Low Cholesterol Levels in Younger Heart Failure Patients May Predict Unfavorable Outcomes.

Background and Objectives: Hypercholesterolemia is a main risk-factor leading to ischemic heart disease (IHD). However, among patients with heart failure, the use of lipid lowering drugs in the presence of low cholesterol might be dangerous. This 18-year longitudinal study of patients ≤51 years old investigated the relationship between baseline total cholesterol, low-density lipoprotein cholesterol (LDL-c) and triglyceride levels, and survival among patients with severe HF. Materials and Methods: The average NYHA score of 82 patients ≤51 years old with heart failure was 2.61. They were followed for a mean of 11.3 years (15 months-20 years). Total mortality was 22%. Patients were divided into three groups. Group 1 had plasma LDL-c levels ≤ 80 mg/dl, Group 2, 80-115 mg/dl and Group 3 > 115 mg/dl. Results: Patients with the highest baseline total cholesterol, triglyceride and LDL-c levels > 115 mg/dl had a better survival rate (83%) compared to those with LDL-c < 80 mg/dl (50% survival, p = 0.043). The association between higher LDL-c levels and lower mortality was most noticeable among patients with heart failure. Conclusion: Longitudinal follow-up found that low LDL-c levels may indicate poorer prognosis among patient with heart failure who are ≤51 years old, similar to elderly heart failure patients. Cholesterol lowering drugs in younger patients with heart failure may increase mortality.

Apolipoprotein E (APOE) Genotypes in the Israeli population.

BACKGROUND: APOE genotype strongly affects plasma lipid levels and risk for cardiovascular disease and cognitive decline. Studies of apo-e allelic and APOE genotype frequencies among several populations have revealed interesting ethnic variations that might affect cardiovascular morbidity and cognition deterioration. OBJECTIVES: To evaluate apo-e allelic frequency among Israeli newborns based on known variances in apo-e allelic frequencies in different countries. METHODS: We examined 498 consecutive neonates born at Tel Aviv Sourasky Medical Center. Umbilical cord blood was sampled for genotyping and lipids. Birth weights were recorded. Demographics and parental risk factors for atherosclerosis were obtained from the mothers. RESULTS: Most parents were native-born Israelis. Other countries of origin of grandparents were Morocco, Russia, and Iraq. The prevalence of APOE genotypes in Israel is APOE 2/2: 1.4%, APOE 2/3: 8.2%, APOE 3/3: 77.7%, and APOE 4/4: 11.8%. There were no associations of APOE genotype with parental country of origin. However, there was a tendency for APOE 3/4 to be more frequent in newborns of parents of Asian and African origin. Genotype 3/3 was more frequent in newborns whose parents came from Europe and America (78%) compared to those from Asia or Africa (69%). CONCLUSIONS: It is important to determine risk factors such as APOE genotype for evaluation of premature atherosclerosis. Determining genetic and environmental risk factors may facilitate earlier treatment and prevent heart and brain atherosclerosis. APOE genotypes did not appear to affect total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride levels in newborns.

Monitoring Pleural Effusion in Elderly Patients Using Internal Thoracic Impedance.

BACKGROUND: Internal thoracic impedance (ITI) measurement is a sensitive method for detecting preclinical pulmonary edema and pleural effusion. OBJECTIVES: To investigate the efficacy of this non-invasive method for detecting early pleural effusion among geriatric patients and to monitor increased ITI during its resolution. METHODS: This prospective, controlled study was conducted between July 2012 and August 2015. The study comprised 70 patients aged 65 to 94 years; and 39 of the patients had pleural effusion. ITI was measured continuously with a RS-207 monitor. The predictive value of ITI monitoring was determined based on a total of eight measurements taken at 12-hour intervals over 84 hours. RESULTS: As a result of medical treatment, the median ITI of the study group increased from 31 (interquartile range [IQR] 28-33 ohms) to 41 ohms (IQR 38-41 ohms; P < 0.001) compared to non-significant changes in the control group. Average respiratory rate (per minute) in the study group decreased from 29 (IQR 28-34) to 19 (IQR 18-20). CONCLUSIONS: ITI monitoring is efficient for diagnosis and for ongoing clinical evaluation of the treatment of elderly patients with pleural effusion. Timely treatment may prevent serious complications of effusions avoiding extended hospitalization.

Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice.

BACKGROUND & AIMS: ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1α is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1α is involved in ER stress-induced apoptosis and steatohepatitis. METHODS: We employed WT and IL-1α-deficient mice to study the role of IL-1α in ER stress-induced steatohepatitis. RESULTS: Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1α deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1α deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1ß, IL-6, TNFα, and CHOP, with no effect on the degree of fatty liver formation. IL-1α was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1ß mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1α deficient compared to WT mice. ER stress induced the expression of IL-1α and IL-1ß also in mouse primary hepatocytes. Recombinant IL-1α treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1α and IL-1ß mRNA levels. CONCLUSION: We show that IL-1α is upregulated in response to ER stress and IL-1α deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1α may contribute to the induction of CHOP intracellularly, while IL-1α released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells.

Peripheral Vascular Disease and Carotid Artery Disease Are Associated with Decreased Bile Acid Excretion.

Low bile acid excretion (BAE) is associated with a higher risk of coronary artery disease (CAD) and cerebrovascular disease (stroke). This study investigated BAE in patients with peripheral vascular disease (PVD) and carotid artery disease (CA) and those without these diseases, compared to patients with CAD, stroke, or no evidence of atherosclerosis. Patients with complaints of chest pain-suspected CAD, syncope, stroke/TIA, severe headache, intermittent claudication, or falls were enrolled. All received a 4-day standard diet with 490 mg of cholesterol and internal standard copper thiocyanate. Fecal BAE was measured using gas-liquid chromatography. One hundred and three patients, sixty-eight (66%) men and thirty-five women (34%), mean age range 60.9 ± 8.9 years, were enrolled in this prospective, 22-year follow-up study. Regression analysis showed that advanced age, total BAE, and excretion of the main fractions were the only significant independent factors that predicted prolonged survival (p < 0.001). Twenty-two years' follow-up revealed only 15% of those with BAE <262.4 mg/24 h survived, compared to >60% of participants without atherosclerosis and a mean BAE of 676 mg/24 h. BAE was lower in patients with polyvascular atherosclerosis than in those with involvement of 1-3 vascular beds. Pearson correlations were found between total BAE and various fractions of BA, as well as HDL cholesterol. BAE and short-term survival were decreased among patients with PVD compared to those with CAD or stroke. Low BAE should be considered a valuable and independent risk factor for PVD.

Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α.

OBJECTIVE: Interleukin (IL)-1α and IL-1ß are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1's. Whereas several studies demonstrate the proatherogenic properties of IL-1ß, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1ß from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1ß deficiency on degradation of LDL and cytokine production. METHODS: We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1ß-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1ß-/-. RESULTS: The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1ß in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1ß-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1ß (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. CONCLUSION: We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.

Usefulness of cardiac biomarkers for prognosis of better outcomes in chronic heart failure: Retrospective 18-year follow-up study.

ABSTRACT: Brain natriuretic peptide is an established, surrogate follow-up marker, strongly correlated with heart failure severity. Several other biomarkers and tests are useful for assessing the prognosis of patients with HF, such as oxidized low-density lipoprotein antibodies and C-reactive protein. Some inflammatory cells, including monocytes, lymphocytes, and neutrophils, are involved in coronary heart disease and may be useful for prognosis also. This study assessed the potential usefulness of various laboratory biomarkers in predicting long-term outcomes and hospitalization among a cohort of outpatients with chronic, advanced HF.This retrospective, 18-year follow-up study included all patients admitted to the Heart Failure Outpatient Unit in our tertiary care medical center from 2000 through 2001 due to chronic HF. Excluded were patients with malignant disease, severe stroke, active inflammatory disease, or infection. At the first visit, blood was sampled for routine analysis and biomarkers NT-proBNP, C-reactive protein, myeloperoxidase, heat shock protein, and antibodies to oxidized low density lipoprotein. left ventricular ejection fraction and New York Heart Association class class were also established. Patients were followed every 3 months. Study endpoints were mortality or first hospitalization.Among 305 study patients, HF duration ranged from 2 months to 18 years. Mean follow-up was 9.1 ±â€Š6 years. Mean time to first hospitalization was 60 ±â€Š58.1 months, median = 38 (range 0-179). Mortality rate was 41%. Regression analysis showed New York Heart Association class, lymphocyte count and alkaline phosphatase were independent predictors of survival, with hazard ratios of 1.0, 0.973, and 1.006, respectively (P < .05).N-terminal pro-B-type natriuretic peptide, alkaline phosphatase, and lymphocyte count are important prognostic predictors for very long-term follow-up among patients with chronic HF.

