Morris Mosseri

Vitamin D Inflammatory Cytokines and Coronary Events: A Comprehensive Review

Myocardial infarction (MI) is the most common cause of cardiac injury in the Western world. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Inflammatory cytokines and vascular cell adhesion molecules (VCAM) promote adhesive interactions between leukocytes and endothelial cells, resulting in the transmigration of inflammatory cells into the site of injury. Low vitamin D levels are associated with higher prevalence of cardiovascular risk factors and a higher risk of MI. In this paper, we examine the effects of short-term vitamin D supplementation on inflammatory cytokine levels after an acute coronary syndrome. We recruited patients arriving to the hospital with an acute MI. All patients received optimal medical therapy and underwent a coronary catheterization. Half of the patients were randomly selected and treated with a daily supplement of vitamin D (4,000xa0IU) for 5xa0days. A short course of treatment with vitamin D effectively attenuated the increase in circulating levels of inflammatory cytokines after an acute coronary event. Control group patients had increased cytokine and cellular adhesion molecules serum concentrations after 5xa0days, while the vitamin D-treated group had an attenuated elevation or a reduction of these parameters. There were significant differences in VCAM-1 levels, C-reactive protein, and interleukin-6. There were trends toward significance in interleukin-8 levels. There were no significant differences in circulating levels of intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and tumor necrosis factor-α. These findings provide information on the anti-inflammatory effects of vitamin D on the vascular system and suggest mechanisms that mediate some of its cardioprotective properties. There is place for further studies involving prolonged vitamin D treatment in patients suffering from ischemic heart disease.

Mortality and Coronary Heart Disease in Euthyroid Patients

BACKGROUNDnSubclinical thyroid dysfunction is associated with increased mortality and cardiovascular risk. It is unknown whether this association remains within normal thyroid function range.nnnMETHODSnThe study was conducted using the computerized database of the Sharon-Shomron district of Clalit Health services. Included were subjects aged ≥40 years with normal thyroid function. Patients with a history of thyroid or cardiovascular diseases or diabetes were excluded. The primary end points were all-cause mortality and the need for coronary revascularization with either percutaneous coronary intervention or coronary artery bypass grafting.nnnRESULTSnThe 42,149 participants were stratified into 3 groups of equal thyrotropin intervals (0.35-1.6, 1.7-2.9, and 3-4.2 mIU/L). During a mean follow-up of 4.5±2.1 years, 4239 (10.1%) participants died and 1575 (3.7%) underwent coronary revascularization. For both women and men, the lowest mortality rates were observed in the intermediate thyrotropin group. Nevertheless, only for the low thyrotropin group, mortality risk remained significantly higher as compared with the intermediate thyrotropin group, even following multivariate model adjusted for the conventional cardiovascular risk factors, in both women (odds ratio 1.22; 95% confidence interval, 1.09-1.36 for the low thyrotropin group, compared with the intermediate group) and men (odds ratio 1.14; 95% confidence interval, 1.01-1.3 for the low thyrotropin group, compared with the intermediate group). There was no significant difference in the need for coronary revascularization among the 3 thyrotropin groups in both men and women.nnnCONCLUSIONSnLow thyrotropin level within the reference range is associated with increased risk for all-cause mortality.

Multidisciplinary rehabilitation program in recently hospitalized patients with heart failure and preserved ejection fraction: Rationale and design of a randomized controlled trial

BACKGROUNDnHeart failure with preserved ejection fraction (HFpEF) comprises a large portion of heart failure patients and portends poor prognosis with similar outcome to heart failure with reduced ejection fraction (HFrEF). Thus far, no medical therapy has been shown to improve clinical outcome in this common condition.nnnTRIAL DESIGNnThe study is a randomized-controlled, multicenter clinical trial aimed to determine whether early posthospitalization comprehensive cardiac rehabilitation (CR) including exercise training (ET) in recently hospitalized HFpEF patients reduces the composite end point of all-cause mortality and hospitalizations in comparison with usual care (UC). After undergoing baseline evaluation, patients are randomized to either UC or to ambulatory comprehensive CR program. Patients in the CR arm will participate in a 6-month biweekly ET program according to a predefined protocol, in addition to a complementary home exercise prescribed by a specialist in CR. Exercise training will include endurance and low-intensity resistance training. Patients in the UC arm will be followed up at the outpatient clinic, with management according to current heart failure guidelines. Physician follow-up visits will be conducted at 3, 6, and 12 months for assessment of adherence to therapy and ET, functional status, quality of life, and clinical events. Secondary end points will include quality-of-life questionnaire, economic end points, blood pressure, and hemoglobin A1C levels.nnnCONCLUSIONSnCardiac rehabilitation and ET are relatively inexpensive and accessible and can be beneficial in HFpEF patients. Our trial is designed to evaluate the impact of early posthospitalization comprehensive rehabilitation program on clinical end points of mortality, hospitalization, and quality of life in HFpEF patients.

