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עמוד בית
Wed, 19.06.24

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January 2024
Yehuda Shoenfeld MD, Joshua Shemer MD, Gad Keren MD

Twenty-five years ago, we, the undersigned together with the chairman of the Israel Medical Association at the time, Prof. Yoram Blachar, and the Secretary General of the Israel Medical Association, Adv. Leah Wapner, joined forces to found an Israeli medical journal in English. The purpose of this journal was to present to the world Israeli clinical medicine and medical research. That journal is none other than the Israel Medical Association Journal (IMAJ), and in 2023 its 300th issue was published. In 2024 we keep going, taking pride in the fact that every one of those past 300 issues has been published and dispatched on time, without delay, regardless of any circumstances.

May 2023
May-Tal Rofe-Shmuel MD, Michael Shapira MD, Gad Keren MD

Romidepsin is an intravenously administered antineoplastic agent, which acts by inhibiting histone deacetylases, thus preventing removal of acetyl groups from histones. The accrual of acetyl groups on histones causes cell cycle arrest and apoptotic cell death. It was approved for use in the United States in 2009 for treatment of refractory or relapsed cutaneous and peripheral T cell lymphomas [1-3].

The most common side effects are mild to moderate in severity and include nausea, vomiting, fatigue, fever, myelosuppression (e.g., anemia, neutropenia, thrombocytopenia), elevated liver enzymes, constipation, and rash. More severe adverse events can include marked neutropenia, thrombocytopenia, serious infections such as line sepsis, acute renal failure, tumor lysis syndrome, and cardiac arrhythmias [1].

November 2020
Hezzy Shmueli MD, Arie Steinvil MD, Galit Aviram MD, Sileman Moaad MD, Adam Sharon MD, Achiude Bendet MD, Simon Biner MD, Yacov Shacham MD, Jack Sherez MD, Ricki Megidish MD, Yifat Hasin MD, Ester Elazar MD, Sevan Letourneau-Shesaf MD, Gad Keren MD ,Shlomo Berliner MD, and Yan Topilsky MD

Background: Acute pulmonary embolism (PE) is considered to be one of the most common cardiovascular diseases with considerable mortality. Conflicting data imply possible role for echocardiography in assessing this disease.

Objectives: To determine which of the echo parameters best predicts short-term and long-term mortality in patients with PE.

Methods: We prospectively enrolled 235 patients who underwent computed tomography of pulmonary arteries (CTPA) and transthoracic Echocardiography (TTE) within < 24 hours. TTE included a prospectively designed detailed evaluation of the right heart including right ventricular (RV) myocardial performance index (RIMP), RV end diastolic and end systolic area, RV fractional area change, acceleration time (AT) of pulmonary flow and visual estimation. Interpretation and performance of TTE were blinded to the CTPA results.

Results: Although multiple TTE parameters were associated with PE, all had low discriminative capacity (AUC < 0.7). Parameters associated with 30-day mortality in univariate analysis were acceleration time (AT) < 81 msec (P = 0.04), stroke volume < 44 cc (P = 0.005), and RIMP > 0.42 (P = 0.05). The only RV independent echo parameter associated with poor long-term prognosis (adjusted for significant clinical, and routine echo associates of mortality) was RIMP (hazard ratio 3.0, P = 0.04). The only independent RV echo parameters associated with mortality in PE patients were RIMP (P = 0.05) and AT (P = 0.05). Addition of RIMP to nested models eliminated the significance of all other parameters assessing RV function.

Conclusions: Doppler-based parameters like pulmonary flow AT, RIMP, and stroke volume, have additive value in addition to visual RV estimation to assess prognosis in patients with PE.

March 2019
Yehuda Shoenfeld MD, Joshua Shemer MD, Gad Keren MD
February 2018
Anat Milman MD PhD and Gad Keren MD

Electrocardiography abnormalities are a common finding in athletes. To facilitate the differentiation of physiological adaptation versus pathological remodeling, a series of guidelines has emerged in the past decade that attempt to improve specificity while maintaining a high sensitivity. Recently, T wave inversion in the athletic population gained more attention, resulting in accelerated research leading to novel findings not yet integrated into clinical practice. We aim to simplify the knowledge to date and integrate it into one easy to use practical flowchart.

September 2017
Jeremy Ben-Shoshan MD PhD, Ayman Jubran MD, Ran Levy PhD, Gad Keren MD and Michal Entin-Meer PhD

Background: Systemic CD11b+ cells have been associated with several cardiac diseases, such as chronic heart failure.

