A novel JAG1 mutation causing Alagille syndrome presenting with giant hepatic nodules and discordant phenotype in monozygotic twins

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Coronary Sinus Diameter to Inferior Vena Cava Diameter Ratio in the Diagnosis of Cardiac Tamponade: A Novel Approach.

BACKGROUND: In cardiac tamponade, coronary sinus (CS) as an intrapericardial structure can be easily compressed, whereas inferior vena cava (IVC) dilates. This inverse relationship may augment their roles in the evaluation of tamponade imaging. AIM: We assessed the usefulness of computerized tomographic measures of CS diameter and also CS/IVC ratio to predict tamponade in clinically stable patients with large pericardial effusion. METHODS: Sixty-six clinically stable patients who had large pericardial effusions were included. Coronary sinus diameter was measured from the point at 1 cm proximal to the CS ostium. Inferior vena cava diameter was measured from the segment between its right atrial orifice and hepatic vein. RESULTS: Patients with tamponade had smaller CS diameter and CS/IVC ratio. After adjusting with other parameters, only either CS diameter or CS/IVC ratio predicted tamponade, respectively. (Nagelkerke r value for CS was 53.7% and 72.1% for CS/IVC ratio). In Receiver Operating Characteristic Curve analysis, a cutoff value of 6.85 mm for CS diameter had 82.6% sensitivity and 83.7% specificity and a cutoff value of 27% for CS/IVC ratio had 87.0% sensitivity and 86.0% specificity for predicting cardiac tamponade. CONCLUSIONS: The tomographic measures of both the CS diameter and the CS/IVC ratio predicted tamponade in clinically stable patients with large pericardial effusion. Compared with CS diameter, CS/IVC ratio seemed to be a more powerful predictor of tamponade.

Right coronary artery-coronary sinus fistula diagnosed by three-dimensional echocardiography.

Right coronary artery-coronary sinus fistula is a very rare congenital anomaly in which a right coronary artery fistula drains into the right atrium, right ventricle, or pulmonary artery. A right coronary artery-coronary sinus fistula was diagnosed in a 44-year-old man by three-dimensional echocardiography and confirmed by computed tomography angiography and surgery. Relevant published experience in diagnosing this kind of anomaly is summarized.

A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis.

Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and hypertension. The aim of this study was to establish a murine model of myocardial edema and elucidate the response of cardiac lymphatics and the myocardium. Myocardial edema without infarction was induced in mice by cauterizing the coronary sinus, increasing pressure in the coronary venous system, and inducing myocardial edema. In male mice, there was rapid development of edema 3 h following coronary sinus cauterization (CSC), with associated dilation of cardiac lymphatics. By 24 h, males displayed significant cardiovascular contractile dysfunction. In contrast, female mice exhibited a temporal delay in the formation of myocardial edema, with onset of cardiovascular dysfunction by 24 h. Furthermore, myocardial edema induced a ring of fibrosis around the epicardial surface of the left ventricle in both sexes that included fibroblasts, immune cells, and increased lymphatics. Interestingly, the pattern of fibrosis and the cells that make up the fibrotic epicardial ring differ between sexes. We conclude that a novel surgical model of myocardial edema without infarct was established in mice. Cardiac lymphatics compensated by exhibiting both an acute dilatory and chronic growth response. Transient myocardial edema was sufficient to induce a robust epicardial fibrotic and inflammatory response, with distinct sex differences, which underscores the sex-dependent differences that exist in cardiac vascular physiology.NEW & NOTEWORTHY Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and high blood pressure. Cardiac lymphatics regulate interstitial fluid balance and, in a myocardial infarction model, have been shown to be therapeutically targetable by increasing heart function. Cardiac lymphatics have only rarely been studied in a noninfarct setting in the heart, and so we characterized the first murine model of increased coronary sinus pressure to induce myocardial edema, demonstrating distinct sex differences in the response to myocardial edema. The temporal pattern of myocardial edema induction and resolution is different between males and females, underscoring sex-dependent differences in the response to myocardial edema. This model provides an important platform for future research in cardiovascular and lymphatic fields with the potential to develop therapeutic interventions for many common cardiovascular diseases.

Double superior venae cavae with absence of the coronary sinus and anomalies of the azygos venous system.

