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James S Forrester

Publications and source records attributed to James S Forrester.

18 recordsLinked to original sources
PubMed2006

Emerging strategies for increasing high-density lipoprotein.

High-density lipoprotein cholesterol is a potent and independent epidemiologic risk factor and is a proved antiatherosclerotic agent in animal models of atherosclerosis, acting through the principal mechanisms of accelerating cholesterol efflux and inhibiting oxidation and inflammation. Lifestyle modification increases serum levels by 5% to 15%, whereas niacin, the drug most widely used to increase high-density lipoprotein cholesterol, increases it by 25% to 35% at the highest doses. This review examines the potent methods of increasing high-density lipoprotein and/or enhancing reverse cholesterol transport, including cholesterol ester transfer protein inhibitors, apolipoprotein A-I Milano, D4F, the dual peroxisome proliferator-activated receptor agonists, and rimonabant, that are now in clinical trials. In conclusion, these new agents, used alone or in combination with existing therapies, carry the potential to markedly reduce the incidence of new coronary disease and cardiac events in this decade.

Animals↗
PubMed2005

Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties.

UNLABELLED: Direct intramyocardial injection of mesenchymal stem cells (MSCs) improves left ventricular ejection fraction (LVEF) and may increase ventricular arrhythmia in hearts with myocardial infarction (MI). We hypothesized that intravenous MSCs given early after acute MI would engraft in injured myocardium, improve LV function, and result in pro-arrhythmic electrical remodeling. We created an apical infarction in swine by balloon occlusion/reperfusion, administered diI-labeled allogeneic bone marrow derived MSCs intravenously 30 min post-reperfusion and measured LVEF and wall thickness at baseline, 1 month, and 3 months. Epicardial effective refractory periods (ERPs) were determined before sacrifice. At 3 months, treated pigs [n=7] had significantly higher LVEF than controls [n=8] (49+/-2% vs. 44+/-3%, P=0.015) and significantly less wall thickening of non-infarcted myocardium. ERPs were significantly shorter than controls at all pacing cycle lengths (P<or=0.002), suggesting a pro-arrhythmic potential. DiI was found in the lungs, in infarct, and peri-infarct myocardium. CONCLUSION: IV infusion of MSCs soon after acute MI in swine improves LVEF and limits wall thickening in the remote non-infarcted myocardium, consistent with a beneficial effect on post-MI ventricular remodeling. Since there is no need for immune suppression or clinical expertise, IV infusion of MSCs may expand the potential clinical application of stem cell therapy.

Animals↗
PubMed2005

Comparison of effectiveness of hand-carried ultrasound to bedside cardiovascular physical examination.

This study compared the accuracy of cardiovascular diagnoses by medical students operating a small hand-carried ultrasound (HCU) device with that of board-certified cardiologists using standard physical examinations. Sixty-one patients (38% women; mean age 70 +/- 19 years) with clinically significant cardiac disease had HCU studies performed by 1 of 2 medical students with 18 hours of training in cardiac ultrasound and physical examinations by 1 of 5 cardiologists. Diagnostic accuracy was determined by standard echocardiography. Two-hundred thirty-nine abnormal findings were detected by standard echocardiography. The students correctly identified 75% (180 of 239) of the pathologies, whereas cardiologists found 49% (116 of 239) (p <0.001). The students' diagnostic specificity of 87% was also greater than cardiologists' specificity of 76% (p <0.001). For nonvalvular pathologies (115 findings), students' sensitivity was 61%, compared with 47% for cardiologists (p = 0.040). There were 124 clinically significant valvular lesions (111 regurgitations, 13 stenoses). Students' and cardiologists' sensitivities for recognizing lesions that cause a systolic murmur were 93% and 62% (p <0.001), respectively. Students' sensitivity for diagnosing lesions that produce a diastolic murmur was 75%; cardiologists recognized 16% of these lesions (p <0.001). The diagnostic accuracy of medical students using an HCU device after brief echocardiographic training to detect valvular disease, left ventricular dysfunction, enlargement, and hypertrophy was superior to that of experienced cardiologists performing cardiac physical examinations.

Aged↗
PubMed2005

Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians.

Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol. Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by >50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective.

Animals↗
PubMed2005

Persistence of inflammatory cytokines cause a spectrum of chronic progressive diseases: implications for therapy.

Chronic progressive disease (CPD) are the Western world's major cause of mortality (National Center for Health Statistics. Vol. 52. National vital 176 statistics reports. Deaths: final data for 2001; 2003, p. 3). Most chronic diseases present with symptoms and signs specific for the dysfunctional organ. Nonetheless, substantial commonalities are identifiable at the tissue and cellular level. These include a striking increase in inflammatory cytokines in both the tissue and the serum, accompanied by tissue destruction, apoptosis and tissue fibrosis. Individual inflammatory cytokines possess the capacity to induce these tissue effects in vitro and in vivo. Further, an elevation in systemic levels of cytokines and CRP predict an increase risk at all stages of these diseases. Therapies that inhibit the stimuli, the mediators or the responses to persistent inflammation appear to have an inhibitory effect on progression of specific diseases. We hypothesize that a unifying paradigm for CPD can be constructed based on these observations. Destabilizing stimuli activate the normal protective homeostatic inflammatory response in tissue. As the stimulus is eliminated and tissue heals, the inflammatory response recedes, re-establishing homeostasis. If inflammatory cytokines persist, however, both cell apoptosis and tissue fibrosis can be induced. Two aspects of evolution provide a potential mechanistic basis for this hypothesis. We may speculate that Darwinian selection favored early development of a system that channeled a broad spectrum of external and internal challenges through a generic response system. Thus, the mediators that respond to noxious stimuli became universal throughout organisms and species. Because these genetic responses were part of the DNA programming of all cells prior to differentiation, the tissue response to inflammation is also both uniform in nature, and narrow in scope. Subsequent cell differentiation resulted in vast differences in tissue function, so that organ dysfunction appears with the myriad symptoms and signs we recognize as individual diseases. Interference with inflammatory cytokines, e.g., with HMG Coa reductase inhibitors, inhibits a spectrum of chronic progressive diseases, independent of any LDL lowering effect.

Apoptosis↗
PubMed2005

Intramyocardial injection of allogenic bone marrow-derived mesenchymal stem cells without immunosuppression preserves cardiac function in a porcine model of myocardial infarction.

BACKGROUND: We investigated the efficacy of directly injected allogenic bone marrow-derived mesenchymal stem cells in improving left ventricular function in a porcine model of myocardial infarction. METHODS: Left ventricular infarction was created in 16 adult Yorkshire pigs by coil embolization and thrombotic occlusion distal to the second diagonal artery. One month after myocardial infarction was induced, the animals were randomized to either direct injection of allogenic mesenchymal stem cells or sham treatment (culture medium). Allogenic bromodeoxyuridine-labeled mesenchymal stem cells (2 +/- 0.1 x 10(8)) were directly injected into the infarct and peri-infarct areas during an open chest procedure. No immunosuppressive therapy was used. The left ventricular function was measured using serial biplane left ventricular angiography at baseline, 30, 60, and 90 days before sacrifice. Mesenchymal stem cells were localized using bromodeoxyuridine, and differentiation of mesenchymal stem cells was assessed by confocal microscopic colocalization of bromodeoxyuridine with immunofluorescent antibodies specific for cardiomyocytes (troponin I and MF-20) and endothelial cells (von Willebrand factor). RESULTS: Mesenchymal stem cells labeled with bromodeoxyuridine engrafted the peri-infarct zone and colocalized with both cardiomyocyte-specific and endothelial cell-specific immunofluorescence. No intramyocardial bromodeoxyuridine was observed in sham-treated animals. At the time of the mesenchymal stem cell injection 30 days after myocardial infarction, the left ventricular ejection fraction (LVEF) was 58% +/- 3% in mesenchymal stem cell-treated pigs and 56% +/- 2% in sham-treated pigs (P = NS). LVEF deteriorated progressively thereafter in untreated pigs (8.5% and 10.5% decline at 60 days and 90 days after myocardial infarction, respectively), but was preserved in mesenchymal stem cell-treated pigs (2.1% increase and -2.0% decline at 60 and 90 days post-MI respectively) (P < .05). CONCLUSIONS: Direct intramyocardial injection of mesenchymal stem cells results in successful intramyocardial engraftment and differentiation into cardiomyocytes and endothelial cells and preserves left ventricular function after myocardial infarction in pigs.