Using the Gensini score to estimate severity of STEMI, NSTEMI, unstable angina, and anginal syndrome.

ABSTRACT: Gensini score (GS) provides valuable information on severity and prognosis of coronary artery disease (CAD).To evaluate the relationship between the severity of CAD determined by the GS and relation to ST-elevation myocardial infarction, non-ST segment elevation myocardial infarction (NSTEMI), unstable angina pectoris, chest pain (suspected angina syndrome on admission) and risk-factors for CAD and predictors of severity.Observational cross-sectional study.Consecutive patients who underwent clinically-indicated coronary angiography for ST-elevation myocardial infarction, NSTEMI, unstable angina pectoris or chest pain were enrolled.Among 600 patients, 417 (average age 67.8 ±â€Š12.2 years) had CAD-related symptoms. Mean GS was 66.7 ±â€Š63.8. Patients presenting with NSTEMI had the highest GS (81.3 ±â€Š42.3; P < .001) Regression analysis of risk-factors showed the best association of GS with multivessel disease and coronary artery bypass graft. Regression analysis of medications showed that clopidogrel, had the best association with low GS.GS correlated with the severity of CAD, multivessel disease, coronary artery bypass graft, and troponin. GS was related to the cardiovascular risk-factors of diabetes, hypertension, and high-density cholesterol.

Methylphenidate has mild hyperglycemic and hypokalemia effects and increases leukocyte and neutrophil counts.

Various psychotropic drugs may affect the hematological and biochemical profiles of plasma and its metabolism. Carbamazepine, the most well-known psychotropic drug, can cause substantial hyponatremia. Methylphenidate, a piperidine derivative structurally related to amphetamines, acts as a central nervous system stimulant. The current study evaluated whether methylphenidate affects hematological and biochemical parameters of patients diagnosed with attention deficit hyperactivity disorder.Patients undergoing treatment for attention deficit hyperactivity disorder at our Adolescent Psychiatric Clinic were enrolled in the study. Blood samples for complete blood count and common biochemical analyses were collected before patients started methylphenidate and after 3 months of continuous treatment.Participants included 64 patients comprised the study cohort. There were 48 (75%) males and 16 (25%) females, with a median age of 16 years (range 11-31). The total median potassium level decreased by 0.6 mg/dL (P < .0001), while glucose rose by 15 mg/dL (P < .0001), sodium decreased in 0.7meq/L, (P = .006). The white blood count rose by 1350 cells/µL (P < .033) due to neutrophilia, lymphocytosis and eosinophilia. Hemoglobin rose slightly by 0.1 (P = .041). Changes in calcium, phosphorus, protein, albumin, and liver enzyme levels were not significant.The results indicate that methylphenidate may cause hypokalemia and elevated glucose, leukocyte, neutrophil, lymphocyte and eosinophil counts.

Reduced bile acid excretion is an independent risk factor for stroke and mortality: A prospective follow-up study.

BACKGROUND AND AIMS: Hypercholesterolemia is a major risk factor for atherosclerosis, which is a cornerstone of coronary artery disease (CAD), stroke, peripheral vascular disease, aortic aneurysm and renal artery stenosis. This study investigated the association of bile acid excretion (BAE) with stroke incidence and mortality. METHODS: Patients admitted to Internal Medicine due to chest pain and suspected CAD were enrolled and followed from 1/1998 to 12/2018. Patients received a standard in-hospital diet containing 490 mg/day cholesterol and performed a 24-h stool collection. A continuous, non-absorbable marker was used to evaluate the amount of BAE. RESULTS: This retrospective, historical, follow-up study included 68 men and 35 women (mean age 61.9 ± 8.9 years) admitted to the hospital from 1996 to 1998 due to chest pain and suspected cardiac event. Mean BAE at first admission was higher among survivors (>608.8 mg) than non-survivors (281.5 mg/24h; p<0.001). Total cholesterol, LDL cholesterol and triglyceride levels at baseline did not differ significantly. The main fractions of deoxycholic, lithocholic, and cholic acids were significantly different in the two groups. They were also higher in the survivors. Total BAE was higher in stroke-free patients compared to those who developed stroke: 561.6 mg/24h and 231.2 mg/24h-respectively (p<0.001). Patients with BAE <262.4 developed stroke in 75% cases (18/24). None of 25 patients with BAE >622 mg/24h developed stroke. CONCLUSION: This retrospective, historical cohort follow-up study showed an association between lower amounts of total bile acid, deoxycholic acid and lithocholic acid excretion with stroke risk. Low BAE remained a significant risk-factor after adjusting for main potential confounders and may be an independent risk-factor for stroke.

Methylphenidate has positive hypocholesterolemic and hypotriglyceridemic effects: new data.

Many psychotropic drugs may affect plasma lipids profile and their metabolism, with carbamazepine being the best known among them. Methylphenidate is a piperidine derivative structurally related to amphetamines and acts as a central nervous system stimulant. Its effect on lipid metabolism has not been investigated. The authors evaluated how methylphenidate affects the lipid profile in the plasma of patients diagnosed as having attention-deficit hyperactivity disorder (ADHD). All consecutive patients undergoing treatment for ADHD at the Adolescent Psychiatric Clinic (2003-2007) were enrolled. Blood samples for total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A, apolipoprotein B, and lipoprotein (a) (Lp(a)) were collected before starting treatment and after 3 months of continuous treatment. Forty-two patients (22 men), median age 16, participated. The median total cholesterol count decreased by 9 mg/dL (P<.0002), LDL-C decreased by 5.0 mg/dL (P<.016), and triglycerides decreased by 8.0 mg/dL (P<.016). Changes in the levels of HDL-C, apolipoprotein A, and apolipoprotein B were nonsignificant, and Lp(a) levels decreased by 2.0 mg/dL (P<.0007). Methylphenidate improves the lipid profile by decreasing total cholesterol, triglycerides, LDL-C, and Lp(a).

Monocytes may be favorable biomarker and predictor of long-term outcome in patients with chronic heart failure: A cohort study.

Although some studies found that an increased monocyte count is a predictive, short-term marker of unfavorable outcomes for patients with acute heart failure (HF), others have reported that monocytosis predicts prolonged survival.The current follow-up study aimed to identify different monocyte count patterns and their prognostic association with HF outcomes.Baseline blood samples for complete blood counts, differential counts, renal function tests, and lipid profiles of 303 chronic HF patients (average NYHA classification 2.8) were prospectively obtained to evaluate whether there is an association between monocyte count and clinical outcomes.Mean follow-up was 11.3 years (range 1 month to 16 years) and 111 (36.6%) patients died during follow-up. Mean monocyte count was 10.6 ±â€Š5.5 and mean left ventricular ejection fraction (LVEF) was 36%. Patients with low monocyte counts (≤6%) had significantly lower survival rates than did those with monocyte counts 6.1% to 14%, or >14% (14.3% vs 70.2% vs. 88%, P < .001). Poorest survival was predicted for patients with NYHA class 3 to 4 and monocyte counts ≤6. Regression analysis showed that monocyte levels, NYHA class, and LVEF values were predictors of mortality, in decreasing importance.The total monocyte count was found to be an important prognostic factor that was inversely associated with predicted long-term mortality among patients with chronic HF. A low total monocyte count was strongly correlated with NYHA class and B-type natriuretic peptide levels, but no correlation was found with LVEF and oxidized low-density lipoproteins. It emerged as an independent risk factor for mortality in patients with chronic HF.

Development of Crohn's disease in a patient with multiple sclerosis treated with copaxone.

