The Annexin code: revealing endocarditis.
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Annexin A5↗
Biomedical subjects
Jagat Narula
Publications and source records attributed to Jagat Narula.
Left ventricular structure and function: basic science for cardiac imaging.
The myofiber geometry of the left ventricle (LV) changes gradually from a right-handed helix in the subendocardium to a left-handed helix in the subepicardium. In this review, we associate the LV myofiber architecture with emerging concepts of the electromechanical sequence in a beating heart. We discuss: 1) the morphogenesis and anatomical arrangement of muscle fibers in the adult LV; 2) the sequence of depolarization and repolarization; 3) the physiological inhomogeneity of transmural myocardial mechanics and the apex-to-base sequence of longitudinal and circumferential deformation; 4) the sequence of LV rotation; and 5) the link between LV deformation and the intracavitary flow direction observed during each phase of the cardiac cycle. Integrating the LV structure with electrical activation and motion sequences observed in vivo provides an understanding about the spatiotemporal sequence of regional myocardial performance that is essential for noninvasive cardiac imaging.
Aging↗
Activation of apoptotic caspase cascade during the transition to pressure overload-induced heart failure.
OBJECTIVES: A pressure overload model was developed to simulate aortic stenosis and assess caspase activity during the transition to heart failure. BACKGROUND: Cardiomyocyte apoptosis is implicated in the pathogenesis of heart failure, and caspase activation is central to this pathophysiological process. METHODS: A total of 10 sheep were banded with variable aortic constriction devices, progressively inflated to increase left ventricular (LV) afterload. Serial LV endomyocardial biopsy samples were obtained to measure caspase activity and presence of apoptosis. RESULTS: Over the first 3 to 4 weeks, hypertrophy developed in the sheep (LV mass index 90.8 +/- 4.9 g/m2 vs. 44.0 +/- 3.0 g/m2, p < 0.01), followed by gradual dilatation of the left ventricle (diastolic LV internal diameter 4.23 +/- 0.08 cm vs. 3.39 +/- 0.07 cm, p < 0.01). Ventricular function remained stable until 7 to 8 weeks after banding, when there was significant deterioration (fractional shortening 18.3 +/- 2.4% vs. 46.9 +/- 2.6%, p < 0.01), associated with clinical heart failure. Serial LV endomyocardial biopsy samples were obtained at each echocardiographically defined stage (LV hypertrophy, LV dilation, and LV failure). Activity of caspases-3, -8, and -9 (measured by specific fluorogenic peptide substrates and immunohistochemistry) increased progressively, particularly with the onset of myocardial dysfunction (caspase-3 7.92 +/- 1.19 vs. 1.00 +/- 0.15, caspase-8 1.94 +/- 0.21 vs. 1.00 +/- 0.04, caspase-9 5.87 +/- 0.97 vs. 1.00 +/- 0.18 relative fluorescent units, p < 0.05). No evidence of deoxyribonucleic acid (DNA) fragmentation, however, was identified by immunohistochemical assays. CONCLUSIONS: Activation of cardiomyocyte caspase enzymes occurs during the transition to heart failure, without completion of apoptotic DNA fragmentation. Increased activity of caspase-8 and -9 suggests both mitochondrial and death-receptor mediated pathways are involved in this pathological process. Further knowledge of these pathways may stimulate development of apoptosis-based strategies for slowing progression of heart failure in aortic stenosis patients.
Animals↗
Imaging vulnerable plaque by ultrasound.
Diagnostic techniques to identify vulnerable plaques are rapidly evolving. Intravascular ultrasound (IVUS) has the ability to detect and localize plaque as well as quantitate plaque burden. Recent IVUS studies have suggested that patients presenting with acute coronary syndromes have an approximate 25% incidence of additional ruptured plaques in arteries other than the culprit lesion. The ability of IVUS to detect vulnerable plaques before rupture is currently being evaluated by novel techniques. Initially, IVUS was shown to be able to characterize plaque broadly as calcified or fibrofatty but was limited in its ability to more precisely detect lipid-rich plaques, necrotic cores, and thrombus. Recent advances in new applications of IVUS, such as integrated backscatter, wavelet analysis, and virtual histology, have focused on evaluating and mathematically transforming the radiofrequency signal from ultrasound waves into a color-coded representation of plaque characteristics such as lipid, fibrous tissue, calcification, and necrotic core. In addition, targeted contrast agents, applicable to both intravascular and transthoracic studies, are being evaluated in experimental models and aim to highlight specific plaque components, such as endothelial adhesion molecules and other plaque components that might be useful in targeting vulnerable plaques. These advances pave the way for future clinical trials in assessing the ability of such techniques to diagnose vulnerable plaques and to assess the effects of both pharmacologic and mechanical therapies on plaque characteristics.
