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Biomedical subjects

Gad Keren

Publications and source records attributed to Gad Keren.

18 recordsLinked to original sources
PubMed2003

Tyrphostin AG-556 reduces myocardial infarct size and improves cardiac performance in the rat.

TNF-alpha is a proinflammatory cytokine, abundantly expressed after myocardial infarction. It has been suggested that it exhibits myocardial suppressive and cytotoxic effects. AG-556 is a tyrosine kinase inhibitor synthesized based on its ability to reduce TNF-alpha production and cell toxicity, and to improve experimental models mediated by TNF-alpha (i.e., peritontitis and experimental autoimmune encephalomyelitis). Daily, for 7 days, rats were injected ip with either AG-556 dissolved in DMSO or with the control vehicle. Infarct size was determined in the hearts as well as in fibrous scar formation. Cardiac TNF-alpha expression was evaluated by ELISA and immunohistochemistry. Functional hemodynamic parameters were evaluated employing echocardiography prior to sacrifice. AG-556 treatment reduced MI size at 7 days with a parallel effect on fibrous tissue formation. TNF-alpha production by splenocytes was reduced upon AG-556 treatment, whereas no differences were evident between the groups with regard to myocardial cytokine expression. AG-556 attenuated the decrease in fractional shortening at the expense of preserving end systolic diameter. AG-556 has proven beneficial in reducing myocardial infarct size and attenuated consequent hemodynamic deterioration in the rat model. If reconfirmed, AG-556 may be of potential clinical use in post-MI patients.

Animals↗
PubMed2003

Immunity to heat shock protein 65--an additional determinant in intimal thickening.

Inflammation occurring consequent to vessel injury is thought to play an important role in atherosclerosis and restenosis. Autoimmunity to HSP65 has been shown to accelerate early atherogenesis in rabbits and mice, whereas in humans epidemiological data support this contention. In the current study, we explored the possibility of HSP65 influencing the extent of neointimal growth in the rat carotid injury model. Rats were either immunized with recombinant mycobacterial HSP65, heat killed preparation of Mycobacterium tuberculosis (MT), or with PBS, all emulsified in incomplete Freund's adjuvant. Animals were boosted with a similar protocol 3 weeks following the primary immunization and 2 weeks later carotid injury was applied in all animals by balloon inflation. Upon sacrifice 2 weeks later, sera were obtained for measurement of anti-HSP65 antibodies by ELISA, splenocytes were assessed for proliferative response to in vitro priming with HSP65, and carotid arteries were removed for evaluation of neointimal growth. Rats immunized with HSP65 exhibited a brisk and sustained humoral immune response to HSP65, and cellular immunity was also evident by thymidine uptake to splenocytes primed with the respective protein. Neointimal/medial ratio was significantly increased in HSP65 immunized rats, in comparison with MT injected and control animals. In conclusion, immunity to HSP65 can play a role in accelerating restenosis following arterial injury. These results should be further investigated in humans as they may provide a possible link between infections and restenosis/accelerated arteriosclerosis.

Animals↗
PubMed2003

Clinical parameters and functional tests are not predictive for in-stent restenosis.

OBJECTIVE: To study the correlation between clinical parameters and the occurrence of in-stent restenosis in a cohort of patients from the Tel Aviv Medical Center who underwent repeat angiograms for clinical indications following stenting. BACKGROUND: After stenting, recurrences of symptoms or ischemia on functional tests are considered to be clinical signs of restenosis. METHODS: The authors' study group consisted of 149 out of 1469 patients (10%) who underwent stent implantation between 1996 and 1998 and were under clinical follow-up. This group had a repeat angiogram for clinical indications: chest pain or a positive functional test (thallium study or ergometry). RESULTS: Sixty-eight patients (45%) had in-stent restenosis (ISR), 32 (21%) had a patent stent site with a significant coronary atherosclerosis elsewhere requiring revascularization (NTLR), and 51 (34%) had a patent stent site and did not require additional revascularization (PS). Baseline characteristics were similar in all the groups. There was a 63% rate of objective evidence of ischemia in the PS group, similar to the ISR (63%) and NTLR (74%) groups. In the ISR versus the NTLR and PS groups the stents were longer (22 +/- 10 versus 17 +/- 7 and 16 +/- 6 mm, p < 0.001) with a smaller diameter (3 +/- 0.4 versus 3.3 +/- 0.5 and 3.2 +/- 0.4 mm, p < 0.05) and a higher rate of multiple stents in the target lesion (34% versus 19% and 14%, p < 0.05) CONCLUSIONS: In the cohort of patients who underwent angiography following stenting for chest pain or a positive functional test, 55% were found to have a patent stent site. The 5% total in-stent restenosis is significantly lower than the rate in angiography-based reports. On the other hand, the group with a patent stent had a higher than expected rate of objective evidence of ischemia. Therefore clinical parameters and functional tests are not predictive for in-stent restenosis.

Aged↗
PubMed2003

The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron.

BACKGROUND: A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications. METHODS: Epo, s.c., was given every 1-3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months. RESULTS: With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g% in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups. CONCLUSION: The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Aged↗
PubMed2003

Effect of correction of anemia with erythropoietin and intravenous iron in resistant heart failure in octogenarians.