Objectives: To assess the levels of circulating CD11b+ cells and pro-inflammatory cytokines in cardiomyopathy induced by chronic adrenergic stimulation.

Methods: Male Lewis rats were injected with low doses of isoproterenol (isoprel) for 3 months. Cardiac parameters were tested by echocardiography. The percentage of CD11b+ cells was tested by flow cytometry. The levels of inflammatory cytokines in the sera were determined by an inflammation array, and the expression levels of cardiac interleukin-1 (IL-1) receptors were analyzed by real-time polymerase chain reactions. Cardiac fibrosis and inflammation were determined by histological analysis.

Results: Chronic isoprel administration resulted in increased heart rate, cardiac hypertrophy, elevated cardiac peri-vascular fibrosis, reduced fractional shortening, and increased heart weight per body weight ratio compared to control animals. This clinical presentation was associated with accumulation of CD11b+ cells in the spleen with no concomitant cardiac inflammation. Cardiac dysfunction was also associated with elevated sera levels of IL-1 alpha and over expression of cardiac IL-1 receptor type 2.

Conclusions: CD11b+ systemic levels and IL-1 signaling are associated with cardiomyopathy induced by chronic adrenergic stimulation. Further studies are needed to define the role of systemic immunomodulation in this cardiomyopathy.

 

June 2016
Einat Hertzberg-Bigelman MsC, Rami Barashi MD, Ran Levy PhD, Lena Cohen MSc, Jeremy Ben-Shoshan MD PhD, Gad Keren MD and Michal Entin-Meer PhD

Background: Chronic kidney disease (CKD) is often accompanied by impairment of cardiac function that may lead to major cardiac events. Erythropoietin (EPO), a kidney-produced protein, was shown to be beneficial to heart function. It was suggested that reduced EPO secretion in CKD may play a role in the initiation of heart damage. 

Objectives: To investigate molecular changes in the EPO/erythropoietin receptor (EPO-R) axis in rat cardiomyocytes using a rat model for CKD.

Methods: We established a rat model for CKD by kidney resection. Cardiac tissue sections were stained with Masson’s trichrome to assess interstitial fibrosis indicating cardiac damage. To evaluate changes in the EPO/EPO-R signaling cascade in the myocardium we measured cardiac EPO and EPO-R as well as the phosphorylation levels of STAT-5, a downstream element in this cascade.

Results: At 11 weeks after resection, animals presented severe renal failure reflected by reduced creatinine clearance, elevated blood urea nitrogen and presence of anemia. Histological analysis revealed enhanced fibrosis in cardiac sections of CKD animals compared to the sham controls. Parallel to these changes, we found that although cardiac EPO levels were similar in both groups, the expression of EPO-R and the activated form of its downstream protein STAT-5 were significantly lower in CKD animals.

Conclusions: CKD results in molecular changes in the EPO/EPO-R axis. These changes may play a role in early cardiac damage observed in the cardiorenal syndrome.

 

February 2016
Michal Laufer Perl MD, Ariel Finkelstein MD, Miri Revivo MHA, Shlomo Berliner MD, Itzhak Herz MD, Itay Rabinovich MD, Tomer Ziv-Baran PhD, Dalit Gotler, Gad Keren MD, Shmuel Bana MD and Yaron Arbel MD

Background: Atherosclerosis is a systemic disease. Nevertheless, the role of specific biomarkers as indicators for both coronary and carotid diseases is debatable.

Objectives: To evaluate the association of biomarkers with coronary and carotid disease.

Methods: We studied 522 consecutive patients with stable angina. All underwent coronary angiography and carotid duplex study on the same day. Patients with no apparent carotid plaques were evaluated for carotid intima-media thickness (CIMT) using an automated system that sampled over 100 samples in each carotid artery. Biochemical markers of cardiovascular disease risk were obtained at the time of coronary angiography, including serum lipid levels, hemoglobin A1C (HbA1c), white blood cell count, fibrinogen and high sensitivity C-reactive protein (hs-CRP).

Results: The mean age of the patients was 66 ± 11; 73% were males. Significant carotid stenosis was associated with higher hs-CRP (9.4 ± 17 vs. 6.3 ± 13 mg/L, P = 0.001), while high HbA1c (6.7 ± 1.6 vs. 5.8 ± 0.8%, P < 0.001) and low high density lipoprotein levels (40 ± 9 vs. 47 ± 14 mg/dl, P < 0.001) were linked with advanced coronary artery disease severity. In contrast, CIMT was not related to any of the biomarkers evaluated.