Comparison of lipid control in patients with coronary versus peripheral artery disease following the first vascular intervention.

Peripheral arterial disease (PAD) is a strong risk factor for cardiovascular morbidity and mortality. Therefore, target low-density lipoprotein (LDL) cholesterol level in patients with PAD is ≤70 mg/dl, similar to patients with coronary artery disease (CAD). However, despite their high cardiovascular risk, patients with PAD less frequently achieve LDL cholesterol goals compared to patients with CAD. We aimed to compare LDL cholesterol control in patients after first coronary or peripheral vascular intervention. Included were patients ≥18 years of age without a history of cardiovascular disease who underwent first coronary or peripheral vascular intervention from 2004 through 2010. Primary end points were percentage of patients who achieved the LDL cholesterol goal of <100 and <70 mg/dl. Of 9,138 patients available for analysis, 7,512 (82.2%) underwent first coronary revascularization and 1,626 (17.8%) underwent first peripheral revascularization. Patients after first coronary revascularization were treated more frequently with any statin and with highly potent statins. Furthermore, they more frequently achieved the LDL cholesterol goals compared to patients after first peripheral intervention. This was true for the LDL cholesterol goal of <100 mg/dl (65% and 46.7%, p <0.0001) and for the lower LDL cholesterol goal of <70 mg/dl (23.3% and 13.3%, p <0.0001). Differences in LDL cholesterol control between the 2 groups remained statistically significant after multivariate adjustment. In conclusion, lipid control in patients with PAD is poor and significantly inferior to that of patients with CAD even after the first vascular intervention.

Cardiovascular Risk in Patients With Fasting Blood Glucose Levels Within Normal Range

Fasting glucose levels elevated beyond the normal range have been associated with increased cardiovascular risk. However, it is unknown whether this association exists for variations of fasting glucose within the normal range. The present study was conducted using the computerized database of the Sharon-Shomron District of Clalit Health Services. Included in the present study were subjects with fasting glucose levels within the normal range (< 100 mg/dl). We excluded patients with a history of cardiovascular disease or diabetes. The primary outcome was the incidence of coronary revascularization with either percutaneous coronary intervention or coronary artery bypass grafting. The 28,263 participants (age 53.7 ± 12.2 years) were divided into quartiles according to the fasting glucose level (75.4 ± 4.5, 83.6 ± 1.7, 88.9 ± 1.4, and 95.1 ± 2.2 mg/dl). During a mean follow-up of 5.9 ± 0.7 years, 424 subjects required coronary revascularization. A progressive increase was seen in the risk of coronary revascularization as the fasting glucose levels increased within the normal range (hazard ratio 1.73, 95% confidence interval 1.3 to 2.3, p > 0.001, between the fourth and first quartiles). However, this association lost its statistical significance after adjustments for the conventional coronary risk factors (hazard ratio 1.17, 95% confidence interval 0.85 to 1.62, p = 0.328). In conclusion, elevated fasting glucose levels within the normal range were associated with an increased cardiovascular risk. This association was caused by the greater prevalence of the other conventional risk factors and not by the glucose level itself.

Prevalence and Significance of Unrecognized Renal Dysfunction in Patients with Acute Coronary Syndrome