BACKGROUND: Congestive heart failure is extremely common in octogenarians and is associated with severe fatigue, shortness of breath, recurrent hospitalizations, and death. These patients, many of whom are anemic, are often resistant to standard CHF therapy including angiotensin-converting enzyme inhibitors, beta-blockers and diuretics. OBJECTIVES: To examine whether correction of the anemia (hemoglobin < 12 g/dl) in CHF patients can improve their clinical condition. METHODS: Forty octogenarians with anemia and severe resistant CHF were administered a combination of subcutaneous erythropoietin and intravenous iron sucrose. RESULTS: This combination therapy led to a marked improvement in cardiac function, shortness of breath and fatigue, a marked reduction in the rate of hospitalization and a stabilizing of renal function. CONCLUSION: Anemia appears to be an important but ignored contributor to the progression of CHF, and its correction may improve cardiac and renal status as well as the quality of life in elderly patients.

Age Factors↗
PubMed2002

Functional inhibition of Ras by S-trans,trans-farnesyl thiosalicylic acid attenuates atherosclerosis in apolipoprotein E knockout mice.

BACKGROUND: Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. METHODS AND RESULTS: We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-kappaB expression were considerably reduced compared with controls. CONCLUSIONS: FTS suppressed atherosclerotic plaques in apolipoprotein E-deficient mice, providing a useful tool for research in atherosclerosis.

Animals↗
PubMed2002

Potential indications for angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease.

Angiotensin-converting enzyme (ACE) inhibitors are well established as first-line therapy for patients with left ventricular dysfunction, diabetic patients with hypertension or renal disease, and patients recovering from myocardial infarction. Angiotensin II and bradykinin regulate cellular proliferation, inflammation, and endothelial function, thus playing an important role in the pathogenesis of atherosclerosis. A large body of experimental evidence reporting that ACE inhibitors limit these effects has formed the rationale for major clinical trials of these drugs in the management of atherosclerotic vascular disease. The first trial to be completed demonstrated that ACE inhibition improves the prognosis of patients who have, or are at risk of, atherosclerotic vascular disease, independent of its effects on left ventricular function and hypertension. Expanding the indications for ACE inhibitors is now evidence driven, although the choice of agent for these new indications remains to be determined by further research.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Detection of a thrombolysis-related reduction in red blood cell adhesiveness/aggregation using a simple slide test.

Increased red cell aggregability might have unfavorable rheological effects in the microcirculation. It has been suggested that thrombolysis-related hypofibrinogenemia might be associated with a reduced erythrocyte adhesiveness/aggregation. We followed the reduction in erythrocyte adhesiveness/aggregation using a simple slide test and image analysis that measures the spaces that are formed between the aggregated erythrocytes. A significant (p = 0.01) reduction in the degree of erythrocyte adhesiveness/aggregation was noted in patients with acute myocardial infarction who received thrombolysis as opposed to individuals with Braunwald Class IIIB unstable angina who had normal fibrinogen concentrations. No change was found in the Westergren erythrocyte sedimentation rate, which is an indirect method to detect changes in aggregability of red blood cells. The present study shows the superiority of using a direct measurement of red blood cell adhesiveness/aggregation. This extremely rapid, cheap and almost bedside methodology to detect changes in erythrocyte adhesiveness/aggregation might be useful to detect changes of hemorheological relevance following thrombolysis.

Aged↗
PubMed2001

Editorial.

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PubMed2001

Editorial.

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Journal Article↗
PubMed2001

Editorial.

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PubMed2000

Editorial.

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Journal Article↗
PubMed2000

Editorial.

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Journal Article↗
PubMed2000

Editorial.

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Journal Article↗
PubMed2000

Editorial.

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Journal Article↗
PubMed1999

Intravascular ultrasound imaging of myocardial-infarction-related arteries after percutaneous transluminal coronary angioplasty reveals significant plaque burden and compensatory enlargement.

We studied patients with acute myocardial infarction (MI) by intravascular ultrasound (IVUS) to elucidate the controversy as to the amount and severity of the atherosclerotic disease at the culprit lesion site in acute MI, as discrepancies exist between angiographic and pathological reports. Twenty-five consecutive patients (age 56 3 10.5 years), with acute MI, underwent IVUS study of the MI-related artery immediately following successful PTCA to the culprit lesion. The IVUS images were analyzed quantitatively and qualitatively and were compared with the angiography of the same arteries. At the PTCA site, 64% of the lesions had an area stenosis of 50-70% and the plaque cross-sectional area (CSA) averaged 0.5 3 0.18 of the arterial CSA. IVUS-defined atherosclerosis was found also in 72% of the segments proximal and distal to the culprit lesion with a plaque/artery CSA ratio of 0.25 3 0.2. The angiogram revealed only 30% of these segments to be abnormal (P 3 0.001). Sixty-nine per cent of all the plaques were defined as 'soft' (low echo-genecity) versus 31% 'hard' (high echo-genecity). The hard plaques were larger than the soft plaques (0.5 3 1.6 versus 0.37 3 0.19 CSA index, respectively, P 3 0.01). With the increase in plaque area there was a significant increase in arterial cross-sectional area. This was demonstrated for all the diseased segments with a correlation coefficient of 0.49 (P 3 0.0001) and for the diseased reference sites a similar correlation coefficient of 0.49 (P 3 0.003) was found. Contrary to coronary angiographic-based reports, this IVUS study revealed a significant atheromatous plaque burden at the culprit lesion of MI-related arteries as well as diffuse atherosclerosis in the reference segments proximal and distal to the lesion. The detection of compensatory enlargement may explain the discrepancies between the histopathological and the angiographic studies.

Journal Article↗