Atherosclerosis↗
Radionuclide imaging for the detection of inflammation in vulnerable plaques.
Imaging of atheromatous plaques has traditionally centered on assessing the degree of luminal stenosis. More recently it has become clear that the vulnerable atherosclerotic plaques responsible for the majority of life-threatening syndromes are characterized by high numbers of inflammatory cells and proteins. This has highlighted the urgent need for suitable imaging techniques that can identify and quantify levels of inflammation within atheromatous lesions. Positron emission tomography and single-photon emission computed tomography imaging hold promise in this regard. Tracer compounds capable of assessing macrophage recruitment, foam cell generation, matrix metalloproteinase production, macrophage apoptosis, and macrophage metabolism have been developed and tested in the carotid and peripheral circulation. The identification of inflamed lesions within the coronary circulation, however, remains elusive owing to small plaque size, cardiac and respiratory motion, and lack of a suitable specific nuclear tracer.
Animals↗
New opportunities for identification and reduction of coronary risk: treatment of vulnerable patients, arteries, and plaques.
Advances in the understanding of the role of vulnerable plaque in the causation of coronary events, coupled with novel diagnostic and therapeutic approaches, create a new opportunity for progress against cardiovascular disease. The recognition that non-flow-limiting plaques often produce cardiac events has led to the development of invasive and non-invasive methods to identify such plaques prospectively. Treatments such as stenting, photodynamic therapy, and novel pharmaceutical agents are under consideration as methods to stabilize the vulnerable plaques and patients that might be detected, thereby enhancing both primary and secondary prevention. Despite the promise of the field, many issues remain to be resolved, including the focality versus systemic nature of the atherosclerotic process, the ability of detectors to identify the target for which they were developed and prove that such a target is linked to clinical events, and the efficacy of specific therapy. If vulnerable plaques and patients can be successfully identified and treated, there will be immense clinical benefits, accompanied by cost savings.
Coronary Artery Disease↗
The sequence of regional ventricular motion.
OBJECTIVE: The chronology of electrical events that mechanically activate the myocardium has been described as initiating at the level of the septum, spreading to the apex, then to the bodies of both ventricles and eventually to the base of the heart (apex-to base activation). It has recently been suggested that the myocardium is a single muscular band that conforms a double-loop helicoid. Contraction of the myocardium would follow the trajectory of the muscular fibers that originate at the pulmonary artery towards the body of the left ventricle and to the aorta (base-to apex contraction). This would explain the movements of the base of the heart and the twisting motion of the ventricles seen at magnetic resonance studies. METHODS: Temporal Fourier analysis of equilibrium radionucleide angiocardiography, by studying the topography of the regional myocardial mechanical displacement corresponding to the wave front of electro-mechanical activation, provides information on the sequence of regional ventricular contraction was used in 29 normal individuals to observe the sequence of myocardial motion. RESULTS: Analysis disclosed that the base of the heart first moves (right then left ventricle) and mechanical movement later descends to involve the apex and the septum. These findings are in concordance with the proposed activation of the helical myocardium and open the way to more complex studies. CONCLUSIONS: Although electrical activation of the myocardium (QRS complex) follows a septum-apex-body-base of the left ventricle sequence, mechanical activation follows a base-to-apex sequence. This is likely to be related to anisotropic propagation of the electromechanical stimulus throughout the myocardial band once the electrical stimulus has been delivered at the base of the heart.
Electrocardiography↗
Role of angiotensin receptor blockers in the prevention and treatment of arrhythmias.
The renin-angiotensin system is a key regulatory system that is activated in many forms of cardiovascular disease. It is well established that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are important therapeutic agents in the treatment of hypertension, myocardial infarction, and congestive heart failure. More recent research has suggested that renin-angiotensin system activation may also play a critical role in the genesis of atrial and ventricular arrhythmias. The possible role of renin-angiotensin system activation in arrhythmogenesis suggests that ACE inhibitors and ARBs may be important therapeutic agents in the prevention and treatment of arrhythmias. This review summarizes the current evidence for the use of ARBs in the treatment of atrial and ventricular arrhythmias.
Angiotensin II↗
Counting heads in the war against cancer: defining the role of annexin A5 imaging in cancer treatment and surveillance.
