The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years. The cohort will be selected from six US field centers. Approximately 38% of the cohort will be White, 28% African-American, 23% Hispanic, and 11% Asian (of Chinese descent). Baseline measurements will include measurement of coronary calcium using computed tomography; measurement of ventricular mass and function using cardiac magnetic resonance imaging; measurement of flow-mediated brachial artery endothelial vasodilation, carotid intimal-medial wall thickness, and distensibility of the carotid arteries using ultrasonography; measurement of peripheral vascular disease using ankle and brachial blood pressures; electrocardiography; and assessments of microalbuminuria, standard CVD risk factors, sociodemographic factors, life habits, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for use in nested case-control studies. DNA will be extracted and lymphocytes will be immortalized for genetic studies. Measurement of selected subclinical disease indicators and risk factors will be repeated for the study of progression over 7 years. Participants will be followed through 2008 for identification and characterization of CVD events, including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, and congestive heart failure; therapeutic interventions for CVD; and mortality.

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Multi-Ethnic Study of Atherosclerosis: Objectives and Design

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

Background Recent studies indicate that magnetic resonance imaging (MRI) after the administration of contrast material can be used to distinguish between reversible and irreversible myocardial ischemic injury regardless of the extent of wall motion or the age of the infarct. We hypothesized that the results of contrast-enhanced MRI can be used to predict whether regions of abnormal ventricular contraction will improve after revascularization in patients with coronary artery disease. Methods Gadolinium-enhanced MRI was performed in 50 patients with ventricular dysfunction before they underwent surgical or percutaneous revascularization. The transmural extent of hyperenhanced regions was postulated to represent the transmural extent of nonviable myocardium. The extent of regional contractility at the same locations was determined by cine MRI before and after revascularization in 41 patients. Results Contrast-enhanced MRI showed hyperenhancement of myocardial tissue in 40 of 50 patients before revascularizat...

https://www.nejm.org/doi/pdf/10.1056/NEJM200011163432003

The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction.

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

Background—Contrast MRI enhancement patterns in several pathophysiologies resulting from ischemic myocardial injury are controversial or have not been investigated. We compared contrast enhancement in acute infarction (AI), after severe but reversible ischemic injury (RII), and in chronic infarction. Methods and Results—In dogs, a large coronary artery was occluded to study AI and/or chronic infarction (n=18), and a second coronary artery was chronically instrumented with a reversible hydraulic occluder and Doppler flowmeter to study RII (n=8). At 3 days after surgery, cine MRI revealed reduced wall thickening in AI (5±6% versus 33±6% in normal, P<0.001). In RII, wall thickening before, during, and after inflation of the occluder for 15 minutes was 35±5%, 1±8%, and 21±10% and Doppler flow was 19.8±5.3, 0.2±0.5, and 56.3±17.7 (peak hyperemia) cm/s, respectively, confirming occlusion, transient ischemia, and reperfusion. Gd-DTPA–enhanced MR images acquired 30 minutes after contrast revealed hyperenhancement...

Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function.

Background—It has been postulated that depending on the type of exercise performed, 2 different morphological forms of athlete’s heart may be distinguished: a strength-trained heart and an endurance-trained heart. Individual studies have not tested this hypothesis satisfactorily. Methods and Results—The hypothesis of divergent cardiac adaptations in endurance-trained and strength-trained athletes was tested by applying meta-analytical techniques with the assumption of a random study effects model incorporating all published echocardiographic data on structure and function of male athletes engaged in purely dynamic (running) or static (weight lifting, power lifting, bodybuilding, throwing, wrestling) sports and combined dynamic and static sports (cycling and rowing). The analysis encompassed 59 studies and 1451 athletes. The overall mean relative left ventricular wall thickness of control subjects (0.36 mm) was significantly smaller than that of endurance-trained athletes (0.39 mm, P=0.001), combined endur...

The athlete's heart. A meta-analysis of cardiac structure and function.

Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxia induced apoptosis occurs. These resistant tumours probably have a more aggressive phenotype and may have decreased responsiveness to treatment. The key regulator of this process, hypoxia inducible factor 1 (HIF-1), can initiate apoptosis by inducing high concentrations of proapoptotic proteins, such as BNIP3, and can cause stabilisation of p53. However, during hypoxia, antiapoptotic proteins, such as IAP-2, can be induced, whereas the proapoptotic protein Bax can be downregulated. During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation. Understanding the regulation of apoptosis during hypoxia and the mechanisms of resistance to apoptosis might lead to more specific treatments for solid tumours.

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The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis.

Breast cancer is the leading cause of death among solid tumours in women, and its incidence is increasing in the West. Adjuvant chemotherapy and hormonal treatment improve survival but have potentially serious side effects, and are costly. Because adjuvant treatment should be given to high risk patients only, and traditional prognostic factors (lymph node status, tumour size) are insufficiently accurate, better predictors of high risk and treatment response are needed. Invasive breast cancer metastasises haematogenously very early on, so many breast cancer prognosticators are directly or indirectly related to proliferation. Although studies evaluating the role of individual proliferation regulating genes have greatly increased our knowledge of this complex process, the functional end result-cells dividing-has remained the most important prognostic factor. This article reviews the prognostic value of different proliferation assays in invasive breast cancer, and concludes that increased proliferation correlates strongly with poor prognosis, irrespective of the methodology used. Mitosis counting provides the most reproducible and independent prognostic value, and Ki67/MIB1 labelling and cyclin A index are promising alternatives that need methodological fine tuning.

https://jcp.bmj.com/content/jclinpath/57/7/675.full.pdf

Prognostic value of proliferation in invasive breast cancer: a review

The authors studied the reproducibility of repeated measurements of left ventricular volumes, weight, and wall stress as determined with cine and spin-echo magnetic resonance (MR) imaging. Two observers analyzed 40 serial MR imaging examinations twice, yielding a total of 160 repeated measurements. Estimates of 95% ranges for change were ejection fraction, 10% and 12%; wall mass, 16% and 21%; and wall stress, 22% and 20%, for measurements derived from cine MR imaging and spin-echo MR imaging, respectively. Reproducibility was not significantly different between cine and spin-echo MR imaging. Intraobserver, interobserver, and interexamination errors were quantitated with variance component analysis. Interexamination variability was the single most important contributor to total variance. Reproducibility of left ventricular chamber volume measurements with MR imaging is superior to that of other imaging modalities. In addition, MR imaging can provide reliable estimates of wall mass and wall stress. Efforts to improve reproducibility should be aimed at lowering interexamination variability.

Left ventricular measurements with cine and spin-echo MR imaging: a study of reproducibility with variance component analysis.

BACKGROUNDPulmonary regurgitation frequently occurs after surgical correction of tetralogy of Fallot. To date, reliable quantitation of pulmonary regurgitation has not been possible, and therefore the clinical significance of pulmonary regurgitation is controversial. Nuclear magnetic resonance (NMR) velocity mapping allows accurate measurement of volumetric flow. The feasibility and accuracy of NMR velocity mapping to quantify pulmonary regurgitation volumes are studied in patients after Fallot repair.METHODS AND RESULTSIn 18 patients (mean age, 16.5 +/- 6.5 years), late (12.6 +/- 5.2 years) after Fallot surgery, forward and regurgitant volume flow was measured in the main pulmonary artery with NMR velocity mapping. To validate the measurements of pulmonary forward flow, right ventricular stroke volume was used as an internal reference standard. Pulmonary regurgitation volumes were compared with the differences between the corresponding right and left ventricular stroke volumes. Ventricular volumes were m...

Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping.

E. E. van der Wall

Papers

The athlete's heart. A meta-analysis of cardiac structure and function.

The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis.

Prognostic value of proliferation in invasive breast cancer: a review

Left ventricular measurements with cine and spin-echo MR imaging: a study of reproducibility with variance component analysis.

Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping.