosities and arterial calcifications.

Automated home telephone self-monitoring reduces hospitalization in patients with advanced heart failure.

We studied 138 patients admitted for heart failure (HF). Patients were allocated one of three treatment strategies. Group 1 (G1, n = 50) were given usual care for HF, Group 2 (G2, n = 56) received a multi-disciplinary team approach, while Group 3 (G3, n = 32) had home telephone self-monitoring. Telemonitoring was based on the answers to three simple queries about bodyweight change, dyspnoea and general health. The system stratified the HF severity of each patient once a week, and recommended a prompt medical appointment or simple follow-up. Over a 12-month follow-up period, there were 43 adverse events (cardiovascular deaths and rehospitalizations for HF: G1 = 22, G2 = 14, G3 = 7). There was no difference between G2 and G3 (P = 0.78) but there was significant disadvantage with usual care (P = 0.02 vs. G2 and P = 0.04 vs. G3). Time to re-admission for HF increased in G2 and G3 compared to G1 (188 and 198 days vs. 95 days, P = 0.03 and P = 0.02 respectively). Automated home telephone self-monitoring reduced rehospitalization in patients with advanced HF.

Validation of noninvasive measurements of cardiac output in mice using echocardiography.

BACKGROUND: Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method. METHODS: Echocardiographic and flow probe measurements of CO were obtained in mice before and after albumin infusion and inferior vena cava occlusions. Echocardiography was also performed before and after endotoxin injection. Cardiac output was calculated using left ventricular volumes obtained from an M-mode or a two-dimensional view, left ventricular stroke volume calculated using the pulmonary flow, or estimated by the measurement of pulmonary velocity time integral (VTI). RESULTS: Close correlations were demonstrated between flow probe-measured CO and all echocardiographic measurements of CO. All echocardiographic-derived CO overestimated the flow probe-measured CO. Two-dimensional image-derived CO was associated with the smallest overestimation of CO. Interobserver variability was lowest for pulmonary VTI-derived CO. CONCLUSION: In mice, CO calculated from two-dimensional parasternal long-axis images is most accurate when compared with flow probe measurements; however, pulmonary VTI-derived CO is subject to less variability.

Noninvasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension.

BACKGROUND: Genetically modified mice offer the unique opportunity to gain insight into the pathophysiology of pulmonary arterial hypertension. In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a noninvasive technique to assess RVSP in mice. METHODS AND RESULTS: Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific overexpression of interleukin-6. Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetrical at baseline to asymmetrical at higher RVSPs. In wild-type and interleukin-6-overexpressing mice, the PAT correlated linearly with RVSP (r(2)=-0.67, P<0.0001), as did PAT/ET (r(2)=-0.76, P<0.0001). Sensitivity and specificity for detecting high RVSP (>32 mm Hg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT, <21 ms; PAT/ET, <39%). Intraobserver and interobserver variability of PAT and PAT/ET were <6%. CONCLUSIONS: Right ventricular systolic pressure can be estimated noninvasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity as well as to assess the effects of treatment on RVSP. This noninvasive technique may permit the characterization of the evolution of pulmonary arterial hypertension in genetically modified mice.