BACKGROUNDnUnrecognized renal insufficiency, defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2) in the presence of normal serum creatinine, is common among patients with acute coronary syndrome. We aimed to determine the prevalence and clinical significance of unrecognized renal insufficiency in a large unselected population of patients with acute coronary syndrome.nnnMETHODSnThe study population consisted of patients with acute coronary syndrome included in the Acute Coronary Syndrome Israeli biennial Surveys during 2000-2013. The estimated glomerular filtration rate was calculated using the simplified Modification of Diet in Renal Disease formula. Patients were stratified into 3 groups: 1) normal renal function (estimated glomerular filtration rates ≥60 mL/min/1/73 m(2)); 2) unrecognized renal insufficiency (estimated glomerular filtration rates <60 mL/min/1/73 m(2) with serum creatinine ≤1.2 mg/dL); and 3) recognized renal insufficiency (estimated glomerular filtration rates <60 mL/min/1/73 m(2) with serum creatinine ≥1.2 mg/dL). The primary endpoint was all-cause mortality at 1 year.nnnRESULTSnIncluded in the study were 12,830 acute coronary syndrome patients. Unrecognized renal insufficiency was present in 2536 (19.8%). Patients with unrecognized renal insufficiency were older and more frequently females. All-cause mortality rates at 1 year were highest among patients with recognized renal insufficiency, followed by patients with unrecognized renal insufficiency, with the lowest mortality rates observed in patients with normal renal function (19.4%, 9.9%, and 3.3%, respectively, P <.0001). Despite their increased risk, patients with renal insufficiency were less frequently referred for coronary angiography and were less commonly treated with guideline-based cardiovascular medications.nnnCONCLUSIONSnAcute coronary syndrome patients with unrecognized renal insufficiency should be considered as a high-risk population. The question of whether this group would benefit from a more aggressive therapeutic approach should still be evaluated.

Incidence and Expression of Circulating Cell Free p53-Related Genes in Acute Myocardial Infarction Patients

AIMnThe circulating RNA levels are predictive markers in several diseases. We determined the levels of circulating p53-related genes in patients with acute ST-segment elevation myocardial infarction (STEMI), indicating major heart muscle damage.nnnMETHODSnPlasma RNA was extracted from the patients (n=45) upon their arrival to the hospital (STEMI 0h) and at four hours post-catheterization (STEMI 4h) as well as from controls (n=34).nnnRESULTSnOf 18 circulating p53-related genes, nine genes were detectable. A significantly lower incidence of circulating p21 (p ＜ 0.0001), Notch1 (p=0.042) and BTG2 (p ＜ 0.0001) was observed in the STEMI 0h samples in comparison to the STEMI 4h and control samples. Lower expression levels (2.1-fold) of circulating BNIP3L (p=0.011), p21 (3.4-fold, p=0.005) and BTG2 (6.3-fold, p=0.0001) were observed in the STEMI 0h samples in comparison to the STEMI 4h samples, with a 7.4-fold lower BTG2 expression (p ＜ 0.001) and 2.6-fold lower p21 expression (p=0.034) compared to the control samples. Moreover, the BNIP3L expression (borderline significance, p=0.0655) predicted the level of peak troponin, a marker of myocardial infarction. In addition, the BNIP3L levels on admission (p=0.0025), at post-catheterization (p=0.020) and the change between the groups (p=0.0079) were inversely associated with troponin. The BNIP3L (p=0.0139) and p21 levels (p=0.0447) were also associated with a longer time to catheterization.nnnCONCLUSIONSnOur results suggest that circulating downstream targets of p53 are inhibited during severe AMI and subsequently re-expressed after catheterization, uncovering possible novel death-or-survival decisions regarding the fate of p53 in the heart and the potential use of its target genes as prognostic biomarkers for oxygenation normalization.

Admission plasma glucose levels within the normal to mildly impaired range and the outcome of patients with acute coronary syndrome.

Background: Elevated admission plasma glucose levels >140 mg/dl are associated with adverse clinical outcomes in both diabetic and non-diabetic patients admitted with acute coronary syndrome (ACS). We aimed to evaluate the association between admission plasma glucose levels <140 mg/dl and the outcome of non-diabetic patients admitted with acute coronary syndrome. Methods: The study population consisted of patients with acute coronary syndrome included in the Acute Coronary Syndrome Israeli Survey during 2000–2013. Diabetic patients were excluded. The primary endpoint was all-cause mortality at one year. Results: The 4520 patients had a mean age of 61.7±13.5 years and were stratified into four quartiles according to admission plasma glucose (60–94, 95–105, 106–119, 120–140 mg/dl). Patients with higher admission plasma glucose were older and included a higher percentage of smokers. In addition, the higher the glucose so also did they have a poorer risk factor profile including a higher body mass index, total and low-density lipoprotein cholesterol and triglyceride levels, and lower high-density lipoprotein cholesterol levels. During the first year 5.2% of patients died. A comparison of one-year mortality according to admission plasma glucose quartiles demonstrated a significant and progressive increase in mortality risk as admission plasma glucose rose (3.5%, 4.1%, 6.1%, 6.4%, respectively, p=0.001). However, this association lost its clinical significance following a multivariate analysis (p=0.08). Conclusions: High admission plasma glucose levels within the normal to mildly impaired range are associated with increased one-year mortality in non-diabetic acute coronary syndrome patients. However, the higher glucose level is probably not the cause for the adverse outcome but rather a marker for high risk. Our findings support the definition of 140 mg/dl as the cutoff for clinically acceptable admission glucose levels in patients with acute coronary syndrome.

