Prognostic Impact of Peak Aortic Jet Velocity on Patients With Acute Myocardial Infarction.

BACKGROUND: Aortic valve stenosis (AS) leads to increased cardiovascular mortality and morbidity, and recent studies reported that even mild-to-moderate AS was associated with poor prognosis in the general population. This study investigated the prognostic impact of mild or moderate AS, defined as 2.0 m/s ≤ peak aortic jet velocity (Vmax) ≤3.9 m/s using echocardiography in acute myocardial infarction (AMI) patients.Methods and Results: This study enrolled 3,049 AMI patients using data from the Mie ACS registry. Patients were divided into 2 groups according to Vmax: Group 1: Vmax <2.0 m/s and/or visually intact aortic valve in which all 3 leaflets are fully and evenly open; Group 2: 2.0 m/s ≤ Vmax ≤ 3.9 m/s. There were 2,976 patients in Group 1and 73 patients in Group 2. The Group 2 patients were older, had a higher percentage of males and had lower body mass index and Killip ≥2 than the Group 1 patients. Angiographic data, door-to-balloon time, and mechanical support were not different between the 2 groups. The Group 2 patients demonstrated a significantly higher all-cause mortality rate (P<0.01) and composite of cardiovascular death and heart failure hospitalization (P<0.01), and Kaplan-Meier analysis showed the same tendency in propensity score-matched patients. CONCLUSIONS: The present study revealed that mild or moderate AS based on Vmax is associated with poor prognosis following AMI.

Moyamoya Disease Complicating Ebstein's Anomaly.

Ebstein's anomaly is an uncommon congenital disorder affecting the tricuspid valve. We herein report a 38-year-old woman who experienced consciousness and sensory disturbance during treatment for heart failure caused by Ebstein's anomaly. Urgent magnetic resonance imaging and cerebral angiography demonstrated acute cerebral infarction and internal carotid artery obstruction with the development of collateral arteries. We diagnosed her with multiple cerebral infarctions due to moyamoya disease. Ebstein's anomaly concomitant with moyamoya disease is extremely rare. However, we should consider the possibility of this rare but important concurrence when treating patients with heart failure due to Ebstein's anomaly to avoid excessive diuresis and vasodilation and irreversible brain injury.

Gap junction protein beta 4 plays an important role in cardiac function in humans, rodents, and zebrafish.

AIMS: GJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function. METHODS AND RESULTS: We examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization. CONCLUSIONS: These results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.

Renal papillary tip extract stimulates BNP production and excretion from cardiomyocytes.

BACKGROUND: Brain natriuretic peptide (BNP) is an important biomarker for patients with cardiovascular diseases, including heart failure, hypertension and cardiac hypertrophy. It is also known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease; however, the mechanism remains unclear. METHODS AND RESULTS: We developed a BNP reporter mouse and occasionally found that this promoter was activated specifically in the papillary tip of the kidneys, and its activation was not accompanied by BNP mRNA expression. No evidence was found to support the existence of BNP isoforms or other nucleotide expression apart from BNP and tdTomato. The pBNP-tdTomato-positive cells were interstitial cells and were not proliferative. Unexpectedly, both the expression and secretion of BNP increased in primary cultured neonatal cardiomyocytes after their treatment with an extract of the renal papillary tip. Intraperitoneal injection of the extract of the papillary tips reduced blood pressure from 210 mmHg to 165 mmHg, the decrease being accompanied by an increase in serum BNP and urinary cGMP production in stroke-prone spontaneously hypertensive (SHR-SP) rats. Furthermore the induction of BNP by the papillary extract from rats with heart failure due to myocardial infarction was increased in cardiomyocytes. CONCLUSIONS: These results suggested that the papillary tip express a substance that can stimulate BNP production and secretion from cardiomyocytes.

Native T1 Mapping and Extracellular Volume Mapping for the Assessment of Diffuse Myocardial Fibrosis in Dilated Cardiomyopathy.

OBJECTIVES: The purpose of this study was to examine the histological correlation of native myocardial T1 and extracellular volume fraction (ECV) measurement at 3-T for the assessment of diffuse pathological changes in the myocardial tissue, including myocardial fibrosis and extracellular space in dilated cardiomyopathy (DCM). BACKGROUND: Cardiac magnetic resonance T1 techniques allow the quantification of diffuse myocardial fibrosis. However, there are no definitive head-to-head studies of native T1 versus ECV for the detection, quantification, and characterization of pathological changes in the myocardial tissue in DCM by using histological samples for confirmation. METHODS: A total of 36 subjects with DCM (31 men, mean age 56 ± 16 years) underwent pre- and post-contrast T1 mapping as well as late gadolinium enhancement (LGE) cardiac magnetic resonance at 3-T. Biopsy samples were used for the quantification of collagen volume fraction using picrosirius red staining and an extracellular space component from hematoxylin and eosin-stained myocardium. RESULTS: Nonischemic LGE was observed in 14 of 36 patients. Although patients with LGE had significantly greater biopsy-proven collagen volume fraction than those without LGE (21 ± 12% vs. 11 ± 8%; p < 0.01), there was substantial overlap of collagen volume fraction values between patients with and without LGE. Both native T1 value and ECV were similarly and significantly associated with biopsy-proven collagen volume fraction (r = 0.77 and r = 0.66, respectively; p < 0.05). Furthermore, ECV had a strong correlation with the biopsy-proven extracellular space component (r = 0.86), whereas native T1 had only a moderate correlation (r = 0.55). Interobserver and intraobserver reproducibility for native T1 and ECV were 0.89, 0.95, 0.96, and 0.98, respectively. CONCLUSIONS: Native T1 exhibited comparable ability as ECV measurement in the detection and quantification of histological collagen volume fraction, with high reproducibility, and therefore diffuse myocardial fibrosis in DCM may be reliably assessed by native T1 mapping without the administration of gadolinium contrast agent. In addition, cardiac magnetic resonance-derived ECV showed excellent agreement with histological extracellular space.