The unveiling of the heterogeneous nature of cell death modes has compromised the long-lived consensus that cancer treatment typically kills cancer cells through apoptosis. Moreover, it implies that measures of apoptosis may be misleading indicators of treatment efficacy. Simultaneously, it has become clear that phosphatidylserine exposition, traditionally considered a hallmark of apoptosis, is also associated with most other cell death programs, rendering phosphatidylserine an attractive target for overall cell death imaging. Annexin A5 binds with strong affinity to phosphatidylserine and hence offers an interesting opportunity for visualization of aggregate cell death, thus providing a fit benchmark for in vivo monitoring of anticancer treatment. This might be of significant value for pharmacologic therapy development as well as clinical monitoring of treatment success.
Animals↗
Cognitive dysfunction in advanced heart failure and prospective cardiac assist device patients.
BACKGROUND: Extended periods of hypoperfusion in an advanced heart failure (HF) places patients at high risk for neurobehavioral compromise, which has not been studied systematically. It is also not clear how intravenous inotropic therapy and mechanical cardiac assist devices (MCAD) affect cognitive function. METHODS: This prospective cross-sectional cognitive preliminary study evaluated 252 potential heart transplant candidates assessing functions in memory, motor, and processing speed. Patients were divided into three HF groups based on severity of disease: group 1 outpatients (n = 113), group 2 in-patients requiring inotropic infusion (n = 83), and group 3 inpatients likely requiring MCAD support (n = 56). Aggregate z-scores for memory, motor, and processing speed and independent samples t tests assessed intergroup differences on 13 cognitive measures. RESULTS: A broad pattern of cognitive impairment was observed within the advanced HF group; fewer deficits were found in group 1 outpatients and more severe deficits in group 3 MCAD subjects. A difference in motor functions was observed as the earliest abnormality, with group 3 showing significant changes compared with group 1. The most dramatic changes were seen in domain mental processing speed along with specific verbal and visual memory functions, which were slower in group 3 compared with groups 1 and 2. CONCLUSIONS: Cognitive deficits are common in advanced HF and worsen with increasing severity of HF. Appropriately designed and randomized studies will be needed to demonstrate if earlier MCAD implantation is warranted to arrest cognitive dysfunction and better postimplantation adaptation.
Adult↗
Clinical implications of apoptosis in ischemic myocardium.
Apoptosis, a genetically programmed form of cell death, contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. The apoptotic program is complex, involving both pro- and anti-apoptotic proteins, and apoptosis occurs when the equilibrium between these opposing factors is perturbed. Some of these factors are intrinsic to the apoptotic pathway, such as the pro- and anti-apoptotic members of the Bcl2 family. Other, extrinsic, cellular factors can also modify the outcome of the response to an apoptotic stimulus. In this review, we have focused on some of these extrinsic factors, such as STAT-1 as a pro-apoptotic agent and the urocortins and Bag-1 as anti-apoptotic factors, since these may be potential therapeutic targets. In addition, we discuss the profound cytoprotective effects of the antibiotic, minocycline.
Animals↗
Mechanisms of disease: apoptosis in heart failure--seeing hope in death.
Apoptosis or programmed cell death is an evolutionarily conserved process of cell death, wherein cells die without provoking significant inflammatory response. There is convincing evidence that apoptosis contributes to the progression of heart failure. Apoptosis occurs through a cascade of subcellular events including cytochrome c release into the cytoplasm and activation of proteolytic caspases. Activated caspases lead to fragmentation of cytoplasmic proteins, including contractile apparatus, to a variable extent. It is proposed that the release of cytochrome c from mitochondria and contractile protein loss in living heart muscle cells contributes to systolic dysfunction. Interestingly, despite extensive changes in the cytoplasm, nuclear damage, which is the final event in apoptosis, is rather infrequent in the failing heart. Since the nucleus remains unaffected and the genetic blueprint intact in cells with interrupted apoptosis, these heart muscle cells might be amenable to cytoplasmic reconstitution. This process of 'apoptosis interruptus' could allow development of novel strategies to reverse or attenuate heart failure.
Animals↗
Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5.