Prevalence and Significance of Unrecognized Renal Dysfunction in Patients with Stroke

BACKGROUNDnUnrecognized renal dysfunction, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2) in the presence of normal serum creatinine levels, is a common comorbidity among patients with various cardiovascular conditions. The current study was aimed to evaluate the prevalence and clinical significance of unrecognized renal dysfunction in patients with acute stroke.nnnMETHODSnThe cohort consisted of patients with acute stroke included in the prospective National Acute Stroke ISraeli (NASIS) registry. Unrecognized renal insufficiency was defined as an estimated glomerular filtration ratexa0<60 mL/min/1.73 m(2) in the presence of serum creatinine ≤1.2 mg/dL. The 2 primary outcomes werexa0in-hospital mortality and the composite of in-hospital mortality or severe disability at hospital discharge.nnnRESULTSnOf the 7900 patients with stroke included in the study, 5571 (70.5%) had normal renal function, 1510 (19.1%) had recognized renal insufficiency, and 819 (10.4%) had unrecognized renal insufficiency. Mortality rates were higher in patients with recognized and unrecognized renal insufficiency compared with patients with normal renal function (9.9%, 9.1%, and 4.4%, respectively, P < .0001). Adjusted odds ratios (ORs) for in-hospital mortality were higher for patients with renal dysfunction recognized (OR, 2.1; 95% confidence interval [CI], 1.6-2.7; P < .001) or unrecognized (OR, 1.6; 95% CI, 1.1-2.2; Pxa0= .006) compared with patients with normal renal function. Likewise, adjusted ORs for the composite of in-hospital mortality or severe disability at hospital discharge were higher for patients with renal dysfunction recognized (OR, 1.3; 95% CI, 1.1-1.5; Pxa0= .004) or unrecognized (OR, 1.2; 95% CI, 1.01-1.5; Pxa0= .04).nnnCONCLUSIONSnUnrecognized renal insufficiency is common among patients with acute stroke and is associated with adverse short-term outcomes.

Lipid control in patients with coronary heart disease treated in primary care or cardiology clinics

BACKGROUNDnGuidelines recommend low-density lipoprotein-cholesterol (LDL-C) target of <70xa0mg/dL in patients with coronary disease. However, this goal is not achieved in many patients.nnnOBJECTIVESnWe compared LDL-C control in patients with coronary disease treated by a primary care physician or with the addition of a cardiologist.nnnMETHODSnIncluded were patients with coronary disease who had full lipid profile. Primary end points included the percentage of patients who achieved the LDL-C goals of <100 mg/dL and <70xa0mg/dL.nnnRESULTSnOf the 27,172 patients, 12,965 (47.7%) were followed only by a primary care physician and 14,207 (52.3%) were also followed by a cardiologist. Overall, 18,366 patients (67.6%) achieved the LDL-C goal of <100 mg/dL, and 6517 patients (24%) achieved the LDL-C goal of <70 mg/dL. Patients followed by a cardiologist more frequently achieved the LDL-C goal of <100 mg/dL (74.3% and 60.3%; P < .0001, in patients treated by a cardiologist or by a primary care physician, respectively), as well as the lower LDL-C goal of <70 mg/dL (27.2% and 20.4%; P < .0001, in patients treated by a cardiologist or by a primary care physician, respectively). Differences in LDL-C control remained significant after a multivariate adjustment. Patients followed by a cardiologist were more commonly treated with highly potent statins and with non-statin cholesterol-lowering drugs.nnnCONCLUSIONSnAmong patients with coronary disease, those followed by a cardiologist receive a more aggressive antilipid treatment and more frequently achieve lipids goals. Nevertheless, the disappointingly poor lipid control in both groups warrants an effort to improve adherence for guidelines in both primary care and cardiology clinics.