Detrimental Impact of Vasopressin V2 Receptor Antagonism in a SU5416/Hypoxia/Normoxia-Exposed Rat Model of Pulmonary Arterial Hypertension.

BACKGROUND: The expression of vasopressin type 2 receptor (V2R) in the lung, and the long-term effects of tolvaptan, a selective V2R antagonist, on pulmonary circulation and right ventricular (RV) remodeling in a pulmonary arterial hypertension (PAH) rat model were evaluated. METHODS AND RESULTS: Six-week-old male Sprague-Dawley rats were injected subcutaneously with 20 mg/kg of SU5416 and were exposed to hypoxia for 3 weeks followed by re-exposure to normoxia for 7 weeks. These rats showed signs of RV failure and upregulation of V2R and cAMP in the lung tissue at 10 weeks after SU5416 injection. They were then treated with either 0.05% tolvaptan in diet (SUHx+Tolv) or normal diet (SUHx) during 5-10 weeks of SU5416 injection. Normal control rats (Cont) were also used for comparison. SUHx+Tolv had significantly higher pulmonary arterial pressure, more progressive pulmonary arterial remodeling, and more severe myocyte hypertrophy and interstitial myocardial fibrosis in the right ventricle compared with SUHx despite achieving successful preload reduction. CONCLUSIONS: Chronic vasopressin V2R antagonism may contribute to the worsening of PAH and the development of RV remodeling.

New Isoform of Cardiac Myosin Light Chain Kinase and the Role of Cardiac Myosin Phosphorylation in α1-Adrenoceptor Mediated Inotropic Response.

BACKGROUND & AIMS: Cardiac myosin light chain kinase (cMLCK) plays an obligatory role in maintaining the phosphorylation levels of regulatory myosin light chain (MLC2), which is thought to be crucial for regulation of cardiac function. To test this hypothesis, the role played by ventricular MLC2 (MLC2v) phosphorylation was investigated in the phenylephrine-induced increase in twitch tension using the naturally-occurring mouse strain, C57BL/6N, in which cMLCK is down regulated. METHODS AND RESULTS: By Western blot and nanoLC-MS/MS analysis, cMLCKs with molecular mass of 61-kDa (cMLCK-2) and/or 86-kDa were identified in mice heart. Among various mouse strains, C57BL/6N expressed cMLCK-2 alone and the closest relative strain C57BL/6J expressed both cMLCKs. The levels of MLC2v phosphorylation was significantly lower in C57BL/6N than in C57BL/6J. The papillary muscle twitch tension induced by electrical field stimulation was smaller in C57BL/6N than C57BL/6J. Phenylephrine had no effect on MLC2v phosphorylation in either strains but increased the twitch tension more potently in C57BL/6J than in C57BL/6N. Calyculin A increased papillary muscle MLC2v phosphorylation to a similar extent in both strains but increased the phenylephrine-induced inotropic response only in C57BL/6N. There was a significant positive correlation between the phenylephrine-induced inotropic response and the levels of MLC2v phosphorylation within ranges of 15-30%. CONCLUSIONS: We identified a new isoform of cMLCK with a molecular mass of 61kDa(cMLCK-2) in mouse heart. In the C57BL/6N strain, only cMLCK-2 was expressed and the basal MLC2v phosphorylation levels and the phenylephrine-induced inotropic response were both smaller. We suggest that a lower phenylephrine-induced inotropic response may be caused by the lower basal MLC2v phosphorylation levels in this strain.

Identification of bovine hibernation-specific protein complex and evidence of its regulation in fasting and aging.

Hibernation-specific protein (HP) is a plasma protein that regulates hibernation in chipmunks. The HP complex (HP20c) consists of three homologous proteins, HP20, HP25 and HP27, all produced by liver and belonging to the C1q family. To date, HP20c has not been identified in any mammalian species except chipmunk and ground squirrel hibernators. Here, we report a bovine HP20 gene isolated from liver tissue and aortic endothelial cells. Total homology between bovine and chipmunk variants was 63% at the amino acid level. Gene expression was highest in the liver. Western blot revealed HP20 protein in foetal, newborn, calf and adult serum, with highest concentrations in the adult. Similar proteins were detected in sera of other ruminants but not in humans, bears, mice or rats. Bovine HP20 protein was found mainly in ovaries, stomach, heart, kidneys, lungs, testes and prostate, but not in the skeletal muscle. Native HP20 was purified from bovine adult serum as a complex containing 25 and 27 kDa proteins. Mass spectrometry revealed that these proteins are orthologues of chipmunk HP25 and HP27, respectively. Interestingly, bovine HP20 was highly expressed in cattle serum after fasting. Native bovine HP20c may be a useful tool for investigating HP function.

A case of aortic thrombosis and embolism preceding the progression of early esophageal cancer.

Aortic thrombosis is rare, especially in non-atherosclerotic aortae. A 51-year-old woman presented with intermittent claudication in the right lower extremity. She was diagnosed as having peripheral artery disease on ultrasound. A computed tomography scan showed a large, sessile, aortic mural thrombus from the infrarenal abdominal aorta to the right common iliac artery. An arteriogram showed an abrupt occlusion of the right superficial femoral artery with collateral arteries. She had no risk factors for atherosclerosis. Interestingly, this occurred before early esophageal cancer progressed. Heparin was administered intravenously and later changed to warfarin. In the follow-up period, the thrombus disappeared, and her symptoms improved. A careful investigation for malignant disease is needed when aortic thrombus occurs in patients with no atherosclerosis risk factors. .