Animals↗
PubMed2004

Common ancestors: chronic progressive diseases have the same pathogenesis.

In multiple organ systems, chronic progressive disease is characterized at the tissue level by increase in inflammatory cytokines, cell apoptosis and progressive fibrosis, suggesting a possible commonality of pathogenesis. This speculation is supported by the observation that elevated systemic levels of cytokines and/or CRP predict the appearance of disease, progression of disease, and disease complications. Some therapeutic interventions that reduce the expression of inflammatory cytokines, such as HMG Co-A reductase inhibitors, slow the progression of a number of chronic diseases, independent of their effect on cholesterol level. Taken together, these data suggest a unifying hypothesis for many chronic progressive diseases. Diverse noxious stimuli activate a normal protective inflammatory response. This response typically defervesces with elimination of the stimulus, reestablishing homeostasis. When homeostasis is not restored, that is, the inflammatory response persists, cell apoptosis and tissue fibrosis can result. The universality of this tissue response derives from the fact that all cells derive from the same blastocyst. Since cell differentiation results in different tissue functions, however, the clinical manifestations of disease are also vastly different, obscuring the underlying disease process. The relevance of this insight is that it provides a potential framework for testing old and new therapies which might inhibit a diverse set of clinical conditions at several levels of the disease process.

Alzheimer Disease↗
PubMed2004

Partial restoration of myocardial function and perfusion by cell therapy following myocardial infarction.

PURPOSE OF REVIEW: In animals, both skeletal myoblasts and stem cells partially restore myocardial function after MI. This review provides a critical analysis of the initial clinical trials of these two therapeutic strategies. RECENT FINDINGS: Direct injection of autologous skeletal myoblasts into the peri-infarct area has been performed at bypass surgery and by subendocardial injection in the catheterization laboratory. Both approaches appear to improve function significantly. Nonetheless, ventricular arrhythmias occur quite frequently in the first week after myoblast injection. In contrast, stem cells can be delivered to the injured myocardium by direct injection, by IV injection, or by bone marrow stimulation. The incidence of ventricular arrhythmia does not seem to increase. The magnitude of absolute improvement in cardiac ejection fraction, however, is only about 7%. The potential limitations of stem cell therapy are cell fusion, creating genetically abnormal cells, and the ability to deliver sufficient numbers of cells to have an important biologic effect. SUMMARY: Cell replacement therapy after MI has considerable promise for restoration of cardiac function. Nonetheless because important theoretical and practical questions remain unanswered, the methodology is not yet ready for widespread clinical application.

Cell Transplantation↗
PubMed2004

Stem-cell repair of infarcted myocardium: ready for clinical application?

In cell culture, adult bone marrow stem cells can develop the phenotypic characteristics of myocytes and endothelial cells, and express myocyte-specific and endothelium-specific proteins. In subsequent animal laboratory studies and early clinical trials, stem cells have been delivered to infarcted myocardium by direct injection, by intravascular injection, and by bone marrow stimulation. In animals, myocyte apoptosis is reduced, capillary density increases, and regional perfusion increases accompanied by a decrease in infarct size. Early clinical trials indicate that a variety of approaches is technically feasible and safe in the short term. The trials suggest that stem-cell therapy may induce a modest preservation of cardiac function. The methodology for clinical application of stem-cell therapy currently exists in most large heart hospitals. Nonetheless, until theoretical and practical limitations are resolved, it seems prudent to confine this therapy to randomized clinical trials.

Animals↗
PubMed2003

Angiographic changes in saphenous vein grafts are predictors of clinical outcomes.