UNLABELLED: Transgenic mice such as apolipoprotein E-deficient (apoE(-/-)) and low-density-lipoprotein receptor-deficient (LDLR(-/-)) mice exhibit hypercholesterolemia and develop complex atherosclerotic lesions similar to those seen in humans. Radiolabeled annexin A5 has been successfully used to noninvasively image experimental and clinical atherosclerotic disease. We evaluated the feasibility of annexin A5 imaging in transgenic apoE(-/-) and LDLR(-/-) mice with or without a cholesterol diet. METHODS: Thirty-three mice (mean age, 62 +/- 0.9 wk old) were used. Of these 33 mice, apoE(-/-) mice with the cholesterol diet for 4 mo (n = 5) and without the cholesterol diet (n = 8) and LDLR(-/-) mice with the cholesterol diet for 6 mo (n = 7) and without the cholesterol diet (n = 7) were compared with 6 normal wild-type (C57BL/6) mice with the same genetic background. (99m)Tc-annexin A5 was injected in 31 animals for noninvasive imaging using micro-SPECT/CT. After in vivo micro-SPECT/CT, aortas were explanted to acquire ex vivo images and calculate the percentage injected dose per gram (%ID/g) annexin uptake, followed by histologic and immunohistochemical characterization. For the evaluation of precise target localization, biotinylated annexin A5 was injected in the remaining 2 normally fed apoE(-/-) mice. RESULTS: Aortic lesions were clearly visualized noninvasively by micro-SPECT and aorta calcification was detectable by micro-CT. The quantitative uptake of annexin A5 was highest in the cholesterol-fed apoE(-/-) (0.88 +/- 0.27 %ID/g) mice, followed by the normal chow-fed apoE(-/-) (0.60 +/- 0.16 %ID/g), the cholesterol-fed LDLR(-/-) (0.59 +/- 0.14 %ID/g), the chow-fed LDLR(-/-) (0.40 +/- 0.31 %ID/g), and the control (0.15 +/- 0.05 %ID/g) mice. The histologic extent of atherosclerosis paralleled radiotracer uptake, and immunohistochemical studies revealed a significant correlation between radiotracer uptake and both macrophage infiltration and the extent of apoptosis. Intravenously injected biotinylated annexin A5 localized in apoptotic and nonapoptotic macrophages. CONCLUSION: This study demonstrates the feasibility of noninvasive imaging of atherosclerosis with radiolabeled annexin A5 in transgenic mouse models of human atherosclerosis.
Animals↗
Annexin A5 inhibits engulfment through internalization of PS-expressing cell membrane patches.
Apoptosis and subsequent clearance of apoptotic cells are important for the prevention of diseases. Therefore, it is essential to understand the mechanisms underlying the biology of phagocytic clearance of apoptotic cells. The best characterized "eat me" signal on the surface of apoptotic cells is phosphatidylserine (PS). Recently, we demonstrated that annexin A5 mediates the internalization of PS-expressing membrane patches and down regulates surface expression of tissue factor. Here, we investigated the role of PS in the phagocytosis of apoptotic cells using annexin A5. Using a novel flow cytometric-based phagocytosis assay, we observed that engulfment was inhibited with 20% if annexin A5 was added to PS-expressing cells that had completed apoptosis. The inhibition increased to more than 50% if annexin A5 was added during the apoptotic process. This inhibition is specific for annexin A5, since the mutant M23 and annexin A1 did not further increase the inhibition of phagocytosis when added during the apoptotic process. Interestingly, cells with internalized annexin A5 still express PS at their surface. We conclude that other ligands within the PS-expressing membrane patch act together with PS as an "eat me" signal.
Animals↗
Ischemic versus nonischemic chest pain in the emergency room: echoes of contrast.
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Chest Pain↗
Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage.
Observational studies of necrotic core progression identify intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization. The rapid accumulation of erythrocyte membranes causes an abrupt change in plaque substrate characterized by increased free cholesterol within the lipid core and excessive macrophage infiltration. Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. Intimal neovascularization is predominantly thought to arise from the adventitia, where there are a plethora of pre-existing vasa vasorum. In lesions that have early necrotic cores, the majority of vessels invading from the adventitia occur at specific sites of medial wall disruption. A breech in the medial wall likely facilitates the rapid in-growth of microvessels from the adventitia, and exposure to an atherosclerotic environment stimulates abnormal vascular development characterized by disorganized branching and immature endothelial tubes with "leaky" imperfect linings. This network of immature blood vessels is a viable source of intraplaque hemorrhage providing erythrocyte-derived phospholipids and free cholesterol. The rapid change in plaque substrate caused by the excessive accumulation of erythrocytes may promote the transition from a stable to an unstable lesion. This review discusses the potential role of intraplaque vasa vasorum in lesion instability as it relates to plaque rupture.
Animals↗
Picking plaques that pop ...
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Arteriosclerosis↗
Highlights of the year in JACC 2004.
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Animals↗