Comparison Between Echocardiography and Cardiac Computed Tomography in the Evaluation of Diastolic Dysfunction and Prediction of Heart Failure.

Recent data indicate that left atrial (LA) function assessment by cardiac computed tomography (CT) is closely related to diastolic dysfunction (DD). Therefore, we aimed to perform a direct comparison between CT and echocardiography for diagnosis of advanced DD and prediction of future heart failure or cardiovascular death. We identified 340 patients who had both spiral cardiac CT and a proximate echocardiogram. LA total emptying fraction (LATEF), a measure of global LA function, was automatically calculated from CT data, as a surrogate for diastolic function and was compared with echocardiographic grades of diastolic function. The area under the receiver operating characteristic curve for LATEF to differentiate between advanced DD (grades 2 and 3) and all other grades was 0.84 (0.79 to 0.88). Over a median of 4 years, 69 events (admissions for heart failure and cardiovascular deaths) occurred. By multivariate Cox analysis, LATEF <40% provided incremental prognostic information after adjustments for advanced DD by echocardiography (hazard ratio 2.15, 95% confidence interval 1.13 to 3.94). There was a significant interaction (p = 0.03) between LATEF and echocardiography-based diastolic grades. Stratified analyses within the diastolic function groups revealed that LATEF <40% was equivalent to echocardiography in predicting events in the subgroup with advanced DD by echocardiography (p = 0.20) but was associated with a significantly higher event rates in patients with normal filling pressures (p = 0.0001) or indeterminate diastolic function (p = 0.04) by echocardiography. In conclusion, LA function derived from CT can accurately detect advanced DD diagnosed by echocardiography and has additive value to echocardiography-derived DD.

Left atrial function by cardiac computed tomography is a predictor of heart failure and cardiovascular death.

OBJECTIVES: We sought to evaluate cardiac CT angiography (CCTA)-based assessment of left atrial (LA) function as a predictor of hospitalizations for heart failure (HF) and cardiovascular (CV) mortality. METHODS: LA function was evaluated using automatic derivation of LA volumes to calculate LA total emptying fraction (LATEF) in 788 consecutive patients with normal sinus rhythm who had undergone spiral CT scans. The relationship between LATEF evaluated by CCTA and the composite endpoint of admission for HF or CV mortality was analyzed using Cox models. RESULTS: During a median follow-up of 4 years, there were 100 events, 62 HF hospitalizations, and 38 cardiovascular deaths. Mean LATEF was 30.7 ± 10.7% and 40.5 ± 11.2% in patients with and without events, respectively (p < 0.0001). A high LATEF (upper tertile > 46%) was associated with a very low event rate (3.5% at 6 years [95% CI 1.7-7.1%]). The adjusted HR for HF or CV mortality was 4.37 (95% CI 1.99-9.60) in the lowest LATEF tertile, and 2.29 (95% CI 1.03-5.14) in the middle tertile, relative to the highest tertile. For the endpoint of HF alone, adjusted HR for the lowest LATEF tertile was 5.93 (95% CI 2.23-15.82) and for the middle tertile 2.89 (95% CI 1.06-7.86). The association of LATEF with outcome was similar for patients with both reduced and preserved left ventricular (LV) ejection fraction (Pinteraction = 0.724). Reduced LATEF was associated with a high event rate, even when coupled with normal LA volume. CONCLUSION: CCTA-derived LA function is a predictor of HF hospitalization or CV death, independent of clinical risk factors, LA volume, and LV systolic function. KEY POINTS: • Left atrial function can be automatically derived from cardiac CTA scans. • Cardiac CTA-derived left atrial function is a predictor of hospitalization for heart failure and cardiovascular death. • Evaluation of left atrial function could be useful in identifying patients at risk of heart failure.

Dual specific phosphatases (DUSPs) in cardiac hypertrophy and failure.

Pressure overload and other stress stimuli elicit a host of adaptive and maladaptive signaling cascades that eventually lead to cardiac hypertrophy and heart failure. Among those, the mitogen-activated protein kinase (MAPK) signaling pathway has been shown to play a prominent role. The dual specificity phosphatases (DUSPs), also known as MAPK specific phosphatases (MKPs), that can dephosphorylate the MAPKs and inactivate them are gaining increasing attention as potential drug targets. Here we try to review recent advancements in understanding the roles of the different DUSPs, and the pathways that they regulate in cardiac remodeling. We focus on the regulation of three main MAPK branches - the p38 kinases, the c-Jun-N-terminal kinases (JNKs) and the extracellular signal-regulated kinases (ERK) by various DUSPs and try to examine their roles.

Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy.