The superior vena cava is formed during the fetal period by the development of anastomoses between the right and left anterior cardinal veins, and the regression of the central part of the left anterior cardinal vein. The persistence of this part of the left anterior cardinal vein causes the formation of a left superior vena cava, which is a rare anomaly in cadaver dissection. We report the case of a persistent left superior vena cava with a normal right superior vena cava in a 95-year-old male cadaver, which was discovered during anatomical dissection for medical students at Kawasaki Medical School in 2016. The left superior vena cava was formed by the confluence of the left internal jugular and left subclavian veins and terminated in the right atrium via what would normally be the coronary sinus. The right and left superior venae cavae received intercostal veins via a right and left azygos vein, respectively. However, the right azygos vein was shorter than the normal azygos vein and received only the second to fifth intercostal veins, whereas the left azygos vein received the fifth to eleventh left intercostal veins and the sixth to eleventh right intercostal veins. We consider that the anomalies of the azygos venous system were the result of regression of right supracardinal vein and the persistence of the left supracardinal vein during development. An awareness of such variations of major thoracic veins is important for the interpretation of unusual CT images.

Profiling of the plasma proteome across different stages of human heart failure.

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.

Incomplete coronary sinus reducer endothelialization as potential mechanism of clinical failure.

The number of patients suffering from refractory angina is constantly increasing. Moreover, these patients are considered at higher risk for new hospitalizations and increased incidence of adverse cardiac events. The coronary sinus reducer was recently introduced as a new therapeutic option in patients with refractory angina and no possibilities for coronary revascularization. However, a consistent percentage of patients, ranging from 15 to 30%, reports no clinical benefits after coronary sinus reducer implantation. The reasons for this lack of effectiveness are at present unknown. We suggest here a possible explanation to this phenomenon.

Thalidomide-induced sinus bradycardia in Crohn's disease: case report and literature review.

Thalidomide is effective in inducing and maintaining clinical remission, as well as mucosal healing, in patients with refractory Crohn's disease (CD). However, long-term use of thalidomide has raised concern because of the high incidence of adverse events. Cardiovascular events induced by thalidomide have been reported in patients with multiple myeloma, amyotrophic lateral sclerosis, and transfusion-dependent refractory anemia. We report here an extremely rare case of sinus bradycardia induced by thalidomide in an adult patient with CD. This patient's heart rate converted back to a normal sinus rhythm after withdrawal of thalidomide, but recurred after restarting of thalidomide. Cardiac toxicity should be closely monitored when using thalidomide in patients with CD.

Persistent Left Superior Vena Cava with Absent Right Superior Vena Cava.

Persistent left superior vena cava (PLSVC) is the most common congenital abnormality of the thoracic systemic venous drainage; in fact, cardiology fellows in training are often quizzed on this when a dilated coronary sinus is noted on an echocardiogram. However, its association with an absent right superior vena cava (RSVC) and how to diagnose this combined condition is less commonly known. We present two cases of PLSVC with an absent RSVC, describe how to recognize and confirm this diagnosis, and discuss its clinical relevance.

Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E deficient mice.

Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient (Apoe-/-) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe-/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe-/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.

NT-proBNP and CA 125 levels are associated with increased pro-inflammatory cytokines in coronary sinus serum of patients with chronic heart failure.

