Fusako Sera

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation.

Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs.

Angioscopic Comparison of Neointimal Coverage Between Zotarolimus-and Sirolimus-Eluting Stents

Drug-eluting stents (DES) have demonstrated reduced late loss (LL) and low target lesion revascularization (TLR) rates through an inhibitory effect on neointimal hyperplasia but might have a risk of late or very late stent thrombosis due to incomplete neointimal coverage (NIC) ([1–3][1]). A

Heterogeneous arterial healing in patients following paclitaxel-eluting stent implantation: comparison with sirolimus-eluting stents.

OBJECTIVES We angioscopically compared paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) to explore differences in arterial healing. BACKGROUND Drug-eluting stents may demonstrate different arterial healing processes. METHODS Angioscopy was performed 9 +/- 2 months after 30 PES and 36 SES were implanted initially in the native coronary artery. Heterogeneity of the neointimal coverage (NIC) as well as the dominant grade was examined. Neointimal coverage was defined as follows: grade 0 = fully visible struts; grade 1 = struts bulged into the lumen, but covered; grade 2 = embedded, but translucent struts; grade 3 = invisible struts. Heterogeneity was judged when the NIC grade variation >or=1. Thrombi and yellow plaques (YP) were also explored. RESULTS In-stent late loss (0.44 +/- 0.44 mm vs. 0.13 +/- 0.33 mm; p < 0.0001) and dominant NIC grade (1.8 +/- 1.1 vs. 1.3 +/- 0.7; p = 0.02) were greater in PES than in SES. Of PES, 48% showed the heterogeneity of 1 grade; 26% showed that of 2 grades. Of SES, 53% showed homogeneous coverage; the remaining SES showed the heterogeneity of 1 grade; and 72% showed dominant grade 1. Thrombi were more common in PES than in SES (43% vs. 19%; p = 0.04). Both stents commonly revealed YP (83% vs. 78%; p = 0.76). CONCLUSIONS NIC was more heterogeneous in PES, associated with a higher incidence of thrombi. Homogeneous NIC may be an important factor for competent arterial healing.

Abdominal adiposity, general obesity, and subclinical systolic dysfunction in the elderly: A population-based cohort study

General obesity, measured by body mass index (BMI), and abdominal adiposity, measured as waist circumference (WC) and waist‐to‐hip ratio (WHR), are associated with heart failure and cardiovascular events. However, the relationship of general and abdominal obesity with subclinical left ventricular (LV) dysfunction is unknown. We assessed the association of general and abdominal obesity with subclinical LV systolic dysfunction in a population‐based elderly cohort.

Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

BACKGROUND Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna(H222P/H222P) mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna(H222P/H222P) mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. METHODS Male Lmna(H222P/H222P) mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. RESULTS Treatment of Lmna(H222P/H222P) mice with either benazepril or selumetinib started at 8weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20weeks of age. CONCLUSIONS Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna(H222P/H222P) mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.

Left ventricular systolic dysfunction by longitudinal strain is an independent predictor of incident atrial fibrillation: A community-based cohort study

Background—The increasing prevalence of atrial fibrillation (AF) represents a public health issue. Identifying new predictors of AF is therefore necessary to plan preventive strategies. We investigated whether left ventricular (LV) systolic dysfunction by global longitudinal strain (GLS), a predictor of cardiovascular events, may predict new-onset AF in a population setting. Methods and Results—Participants (n=675; mean age, 71±9 years; 60% women) in sinus rhythm from the population-based Northern Manhattan Study (NOMAS) underwent 2- and 3-dimensional echocardiography as part of the Cardiac Abnormalities and Brain Lesions (CABL) study. LV systolic function was assessed by LV ejection fraction and speckle-tracking GLS. During a mean follow-up of 63.6±18.7 months, 32 (4.7%) new confirmed cases of AF occurred. Lower GLS (adjusted hazard ratio/unit decrease, 1.22; 95% confidence interval, 1.04–1.43; P=0.015) and increased left atrial volume index (LAVi; adjusted hazard ratio/unit increase, 1.12; 95% confidence interval, 1.07–1.17; P<0.001) were significantly associated with incident AF, whereas LV ejection fraction was not (P=0.176). Abnormal GLS (>–14.7%) was associated with risk of new-onset AF with an adjusted hazard ratio of 3.2 (95% confidence interval, 1.4–7.5; P=0.007). The coexistence of abnormal GLS/abnormal LAVi was associated with a 28.6% incidence of AF (adjusted hazard ratio, 12.1; 95% confidence interval, 3.3–44.8; P<0.001) compared with participants with normal GLS/normal LAVi (AF incidence, 2.0%). AF incidence was intermediate in those with either abnormal GLS or abnormal LAVi (9.3% and 11.1%, respectively). GLS prognostic value for incident AF was incremental over risk factors and LAVi. Conclusions—LV systolic dysfunction by GLS was a powerful and independent predictor of incident AF. GLS assessment may improve AF risk stratification in addition to established parameters.

Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation

Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans.

Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice

We previously showed that striated muscle-selective depletion of lamina-associated polypeptide 1 (LAP1), an integral inner nuclear membrane protein, leads to profound muscular dystrophy with premature death in mice. As LAP1 is also depleted in hearts of these mice, we examined their cardiac phenotype. Striated muscle-selective LAP1 knockout mice display ventricular systolic dysfunction with abnormal induction of genes encoding cardiomyopathy related proteins. To eliminate possible confounding effects due to skeletal muscle pathology, we generated a new mouse line in which LAP1 is deleted in a cardiomyocyte-selective manner. These mice had no skeletal muscle pathology and appeared overtly normal at 20 weeks of age. However, cardiac echocardiography revealed that they developed left ventricular systolic dysfunction and cardiac gene expression analysis revealed abnormal induction of cardiomyopathy-related genes. Our results demonstrate that LAP1 expression in cardiomyocytes is required for normal left ventricular function, consistent with a report of cardiomyopathy in a human subject with mutation in the gene encoding LAP1.

Objective Interpretation of Dobutamine Stress Echocardiography by Diastolic Dyssynchrony Imaging: A Practical Approach

BACKGROUND Postsystolic shortening is a sensitive maker of myocardial ischemia. The aim of this study was to investigate whether diastolic dyssynchrony imaging is useful for the objective interpretation of dobutamine stress echocardiography. METHODS Postsystolic shortening was detected by using tissue Doppler imaging displacement timing analysis: the delays of the displacement peaks from end-systole were displayed from green to red, depending on the preset time window on diastolic dyssynchrony imaging. Dobutamine stress echocardiography was performed in 59 patients with suspected coronary artery disease who presented with normal left ventricular wall motion at rest (age range, 44-83 years; 20 women). The optimal time windows for diastolic dyssynchrony imaging at rest and at peak dobutamine were determined by receiver operating characteristic analysis by measuring the delays of the displacement peaks in the left ventricular myocardial segments. Diastolic dyssynchrony imaging was performed using time windows of 100 msec at rest and 80 msec at peak dobutamine. The diagnostic power of diastolic dyssynchrony imaging was assessed with quantitative coronary angiography as the gold standard (>50% diameter stenosis) both at rest and at peak dobutamine. RESULTS Coronary artery disease was present in 37 patients (63%). Diastolic dyssynchrony imaging at peak dobutamine predicted the presence of coronary artery disease with sensitivity of 89%, specificity of 77%, predictive accuracy of 85%, positive predictive value of 79%, and negative predictive value of 81%. Diastolic dyssynchrony imaging at rest yielded sensitivity of 62%, specificity of 73%, predictive accuracy of 66%, positive predictive value of 79%, and negative predictive value of 53%. Importantly, diastolic dyssynchrony imaging demonstrated excellent intraindividual (97%) and interindividual (90%) agreement. CONCLUSION Diastolic dyssynchrony imaging is useful in the objective interpretation of dobutamine stress echocardiography.

Arterial wave reflection and aortic valve calcification in an elderly community-based cohort.

BACKGROUND Aortic valve calcification (AVC) without stenosis is common in the elderly, is associated with cardiovascular morbidity and mortality, and may progress to aortic valve stenosis. Arterial stiffness and pulse-wave reflection are important components of proximal aortic hemodynamics, but their relationship with AVC is not established. METHODS To investigate the relationship of arterial wave reflection and stiffness with AVC, pulse wave analysis and AVC evaluation by echocardiography were performed in 867 participants from the Cardiovascular Abnormalities and Brain Lesions study. Participants were divided into four categories on the basis of the severity and extent of AVC: (1) none or mild focal AVC, (2) mild diffuse AVC, (3) moderate to severe focal AVC, and (4) moderate to severe diffuse AVC. Central blood pressures and pulse pressure, total arterial compliance, augmentation index, and time to wave reflection were assessed using applanation tonometry. RESULTS Indicators of arterial stiffness and wave reflection were significantly associated with AVC severity, except for central systolic and diastolic pressures and time to reflection. After adjustment for pertinent covariates (age, sex, race/ethnicity, and estimated glomerular filtration rate), only augmentation pressure (P = .02) and augmentation index (P = .002) were associated with the severity of AVC. Multivariate logistic regression analysis revealed that augmentation pressure (odds ratio per mm Hg, 1.14; 95% confidence interval, 1.02-1.27; P = .02) and augmentation index (odds ratio per percentage point, 1.07; 95% confidence interval, 1.01-1.13; P = .02) were associated with an increased risk for moderate to severe diffuse AVC, even when central blood pressure value was included in the same model. CONCLUSIONS Arterial wave reflection is associated with AVC severity, independent of blood pressure values. Increased contribution of wave reflection to central blood pressure could be involved in the process leading to AVC.