BACKGROUND: Copaxone (glatiramer acetate) is a synthetic copolymer mimicking a portion of myelin basic protein, one of several putative autoantigens in multiple sclerosis (MS). Copaxone suppresses the production of tumor necrosis factor (TNF)-alpha, a key mediator of inflammation in MS as well as in other pathologies, such as colitis of interstitial bowel disease (IBD). Copaxone is a drug approved for the treatment of MS, and one that is very well tolerated with a high safety profile and relatively few side effects. Crohn's disease has not been associated with its administration. METHODS: We describe a patient with MS in remission who had not exhibited any signs of IBD in the past. She had been on Copaxone 20 mg/day treatment for 2 years when she first exhibited gastrointestinal symptoms. RESULTS: Our patient developed Crohn's disease while on Copaxone treatment as a consequence of long-term immunosuppression. CONCLUSIONS: Clinicians should be aware that Crohn's disease is a potential novel adverse drug effect of Copaxone.

Diminished bile acids excretion is a risk factor for coronary artery disease: 20-year follow up and long-term outcome.

BACKGROUND: Patients with coronary artery disease (CAD) had significantly lower bile acid excretion (BAE) compared with non-CAD patients, leading to the hypothesis that the inability to efficiently excrete bile acids leads to coronary atherosclerosis development. We investigated the long-term role of BAE in CAD development and related mortality in 50 patients with proven CAD compared with that of 50 patients with chest pain and no CAD (controls) matched for clinical and laboratory characteristics. METHODS: All subjects received a 4-day standard diet that included ~500 mg of cholesterol. Fecal bile acids from 24-h stool collections were measured by gas liquid chromatography. RESULTS: CAD patients excreted lower amounts of total bile acids than controls (p < 0.001), less deoxycholic acid (p < 0.0001) and less lithocholic acid (p < 0.01). BAE was the best significant independent laboratory factor that predicted CAD (p < 0.05). Mortality and CAD development rates were significantly lower for the controls at the 20-year follow up. CONCLUSIONS: These results showed that CAD patients had markedly decreased BAE levels compared with non-CAD controls. BAE <415 mg/day was associated with increased CAD long-term mortality. Impaired ability to excrete cholesterol might be considered an additional independent risk factor for CAD development.

An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo.

OBJECTIVE: Humans with high expression of apolipoprotein(a) [apo(a)] and high plasma levels of lipoprotein(a) [Lp(a)] are at increased risk for atherosclerosis, but the mechanism is not known. We have previously shown that the KIV(5-8) domain of apo(a) has unique cell-surface binding properties, and naturally occurring fragments of apo(a) encompassing this domain are thought to be atherogenic in humans. To investigate the effect of KIV(5-8) on lipoprotein metabolism and atherosclerosis in vivo, we created several independent lines of liver-targeted KIV(5-8) transgenic mice. METHODS AND RESULTS: The transgenic mice have plasma apo(a) peptide concentrations that are similar to Lp(a) concentrations in humans at risk for coronary artery disease. Remarkably, the transgenic mice had a 2- to 4-fold increase in cholesterol-rich remnant lipoproteins (RLPs) when fed a cholesterol-rich diet, and a 5- to 20-fold increase in atherosclerosis lesion area in the aortic root. Using an in vivo clearance study, we found only slight differences in the triglyceride and apolipoprotein B secretion rates between the 2 groups of mice, suggesting an RLP clearance defect. Using an isolated perfused mouse liver system, we showed that transgenic livers had a slower rate of RLP removal, which was retarded further when KIV(5-8), full-length apo(a), or Lp(a) were added to the perfusate. An apo(a) peptide that does not interact with cells, K(IV2)3, did not retard RLP removal, and low-density lipoprotein (LDL) had a much smaller effect than Lp(a). CONCLUSIONS: We propose that high levels of apo(a)/Lp(a), perhaps acting via a specific cell-surface binding domain, inhibit hepatic clearance of remnants, leading to high plasma levels of RLPs and markedly enhanced atherosclerosis. We speculate that the KIV(5-8) region of apo(a) competes with one or more receptors for remnant clearance in the liver and that this process may represent one mechanism accounting for increased atherosclerosis in humans with high secretion levels of apo(a).

Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants.