PURPOSE: Heart failure (HF) is considered to be a complex syndrome associated with neurohormonal and cytokine activation, that contribute to its progression. There are evidences which showed that, carbohydrate antigen 125 (CA 125), a tumor marker widely used for ovarian cancer therapy monitoring, was significantly elevated in HF patients. We hypothesized that inflammatory stimuli may be responsible for amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and CA-125 production and release in chronic HF (CHF). We aimed to measure the levels of NT-proBNP, CA 125, pro-anti-inflammatory cytokines (IL-6, IL-1ß, IL-8, TNF-α and IL-4), from peripheral venous (PV) and coronary sinus (CS) blood samples, in patients with CHF and to assess their correlation with echocardiographic indices. METHODS: We enrolled 32 subjects (20M/12F) with CHF (III-IV NYHA functional class) who were to undergo cardiac resynchronization therapy (CRT) device implantation and 30 healthy controls (18M/12F). Two blood samples, from PV and CS, were collected at the time of CRT for each CHF patient. Serum levels of biomarkers were measured by ELISA. Cardiac function was assessed echocardiographically. RESULTS: All investigated biomarkers were significantly higher in CHF patients than in non-CHF controls (P < 0.001). There were positive correlations between biomarkers concentrations in PV and CS (r between 0.54 and 0.98, all P < 0.003). NT-proBNP, IL-6 and IL-1ß levels were 17%, 86% and 36% higher in CS than in PV, these increases being very well correlated each other, while CA 125 levels were 86% higher in PV than in CS. Moreover, CS NT-proBNP, CS IL-6 and CS IL-1ß serum concentrations were inversely related to the echocardiographically determined left ventricular ejection fraction (LVEF) (r = -0.61, P < 0.001; r = -0.71, P < 0.001 and r = -0.48, P = 0.005, respectively). A positive relationship was found between CA 125 and IL-1ß (r = 0.51, P = 0.003) in CS serum and between CA 125 and IL-6 (r = 0.43, P = 0.015), TNF-α (r = 0.46, P = 0.008) in PV serum. CA 125 concentrations were closely related to NT-proBNP both in CS (r = 0.46, P = 0.008) and PV (r = 0.52, P = 0.002). CONCLUSIONS: CS sampling of NT-proBNP, CA 125 and pro-anti-inflammatory cytokines provides an additional insight into the possible mechanisms by which these biomarkers lead to left ventricular remodeling. Our results clearly suggest that serum NT-proBNP and CA 125 levels not only in PV, but also in CS of patients with CHF, may be dependent on inflammation as a consequence of cytokine network activation.

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca2+-Activated K+ Current in Patients with Chronic Atrial Fibrillation.

BACKGROUND Increased small-conductance Ca2+-activated K+ current (SK), abnormal intracellular Ca2+ handling, and enhanced expression and activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been found in clinical and/or experimental models of atrial fibrillation (AF), but the cumulative effect of these phenomena and their mechanisms in AF are still unclear. This study aimed to test the hypothesis that CaMKII increases SK current in human chronic AF. MATERIAL AND METHODS Right atrial appendage tissues from patients with either sinus rhythm (SR) or AF and neonatal rat atrial myocytes were used. Patch clamp, qRT-PCR, and Western blotting techniques were used to perform the study. RESULTS Compared to SR, the apamin-sensitive SK current (IKAS) was significantly increased, but the mRNA and protein levels of SK1, SK2, and SK3 were significantly decreased. In AF, the steady-state Ca2+ response curve of [i]IKAS[/i] was shifted leftward and the [Ca2+]i level was significantly increased. CaMKII inhibitors (KN-93 or autocamtide-2-related inhibitory peptide (AIP)) reduced the IKAS in both AF and SR. The inhibitory effect of KN-93 or AIP on [i]IKAS[/i] was greater in AF than in SR. The expression levels of calmodulin, CaMKII, and autophosphorylated CaMKII at Thr287 (but not at Thr286) were significantly increased in AF. Furthermore, KN-93 inhibited the expression of (Thr287)p-CaMKII and SK2 in neonatal rat atrial myocytes. CONCLUSIONS SK current is increased via the enhanced activation of CaMKII in patients with AF. This finding may explain the difference between SK current and channels expression in AF, and thus may provide a therapeutic target for AF.

The relationship between the P wave and local atrial electrogram in predicting conduction block during catheter ablation of cavo-tricuspid isthmus-dependent atrial flutter.

PURPOSE: The endpoint for radiofrequency catheter ablation (RFA) of cavo-tricuspid isthmus (CTI)-dependent atrial flutter (AFL) is complete conduction block along the CTI. The purpose of this study is to evaluate the utility of the temporal relationship between the P wave and the local atrial electrograms in determining complete CTI block. METHODS: RFA of CTI was performed in 125 patients (age 63 ± 11 years). During pacing from the coronary sinus (CS), the intervals from the peak of the P wave (Ppeak) in lead V1 to the second component of the local atrial electrogram (A2) along the ablation line (Ppeak-A2) and from the end of the P wave (Pend) to A2 (Pend-A2) were investigated before and after complete block in the first 100 patients (training set). In the next 25 patients (validation set), Ppeak-A2 and Pend-A2 intervals were prospectively assessed to determine CTI block. RESULTS: The mean Ppeak-A2 and Pend-A2 immediately before complete block were - 15±24 and - 39±23 ms compared to 49 ± 17 and 21 ± 16 ms after CTI block (P < 0.0001). Ppeak-A2 ≥ 20 ms and Pend-A2 ≥ 0 ms predicted CTI block with 98% sensitivity and 95% specificity and 96% sensitivity and 100% specificity, respectively. In the validation set, the positive and negative predictive values of Ppeak-A2 ≥ 20 ms or Pend-A2 ≥ 0 ms were 100 and 96%, respectively. The diagnostic accuracy was 98%. CONCLUSIONS: During pacing from the CS, the temporal relationship between the P wave in lead V1 and A2 is a simple and reliable indicator of complete block during RFA of CTI-AFL.

