Coronary Artery Tracking in 3D Cardiac CT Images Using Local Morphological Reconstruction Operators

Automatic segmentation and tracking of the coronary artery tree from Cardiac Multislice-CT images is an important goal to improve the diagnosis and treatment of coronary artery disease. This paper presents a semi-automatic algorithm (one input point per vessel) based on morphological grayscale local reconstructions in 3D images devoted to the extraction of the coronary artery tree. The algorithm has been evaluated in the framework of the Coronary Artery Tracking Challenge 2008 [1], obtaining consistent results in overlapping measurements (a mean of 70% of the vessel well tracked). Poor results in accuracy measurements suggest that future work should refine the centerline extraction. The algorithm can be efficiently implemented and its general strategy can be easily extrapolated to a completely automated centerline extraction or to a user interactive vessel extraction

Low-Intensity Pulsed Ultrasound Improves the Functional Properties of Cardiac Mesoangioblasts

Cell-based therapy is a promising approach for many diseases, including ischemic heart disease. Cardiac mesoangioblasts are committed vessel-associated progenitors that can restore to a significant, although partial, extent, heart structure and function in a murine model of myocardial infarction. Low-intensity pulsed ultrasound (LIPUS) is a noninvasive form of mechanical energy that can be delivered into biological tissues as acoustic pressure waves, and is widely used for clinical applications including bone fracture healing. We hypothesized that the positive effects of LIPUS on bone and soft tissue, such as increased cell differentiation and cytoskeleton reorganization, could be applied to increase the therapeutic potential of mesoangioblasts for heart repair. In this work, we show that LIPUS stimulation of cardiac mesoangioblasts isolated from mouse and human heart results in significant cellular modifications that provide beneficial effects to the cells, including increased malleability and improved motility. Additionally, LIPUS stimulation increased the number of binucleated cells and induced cardiac differentiation to an extent comparable with 5´-azacytidine treatment. Mechanistically, LIPUS stimulation activated the BMP-Smad signalling pathway and increased the expression of myosin light chain-2 together with upregulation of β1 integrin and RhoA, highlighting a potentially important role for cytoskeleton reorganization. Taken together, these results provide functional evidence that LIPUS might be a useful tool to explore in the field of heart cell therapy

Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome

The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential. This delay in cellular repolarization can lead to potentially fatal arrhythmias. One form of LQTS (LQT3) has been linked to the human cardiac voltage-gated sodium channel gene (SCN5A). Three distinct mutations have been identified in the sodium channel gene. The biophysical and functional characteristics of each of these mutant channels were determined by heterologous expression of a recombinant human heart sodium channel in a mammalian cell line. Each mutation caused a sustained, non-inactivating sodium current amounting to a few percent of the peak inward sodium current, observable during long (>50 msec) depolarizations. The voltage dependence and rate of inactivation were altered, and the rate of recovery from inactivation was changed compared with wild-type channels. These mutations in diverse regions of the ion channel protein, all produced a common defect in channel gating that can cause the long QT phenotype. The sustained inward current caused by these mutations will prolong the action potential. Furthermore, they may create conditions that promote arrhythmias due to prolonged depolarization and the altered recovery from inactivation. These results provide insights for successful intervention in the disease.

Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: Insights into disease pathogenesis and troponin function

Mutations in a number of cardiac sarcomeric protein genes cause hypertrophic cardiomyopathy (HCM). Previous findings indicate that HCM-causing mutations associated with a truncated cardiac troponin T (TnT) and missense mutations in the β-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. In contrast, Lin et al. [Lin, D., Bobkova, A., Homsher, E. & Tobacman, L. S. (1996) J. Clin. Invest. 97, 2842–2848] characterized a TnT point mutation (Ile79Asn) and concluded that it might lead to hypercontractility and, thus, potentially a different mechanism for HCM pathogenesis. In this study, three HCM-causing cardiac TnT mutations (Ile79Asn, Arg92Gln, and ΔGlu160) were studied in a myotube expression system. Functional studies of wild-type and mutant transfected myotubes revealed that all three mutants decreased the calcium sensitivity of force production and that the two missense mutations (Ile79Asn and Arg92Gln) increased the unloaded shortening velocity nearly 2-fold. The data demonstrate that TnT can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a greater role in modulating muscle contractile performance than was recognized previously. Furthermore, these data suggest that these TnT mutations may cause disease via an increased energetic load on the heart. This would represent a second paradigm for HCM pathogenesis.

Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A

Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA have elevated blood pressures and hearts exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation are evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in one of 16 females in our study. Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients.

Lipotoxic heart disease in obese rats: Implications for human obesity

To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-α. Levels of ceramide, a mediator of apoptosis, were 2–3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.

Cardiac βARK1 inhibition prolongs survival and augments β blocker therapy in a mouse model of severe heart failure

Chronic human heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased levels of βAR kinase 1 (βARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of βARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of βARK1 (βARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca2+-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 ± 1 weeks). In contrast, CSQ/βARKct mice exhibited a significant increase in mean survival age (15 ± 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/βARKct, left ventricular end diastolic dimension 5.60 ± 0.17 mm vs. 4.19 ± 0.09 mm, P < 0.005; % fractional shortening, 15 ± 2 vs. 36 ± 2, P < 0.005). The enhancement of the survival rate in CSQ/βARKct mice was substantially potentiated by chronic treatment with the βAR antagonist metoprolol (CSQ/βARKct nontreated vs. CSQ/βARKct metoprolol treated, 15 ± 1 weeks vs. 25 ± 2 weeks, P < 0.0001). Thus, overexpression of the βARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with β-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of βARK1 inhibition.

Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy.

In 10-30% of hypertrophic cardiomyopathy kindreds, the disease is caused by > 29 missense mutations in the cardiac beta-myosin heavy chain (MYH7) gene. The amino acid sequence similarity between chicken skeletal muscle and human beta-cardiac myosin and the three-dimensional structure of the chicken skeletal muscle myosin head have provided the opportunity to examine the structural consequences of these naturally occurring mutations in human beta-cardiac myosin. This study demonstrates that the mutations are related to distinct structural and functional domains. Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close proximity to the interface of the heavy chain with the essential light chain. The remaining five mutations are in the myosin rod. The locations of these mutations provide insight into the way they impair the functioning of this molecular motor and also into the mechanism of energy transduction.

Iontophoresis for modulation of cardiac drug delivery in dogs.

Cardiac arrhythmias are a frequent cause of death and morbidity. Conventional antiarrhythmia therapy involving oral or intravenous medication is often ineffective and complicated by drug-associated side effects. Previous studies from our laboratory have demonstrated the advantages of cardiac drug-polymer implants for enhanced efficacy for cardiac arrhythmia therapy compared with conventional administration. However, these studies were based on systems that deliver drugs at a fixed release rate. Modulation of the drug delivery rate has the advantage of regulating the amount of the drug delivered depending upon the disease state of the patient. We hypothesized that iontophoresis could be used to modulate cardiac drug delivery. In this study, we report our investigations of a cardiac drug implant in dogs that is capable of iontophoretic modulation of the administration of the antiarrhythmic agent sotalol. We used a heterogeneous cation-exchange membrane (HCM) as an electrically sensitive and highly efficient rate-limiting barrier on the cardiac-contacting surface of the implant. Thus, electric current is passed only through the HCM and not the myocardium. The iontophoretic cardiac implant demonstrated in vitro drug release rates that were responsive to current modulation. In vivo results in dogs have confirmed that iontophoresis resulted in regional coronary enhancement of sotalol levels with current-responsive increases in drug concentrations. We also observed acute current-dependent changes in ventricular effective refractory periods reflecting sotalol-induced refractoriness due to regional drug administration. In 30-day dog experiments, iontophoretic cardiac implants demonstrated robust sustained function and reproducible modulation of drug delivery kinetics.

Interplay between cardiac function and heart development

Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease. This requires cardiomyocytes to be mechanically durable and able to mount coordinated responses to a variety of environmental signals on different time scales, including cardiac pressure loading and electrical and hemodynamic forces. During physiological growth, myocytes, endocardial and epicardial cells have to adaptively remodel to these mechanical forces. Here we review some of the recent advances in the understanding of how mechanical forces influence cardiac development, with a focus on fluid flow forces. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Indications for treatment in adults with tricuspid valve dysfunction due to a congential cardiac anomaly

The tricuspid valve is frequently affected in adults with congenital heart disease (CHD). Disease of this valve can occur primarily or develop secondary to changes in the right ventricle caused by other defects. Quantitative echocardiographic assessment of tricuspid regurgitation is essential to assess its cause and prognosis. Treatment options vary depending on the underlying defect and right ventricular function. Surgical management of tricuspid valve disease is complex and evolving.

Evidence of cardiac injury and arrhythmias in dogs with acute kidney injury

OBJECTIVES Cardiac involvement in the course of acute kidney injury is described in humans as cardiorenal syndrome type 3 but has received only limited attention in dogs. This study was designed to evaluate cardiac injury and dysfunction in acute kidney injury in dogs and its association with outcome. METHODS This prospective cohort study enrolled 24 client-owned dogs with acute kidney injury. Cardiac disorders were evaluated with thoracic radiographs, echocardiography, 24-hour Holter monitoring and cardiac troponin I concentrations within 2 days of admission and 7 to 10 days later. RESULTS Most dogs were diagnosed with leptospirosis (n=18, 75%) and presented with moderate-to-severe acute kidney injury, International Renal Interest Society grades III to V. Dogs with ê100 ventricular premature complexes per 24 hour in the first examination (n=8) had significantly higher initial cTnI concentrations (P=0·007) compared to dogs with fewer than 100. In receiver operating characteristic curve analysis, the number of ventricular premature complexes was predictive of outcome (AUC 0·83, P<0·001). CLINICAL SIGNIFICANCE Acute kidney injury seems to be associated with cardiac injury and arrhythmias in dogs. The data do not indicate a cardiac cause of poor outcome in dogs with increased number of ventricular premature complexes but the association may reflect the severity of disease.

Drugs and heart disease; a review of research grants supported by the National Heart Institute July 1, 1949 to June 30, 1962.

Includes bibliographies.

Air pollution exposure and novel biomarkers of inflammation and cardiac stress in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air)

Thesis (Master's)--University of Washington, 2016-06