Conclusions: Although atherosclerosis is considered a systemic disease, different biomarkers are associated with coronary and carotid artery disease. Identifying the specific biomarkers for each disease is important for both prevention and for exposing the underlying pathophysiologic mechanism.

 

December 2015
May-Tal Rofe MD, Ran Levi PhD, Einat Hertzberg-Bigelman MSc, Pavel Goryainov MSc, Rami Barashi MD, Jeremy Ben-Shoshan MD PhD, Gad Keren MD and Michal Entin-Meer PhD
 

Background: Chronic kidney disease (CKD) is a prevalent clinical condition affecting 15% of the general population. Cardiorenal syndrome (CRS) type 4 is characterized by an underlying CKD condition leading to impairment of cardiac function and increased risk for major cardiovascular events. To date, the mechanisms leading from CKD to CRS are not completely understood. In particular, it is unclear whether the pathological changes that occur in the heart in the setting of CKD involve enhanced cell death of cardiac cells.  


Objectives: To assess whether CKD may mediate loss of cardiac cells by apoptosis. 


Methods: We established rat models for CKD, acute myocardial infarction (acute MI), left ventricular dysfunction (LVD), and sham. We measured the cardiac-to-body weight as well as kidney-to-body weight ratios to validate that renal and cardiac hypertrophy occur as part of disease progression to CRS. Cardiac cells were then isolated and the percent of cell death was determined by flow cytometry following staining with annexin-FITC and propidium iodide. In addition, the levels of caspase-3-dependent apoptosis were determined by Western blot analysis using an anti-cleaved caspase-3 antibody. 


Results: CKD, as well as acute MI and LVD, resulted in significant cardiac hypertrophy. Nevertheless, unlike the increased levels of cell death observed in the acute MI group, in the CKD group, cardiac hypertrophy was not associated with induction of cell death of cardiac cells. Caspase-3 activity was even slightly reduced compared to sham-operated controls. 


Conclusions: Our data show that while CKD induces pathological changes in the heart, it does not induce cardiac cell death. 


 

 
October 2015
Haim Shmilovich MD, Svetlana Trestman MD, Stella Bak MD, Galit Aviram MD, Shmuel Banai MD, Arie Steinvil MD and Gad Keren MD
August 2015
Yaron Arbel MD, Assi Milwidsky MD, Ariel Finkelstein MD, Amir Halkin MD, Miri Revivo MHA, Shlomo Berliner MD PhD, Martin Ellis MD, Itzhak Herz MD, Gad Keren MD and Shmuel Banai MD

Background: Anemia confers an adverse prognosis in patients with ST-elevation myocardial infarction (STEMI). Several mechanisms have been implicated in the etiology of anemia in this setting, including inflammation, blood loss, and the presence of comorbidities such as renal failure.

Objectives: To evaluate the adequacy of bone marrow response as potentially reflected by elevation in blood and reticulocyte counts.

Methods: Consecutive men with STEMI who underwent primary percutaneous intervention within 6 hours of symptom onset and who presented to our catheterization laboratory during a 36 month period were included in the study. The cohort was divided into quartiles according to hemoglobin concentration, and differences in clinical and laboratory characteristics between the groups were evaluated.

Results: A total of 258 men with STEMI were recruited, 22% of whom suffered from anemia according to the World Health Organization classification (hemoglobin < 13 g/dl). Men in the lowest quartile of hemoglobin concentration presented with significantly lower white blood cell and platelet counts (9.6 ± 2.9 vs. 12.6 ± 3.6 x103/µl, P < 0.001) and (231 ± 79 vs. 263 ± 8 x103/µl, P < 0.01), respectively, despite higher inflammatory biomarkers (C-reactive protein and fibrinogen) compared with patients in the upper hemoglobin concentration quartile. Reticulocyte production index was not significantly higher in anemic patients with a value of 1.8, 1.4, 1.5 and 1.6 in the ascending hemoglobin quartiles, respectively (P = 0.292). 

Conclusions: Anemic men with STEMI have relatively lower leukocyte and platelet counts as well as a reduced reticulocyte count despite higher inflammatory biomarkers. These findings might suggest inadequate bone marrow response. 

 

June 2015
Yacov Shacham MD, Eran Leshem-Rubinow MD, Arie Steinvil MD, Gad Keren MD, Arie Roth MD and Yaron Arbel MD

Abstract

Background: In the era of primary percutaneous coronary intervention (PPCI), information on the incidence and prognostic significance of high degree atrioventricular block (AVB) in ST elevation myocardial infarction (STEMI) patients is limited.

