Biomedical subjects
Publications and source records attributed to Valentin Fuster.
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The ability to specifically image macrophages may enable improved detection and characterization of atherosclerosis. In this study we evaluated the in vitro uptake of gadolinium (Gd)-containing immunomicelles (micelles linked to macrophage-specific antibody), micelles, and standard contrast agents by murine macrophages, and sought to determine whether immunomicelles and micelles improve ex vivo imaging of apolipoprotein E knockout (ApoE KO) murine atherosclerosis. Murine RAW 264.7 macrophages were incubated with Gd-DTPA, micelles, and immunomicelles. Cell pellets were prepared and imaged using a 1.5 T MR system with an inversion recovery spin-echo sequence to determine the in vitro T1 values. Ex vivo analysis of mouse aortas was performed using a 9.4T MR system with a high-spatial-resolution sequence (78x39x78 microm3). The T1 value was significantly decreased in cells treated with micelles compared to Gd-DTPA (P<0.0001), and in cells incubated at 4 degrees C with immunomicelles compared to micelles (P<0.05). Ex vivo MRI signal intensity (SI) was significantly increased by 81% and 20% in aortas incubated with immunomicelles and micelles, respectively. Confocal microscopy demonstrated in vitro and ex vivo uptake of fluorescent immunomicelles by macrophages. Immunomicelles and micelles improve in vitro and ex vivo MR detection of macrophages, and may prove useful in the detection of macrophage-rich plaques.
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OBJECTIVE: This study used a canine model of abdominal aortic aneurysms (AAAs) to compare intra-aneurysmal pressure and thrombus formation after exclusion with Dacron and expanded polytetrafluoroethylene (ePTFE) stent-grafts. METHODS: Prosthetic AAAs with implanted strain-gauge pressure transducers were treated by stent-graft exclusion using Food and Drug Administration-approved devices in 10 mongrel dogs: five Dacron (AneuRx) and five ePTFE (original Excluder). Intra-aneurysmal pressure was measured over 4 weeks after AAA exclusion and indexed to the systemic pressure, represented as a percentage of a simultaneously obtained systemic pressure (value = 1.0). Magnetic resonance imaging (MRI) of the intra-aneurysmal thrombus was performed at 1, 2, and 4 weeks after exclusion and expressed as a signal-to-noise ratio (S:N) to control for background signal intensity. Comparisons of pressures and S:N between the two stent-grafts was analyzed with the Student's t test. Intra-aneurysmal thrombus was characterized histologically. RESULTS: In animals excluded with both Dacron and ePTFE stent-grafts, the intra-aneurysmal pressure was nonpulsatile and reduced to <30% of systemic pressure. Significantly greater pressure transmission was observed after AAA exclusion using ePTFE compared with Dacron stent grafts (systolic pressure: ePTFE, 0.28 +/- 0.12 vs Dacron, 0.11 +/- 0.02, P < .001; mean pressure: ePTFE, 0.16 +/- 0.08 vs Dacron, 0.06 +/- 0.02, P < .001). MRI confirmed the absence of perfusion in all aneurysms. The T1-weighted signal intensity remained persistently elevated (S:N at 1 week, 2.7 +/- 0.4 vs 2 weeks, 4.0 +/- 0.2 vs 4 weeks, 5.4 +/- 1.3) in ePTFE-treated intra-aneurysmal thrombus, suggesting an absence of thrombus organization. In contrast, progressive evolution of T1 signal intensity in aneurysms excluded by Dacron stent-grafts was consistent with maturation from intact red blood cells (S:N at 1 week, 3.3 +/- 0.4) to methemoglobin (S:N at 2 weeks, 6.1 +/- 0.8), and then hemosiderin and ferritin (S:N at 4 weeks, 2.4 +/- 0.5). Histologically, ePTFE-excluded aneurysms contained poorly organized thrombus with red blood cell fragments and haphazardly arranged fibrin deposition indicative of active remodeling and continued influx of transudated serum. In aneurysms excluded by Dacron stent-grafts, dense, mature collagenous connective tissue and organized fibrin were present, indicative of greater thrombus organization. CONCLUSIONS: Stent-graft treatment reduces intra-aneurysmal pressure to <30% of systemic pressure when no endoleak is present; however, significantly greater pressure is present in aneurysms treated with porous ePTFE stent-grafts than Dacron grafts. Histologic and MRI imaging analysis suggest that active transudation of serous blood components may be contributing to this increased intra-aneurysmal pressure.
Definitive recommendations on anticoagulation strategy in pregnant women who have prosthetic heart valves are lacking because of the paucity of prospectively collected data. The use of warfarin, UFH, LMWH, or any combination of these choices has potentially adverse outcomes for the mother and fetus. Although there is no treatment option that has proven to be completely satisfactory, there is agreement that failures are most often due to underdosing and the lack of intensive monitoring of anticoagulation. A careful discussion with the patient must be undertaken so that she and the clinician can come to a decision about the most appropriate protocol.
The past decade has seen the emergence of paradigm shifts in concepts involving cardiovascular tissue regeneration, including the idea that adult stem cells originate in hematopoietic or bone marrow cells, the belief that even adult organs, such as the heart and nervous system, are capable of post-mitotic regeneration, and the concept of inherent plasticity in cells that have undergone limited lineage differentiation. There has consequently been a flurry of proposed regenerative strategies, and safety and limited efficacy data from both animal and limited human trials have been presented. The drive to push these advances from the bench to the bedside has created a unique environment where the therapeutic agents, delivery approaches, and methods of measuring efficacy (often imaging technology) are evolving practically in parallel. The encouraging results of recent cell-therapy trials should therefore be assessed cautiously and in consonance with an understanding of the advantages and limitations of delivery strategies and end points. Arguably, the use of imaging technologies to evaluate surrogate end points might help overcome the difficulty posed by large sample sizes required for hard end point trials in cardiovascular therapeutics. Cardiac magnetic resonance imaging is one of the most sensitive techniques available to assess spatial and temporal changes following local or systemic therapies, and the availability of a bevy of complementary techniques enables interrogation of physiology, morphology, and metabolism in one setting. We contend that cardiac magnetic resonance imaging is ideally suited to assess response to myocardial regeneration therapy and can be exploited to yield valuable insights into the mechanism of action of myocardial regeneration therapies.
Heart failure is a deadly disease. Every year, tens of thousands of patients die from this condition, many of them suddenly. Efforts aimed at reducing mortality centered initially on antagonizing the neurohormonal system, which is maladaptively upregulated in response to myocardial failure. Antagonists of the renin-angiotensin-aldosterone and adrenergic nervous systems have reduced the rates of cardiovascular mortality and sudden cardiac death. Antiarrhythmic drug therapy has not fared as well. Consequently, efforts to reduce the risk of sudden death have focused on the use of implantable cardioverter-defibrillators (ICDs). How best to identify patients who will benefit from this invasive and expensive therapy has yet to be clearly determined. In this review, we discuss the effectiveness of ICDs in primary and secondary prevention of sudden death in heart failure patients, and examine the impact that the use of ICDs has had on clinical decision making.
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BACKGROUND: A 57-year-old man presented with dyspnea and presyncope on exertion. He had previously been diagnosed with hypertension, hypercholesterolemia and atrial fibrillation. A soft (grade II/VI), dynamic continuous murmur was noted in the mid precordium. INVESTIGATIONS: Electrocardiography, stress echocardiography and coronary angiography. DIAGNOSIS: Right coronary artery to coronary sinus fistula with coronary steal, exertional ischemia and ventricular arrhythmia. MANAGEMENT: Coil embolization of coronary left ventricular fistula.
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