Association of Difference in Coronary Sinus Diameter by Computed Tomographic Angiography Between Patients in and Not in Stable Atherosclerotic Plaque(S).

BACKGROUND Pathological finding fail to describe the morphology of coronary arterial plaques. Retrograde cardiac arteriography is a complicated procedure and does not detect all left posterior and marginal veins of the heart. Magnetic resonance angiography has long scan time and low spatial resolution. The objective of the present study was to assess the possible utility of the difference in coronary sinus diameter to quantify stable atherosclerotic plaque(s) using 256-slice coronary computed tomographic angiography. MATERIAL AND METHODS A total of 336 patients were divided into 2 groups with 168 patients each. Patients who had heart failure were included in the study group and those who did not were included in the non-study group. Patients were subjected to cross-sectional study. Cardiovascular images were performed with 256-slice coronary computed tomographic angiography with a prospective electrocardiogram and clinical manifestation. Two-tailed paired t test following Dunnett's multiple comparison tests was performed for the quantitative measurement of coronary computed tomographic angiography and clinical manifestation at 99% confidence level. RESULTS The clinical manifestation did not clearly show cardiac abnormality. The diameters of the superoinferior coronary sinus ostium was than that of the anteroposterior coronary sinus ostium, (p<0.0001, q=26.325). There was the difference in size of the coronary sinus ostium between patients in and not in heart failure (p<0.0001). The study group patients had longer coronary sinuses than patients in the non-study group (p<0.0001). CONCLUSIONS 256-slice computed tomographic angiography is a feasible and is non-invasive bio-tool for evaluation of coronary artery anatomy.

A simplified approach for evaluating sustained slow pathway conduction for diagnosis and treatment of atrioventricular nodal reentry tachycardia in children and adults.

PURPOSE: During incremental atrial pacing in patients with atrioventricular nodal reentrant tachycardia, the PR interval often exceeds the RR interval (PR > RR) during stable 1:1 AV conduction. However, the PR/RR ratio has never been evaluated in a large group of patients with pacing from the proximal coronary sinus and after isoproterenol challenge. Our study validates new site of pacing and easier method of identification of PR > RR. MATERIAL AND METHODS: A prospective protocol of incremental atrial pacing from the proximal coronary sinus was carried out in 398 patients (AVNRT-228 and control-170). The maximum stimulus to the Q wave interval (S-Q = PR), SS interval (S-S), and Q-Q (RR) interval were measured at baseline and 10 min after successful slow pathway ablation and after isoproterenol challenge (obligatory). RESULTS: The mean maximum PR/RR ratios at baseline were 1.17 ±â€¯0.24 and 0.82 ±â€¯0.13 (p < 0.00001) in the AVNRT and controls respectively. There were no PR/RR ratios ≥1 at baseline and after isoproterenol challenge in 12.3% of the AVNRT group and in 95.9% of the control group (p < 0.0001). PR/RR ratios ≥1 were absent in 98% of AVNRT cases after slow pathway ablation/modification in children and 99% of such cases in adults (P = NS). The diagnostic performance of PR/RR ratio evaluation before and after isoproterenol challenge had the highest diagnostic performance for AVNRT with PR/RR > = 1 (sensitivity: 88%, specificity: 96%, PPV-97%, NPV-85%). CONCLUSIONS: The PR/RR ratio is a simple tool for slow pathway substrate and AVNRT evaluation. Eliminating PR/RR ratios ≥1 may serve as a surrogate endpoint for slow pathway ablation in children and adults with AVNRT.