Objectives: To assess the incidence, time of onset, predictors and prognostic significance of high degree AVB in a large cohort of consecutive STEMI patients undergoing PPCI.

Methods: We retrospectively studied 1244 consecutive STEMI patients undergoing PPCI. Patient records were reviewed for the presence of high degree AVB, its time of occurrence and relation to in-hospital complications, as well as long-term mortality over a 5 year period.

Results: High degree AVB was present in 33 patients (3.0%), in 25 (76%) of whom the conduction disorder occurred prior to PPCI. Twelve patients (36%) required temporary pacing, all prior to or during coronary intervention, and all AVB resolved spontaneously before hospital discharge. AVB was associated with a significantly higher 30 day (15 % vs. 2.0%, P = 0.001) and long-term mortality rate (30% vs. 6.0%, P < 0.001). Time of AVB had no effect on mortality. In a multivariate regression model, AVB emerged as an independent predictor for long-term mortality (hazard ratio 2.8, 95% confidence interval 1.20–6.44, P = 0.001).

Conclusions: High degree AVB remains a significant prognostic marker in STEMI patients in the PPCI era, albeit transient.

Haim Shmilovich MD, Itzhak Herz MD and Gad Keren MD
November 2013
O. Havakuk, M. Entin-Meer, J. Ben-Shoshan, P. Goryainov, S. Maysel-Auslender, E.l Joffe and G. Keren
 Background: Vitamin D has been shown to induce beneficial effects on cardiovascular and renal morbidity by regulating inflammation and tissue fibrosis.

Objectives: To evaluate the effect of vitamin D analogues on cardiac function and fibrosis in an animal model of cardiorenal syndrome.

Methods: Unilateral nephrectomy was performed and myocardial infarction induced in rats. Rats were treated with vitamin D receptor activator (VDRA, paricalcitol, 40 ng/250 g x 3/week) versus a vehicle. A third group of animals, which served as the control, underwent sham surgery and received no treatment. After 4 weeks of treatment, cardiac function and fibrosis were assessed by trans-thoracic echo and histology, respectively. As a parameter of systemic inflammation, previously shown to be altered in acute coronary syndrome, T regulatory (Treg) cell levels were measured by flow cytometry. Renal dysfunction was documented by standard laboratory tests.

Results: After 4 weeks of treatment, no significant improvement in cardiac function parameters was noted following VDRA administration. VDRA treatment did not significantly alter Treg cell systemic levels. Consistently, despite a trend toward less extent of myocardial fibrosis, we found no clear beneficial effects of VDRA on myocardial tissue inflammation and remodeling.

Conclusions: Vitamin D treatment showed no beneficial effects on cardiac function parameters and fibrosis in an animal model of cardiorenal syndrome. 

October 2013
A. Finkelstein, E.Y. Birati, Y. Abramowitz, A. Steinvil, N. Sheinberg, S. Biner, S. Bazan, Y. Ben Gal, A. Halkin, Y. Arbel, E. Ben-Assa, E. Leshem-Rubinow, G. Keren and S. Banai
 Background: Transcatheter aortic valve implantation (TAVI) has recently become an alternative to surgical aortic valve replacement in selected patients with high operative risk.

Objectives: To investigate the 30 day clinical outcome of the first 300 consecutive patients treated with transfemoral TAVI at the Tel Aviv Medical Center.

Methods: The CoreValve was used in 250 patients and the Edwards-Sapien valve in 50 patients. The mean age of the patients was 83 ± 5.3 years (range 63–98 years) and the mean valve area 0.69 ± 0.18 cm2 (range 0.3–0.9 cm2); 62% were women.

Results: The procedural success rate was 100%, and 30 day follow-up was done in all the patients. The average Euro-score for the cohort was 26 ± 13 (range 1.5–67). Total in-hospital mortality and 30 day mortality were both 2.3% (7 patients). Sixty-seven patients (22%) underwent permanent pacemaker implantation after the TAVI procedure, mostly due to new onset of left bundle brunch block and prolonged PR interval or to high degree atrioventricular block. The rate of stroke was 1.7% (5 patients). Forty-one patients (13.7%) had vascular complications, of whom 9 (3%) were defined as major vascular complications (according to the VARC definition).

Conclusions: The 30 day clinical outcome in the first 300 consecutive TAVI patients in our center was favorable, with a mortality rate of 2.3% and low rates of stroke (1.7%) and major vascular complications (3%).

 

 







 VARC = Valve Academic Research Consortium


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