BACKGROUND: Previous studies have suggested that angiographic evidence of disease progression in coronary arteries increases the risk of subsequent coronary clinical events. This study ascertained whether patients enrolled in the Post Coronary Artery Bypass Graft Clinical Trial (POST CABG) who had substantial progression of atherosclerosis in >or=1 saphenous vein grafts (on the basis of assessment of baseline and follow-up angiograms obtained 4-5 years after study entry), but who had not reported clinical symptoms before follow-up angiography, were at a higher risk of subsequent events than patients who did not have substantial progression of atherosclerosis (decrease >or=0.6 mm in lumen diameter at site of greatest change from baseline). METHODS: All 1351 patients enrolled in the trial underwent baseline angiography; only the 961 patients who had follow-up angiography and no coronary events before the follow-up study were included in this analysis. The clinical center staff contacted patients to ascertain the events that had occurred after follow-up angiography (approximately 3.4 years later). RESULTS: Sixty-nine patients had died; 870 patients or relatives were interviewed, and 22 patients could not be contacted. Univariable estimates of relative risk associated with substantial progression ranged from 2.2 (P <.001) for cardiovascular death or nonfatal myocardial infarction to 3.3 (P <.001) for revascularization. Multivariable and univariable estimates of risk were similar. CONCLUSIONS: The findings provide evidence that patients who had substantial progression of atherosclerosis in vein grafts are at an increased risk for subsequent coronary events and suggest that angiographic changes in vein grafts are appropriate surrogate measures for clinical outcomes.

Aged↗
PubMed2002

Prevention of plaque rupture: a new paradigm of therapy.

Acute coronary syndromes--unstable angina, myocardial infarction, and sudden cardiac death--are caused by acute disruption of an unstable coronary atheroma. Unstable plaques have three histologic characteristics: a large lipid core, many inflammatory cells, and a thin fibrous cap. Because the unstable plaque is not necessarily obstructive, it may cause no symptoms before rupture. The cellular processes that lead to the characteristic histologic features of unstable plaque have recently been identified. This new understanding of the cell biology of plaque instability suggests new therapeutic strategies: passivation of the endothelium, reduction of low-density lipoprotein (LDL) in the vessel wall by decreasing serum LDL levels or accelerating reverse cholesterol transport, inhibition of LDL oxidation, inhibition of inflammatory cytokine expression, and inhibition of thrombus formation. Although the morbidity and mortality resulting from acute coronary disease have been reduced by more than 50% over the past 30 years, it is reasonable to anticipate further reductions of similar magnitude in the decade ahead.

Cholesterol, HDL↗
PubMedDate not supplied

Risk stratification post-myocardial infarction: is early coronary angiography the more effective strategy?

The primary management strategy for the post-myocardial infarction patient continues to be controversial despite published guidelines. In part, this is the consequence of study designs that are not directly applicable to individual patients, but also to the rapidly changing pharmacological and mechanical device armamentarium that rapidly renders clinical trial results obsolete within a few years. This review attempts to highlight those areas where there is consensus as well as to explicate those situations where common clinical practice appears to be in conflict with accepted guidelines.

Acute Disease↗
PubMedDate not supplied

Lipoprotein lipase locus and progression of atherosclerosis in coronary-artery bypass grafts.

PURPOSE: Our aim was to test whether polymorphisms in the lipoprotein lipase (LPL) gene were associated with the progression of atherosclerosis in grafts examined in the Post-Coronary Artery Bypass Graft Trial (Post-CABG Trial). METHODS: 843 subjects in the post-CABG trial were genotyped for the LPL-D9N, N291S, PvuII, (TTTA)n, and HindIII polymorphisms. Associations between genotype and angiographically measured progression of atherosclerosis in grafts, medical history, and family history were examined. RESULTS: Greater progression of atherosclerosis was observed in subjects with LPL-HindIII 2/2 (56% versus 42% of those with other LPL HindIII genotypes, P = 0.025) and with LPL (TTTA)n 4/4 (63% versus 43% of those with other (TTTA)n genotypes, P = 0.020). Mantel-Haenszel analysis yielded an odds ratio of 1.84 for the effect of LPL HindIII 2/2 genotype on the progression of atherosclerosis in grafts (P = 0.015) and demonstrated that the effect of genotype on progression was of the same magnitude as, but independent of, the effect of drug treatment. CONCLUSION: The LPL-HindIII 2/2 genotype is a marker for genetic variation in the 3'-end of LPL that acts as an independent risk factor for the progression of atherosclerosis in grafts examined in the Post-CABG Trial.

Arteriosclerosis↗