BACKGROUND: Chronic pressure overload and a variety of mediators induce concentric cardiac hypertrophy. When prolonged, cardiac hypertrophy culminates in decreased myocardial function and heart failure. Activation of the extracellular signal-regulated kinase (ERK) is consistently observed in animal models of hypertrophy and in human patients, but its role in the process is controversial. METHODS: We generated transgenic mouse lines with cardiomyocyte restricted overexpression of intrinsically active ERK1, which similar to the observations in hypertrophy is phosphorylated on both the TEY and the Thr207 motifs and is overexpressed at pathophysiological levels. RESULTS: The activated ERK1 transgenic mice developed a modest adaptive hypertrophy with increased contractile function and without fibrosis. Following induction of pressure-overload, where multiple pathways are stimulated, this activation did not further increase the degree of hypertrophy but protected the heart through a decrease in the degree of fibrosis and maintenance of ventricular contractile function. CONCLUSIONS: The ERK pathway acts to promote a compensated hypertrophic response, with enhanced contractile function and reduced fibrosis. The activation of this pathway may be a therapeutic strategy to preserve contractile function when the pressure overload cannot be easily alleviated. The inhibition of this pathway, which is increasingly being used for cancer therapy on the other hand, should be used with caution in the presence of pressure-overload.

Localization of transcripts, translation, and degradation for spatiotemporal sarcomere maintenance.

The mechanisms responsible for maintaining macromolecular protein complexes, with their proper localization and subunit stoichiometry, are incompletely understood. Here we studied the maintenance of the sarcomere, the basic contractile macromolecular complex of cardiomyocytes. We performed single-cell analysis of cardiomyocytes using imaging of mRNA and protein synthesis, and demonstrate that three distinct mechanisms are responsible for the maintenance of the sarcomere: mRNAs encoding for sarcomeric proteins are localized to the sarcomere, ribosomes are localized to the sarcomere with localized sarcomeric protein translation, and finally, a localized E3 ubiquitin ligase allow efficient degradation of excess unincorporated sarcomeric proteins. We show that these mechanisms are distinct, required, and work in unison, to ensure both spatial localization, and to overcome the large variability in transcription. Cardiomyocytes simultaneously maintain all their sarcomeres using localized translation and degradation processes where proteins are continuously and locally synthesized at high rates, and excess proteins are continuously degraded.

Extracellular signal-regulated kinases 1/2 as regulators of cardiac hypertrophy.

Cardiac hypertrophy results from increased mechanical load on the heart and through the actions of local and systemic neuro-humoral factors, cytokines and growth factors. These mechanical and neuroendocrine effectors act through stretch, G protein-coupled receptors and tyrosine kinases to induce the activation of a myriad of intracellular signaling pathways including the extracellular signal-regulated kinases 1/2 (ERK1/2). Since most stimuli that provoke myocardial hypertrophy also elicit an acute phosphorylation of the threonine-glutamate-tyrosine (TEY) motif within the activation loops of ERK1 and ERK2 kinases, resulting in their activation, ERKs have long been considered promotors of cardiac hypertrophy. Several mouse models were generated in order to directly understand the causal role of ERK1/2 activation in the heart. These models include direct manipulation of ERK1/2 such as overexpression, mutagenesis or knockout models, manipulations of upstream kinases such as MEK1 and manipulations of the phosphatases that dephosphorylate ERK1/2 such as DUSP6. The emerging understanding from these studies, as will be discussed here, is more complex than originally considered. While there is little doubt that ERK1/2 activation or the lack of it modulates the hypertrophic process or the type of hypertrophy that develops, it appears that not all ERK1/2 activation events are the same. While much has been learned, some questions remain regarding the exact role of ERK1/2 in the heart, the upstream events that result in ERK1/2 activation and the downstream effector in hypertrophy.

Clinical implications of sleep disordered breathing in acute myocardial infarction.

BACKGROUND: Sleep disordered breathing (SDB), characterized by nightly intermittent hypoxia, is associated with multiple pathophysiologic alterations that may adversely affect patients with acute myocardial infarction (AMI). This prospective study investigated whether the metabolic perturbations associated with SDB are present when these patients develop AMI and if they affect clinical outcomes. METHODS: We prospectively enrolled 180 AMI patients. SDB was defined as oxygen desaturation index (ODI) >5 events/hour based on a Watch Pat-100 sleep study. Blood samples were obtained for high-sensitivity C-reactive protein (hs-CRP) and markers of oxidative stress (lipid peroxides [PD] and serum paraoxonase-1 [PON-1] (arylesterase activity). Echocardiography was performed to evaluate cardiac dimensions and pulmonary artery systolic pressure. RESULTS: SDB was present in 116 (64%) patients. Hs-CRP levels, PD and PON-1 were similar in patients with and without SDB. Echocardiography revealed higher left atrial dimension (4.1 ± 0.5 vs 3.8 ± 0.5 cm; P = 0.003) and a significant positive correlation between ODI and pulmonary artery systolic pressure (r = 0.41, P<0.0001). After a median follow up of 68 months, no significant differences were observed between the study groups with regard to clinical outcomes, including death, heart failure, myocardial infarction and unstable angina. CONCLUSION: There is a high prevalence of previously undiagnosed SDB among patients with AMI. SDB in the setting of AMI is associated with higher pulmonary artery systolic pressure. SDB was not associated with adverse clinical outcomes.

Severe coronary artery spasm induced by epidural injection of bupivacaine hydrochloride: a case report.

This report describes a case of variant angina induced by epidural infusion of bupivacaine hydrochloride for the treatment of intractable low back pain in a 66-year-old male patient with lumbar discopathy. Severe reversible coronary artery spasm of right coronary artery was demonstrated by coronary angiography. Withdrawal of epidural anesthesia and treatment with nitrates and calcium channel antagonists resulted in cessation of variant angina.