OBJECTIVE: ApoAV, a newly discovered apoprotein, affects plasma triglyceride level. To determine how this occurs, we studied triglyceride-rich lipoprotein (TRL) metabolism in mice deficient in apoAV. METHODS AND RESULTS: No significant difference in triglyceride production rate was found between apoa5(-/-) mice and controls. The presence or absence of apoAV affected TRL catabolism. After the injection of 14C-palmitate and 3H-cholesterol labeled chylomicrons and (125)I-labeled chylomicron remnants, the disappearance of 14C, 3H, and (125)I was significantly slower in apoa5(-/-) mice relative to controls. This was because of diminished lipolysis of TRL and the reduced rate of uptake of their remnants in apoa5(-/-) mice. Observed elevated cholesterol level was caused by increased high-density lipoprotein (HDL) cholesterol in apoa5(-/-) mice. VLDL from apoa5(-/-) mice were poor substrate for lipoprotein lipase, and did not bind to the low-density lipoprotein (LDL) receptor as well as normal very-low-density lipoprotein (VLDL). LDL receptor levels were slightly elevated in apoa5(-/-) mice consistent with lower remnant uptake rates. These alterations may be the result of the lower apoE-to-apoC ratio found in VLDL isolated from apoa5(-/-) mice. CONCLUSIONS: These results support the hypothesis that the absence of apoAV slows lipolysis of TRL and the removal of their remnants by regulating their apoproteins content after secretion.

Bezafibrates cause moderate, reversible impairment in renal function in patients without prior renal disease.

BACKGROUND/AIMS: To determine whether bezafibrates have adverse effects on renal function. METHODS: (1) A 3-year retrospective survey of 526 patients who were on bezafibrate for a while and 614 controls following fluctuations of serum creatinine levels. (2) A prospective study on 33 patients with previous evidence of bezafibrate-induced elevation in serum creatinine. The patients were examined after 3 months on bezafibrate 400 mg/day and then after 3 months without bezafibrate. Eight patients repeated the tests after 3 months on bezafibrate 200 mg/day. RESULTS: Retrospective: 295 bezafibrate-treated patients (56%) and 67 controls (11%) demonstrated fluctuations > or = 0.2 mg/dl in serum creatinine levels (p < 0.001); 113 patients (21%) and 16 controls (3%) showed fluctuations > or = 0.3 mg/dl (p < 0.001). Prospective: bezafibrate 400 mg/dl increased serum creatinine from 1.16 +/- 0.19 to 1.42 +/- 0.2 mg/dl (p < 0.001) and urea from 37 +/- 8 to 44 +/- 8 mg/dl (p < 0.001); creatinine clearance (Ccr) decreased from 104 +/- 23 to 82 +/- 27 ml/min (p < 0.001). CPK increased from 82 +/- 32 to 130 +/-58 mg/dl (p < 0.0001) and urinary myoglobin increased from 95.4 +/- 21 to 199 +/- 99 mg/dl (p < 0.0001). The 8 patients given bezafibrate 200 mg/dl experienced similar dose-dependent changes. CONCLUSIONS: Bezafibrate causes quiet common, dose-dependent and reversible changes in serum creatinine in patients with normal renal function, associated with a significant increase in serum CPK and urine myoglobin, suggestive of drug-induced mild subclinical skeletal muscle injury compromising renal function.

Usefulness of Antibodies to Oxidized Low-Density Lipoproteins as Predictors of Morbidity and Prognosis in Heart Failure Patients Aged ≥65 Years.

Elevated level of antibodies to oxidized low-density lipoproteins (OxLDL-Ab) was shown to reliably predict morbidity and mortality in patients with heart failure (HF). Two hundred and eleven patients aged ≥65 years treated at the Heart Failure Unit, Tel Aviv-Sourasky Medical Center, were included in this retrospective study. The end points were time to the first hospitalization (morbidity), all-cause mortality, and a combination of the two (composite outcome). HF duration ranged from 8 to 10.5 years. Mean follow-up was 5.2 ± 1.9 years. The mean number of clinical visits was 18.3 ± 2.4. Participants were divided according to OxLDL-Ab level. Group 1 had Ox LDL-Ab level <200 arbitrary U/ml. Group 2 had OxLDL-Ab level ≥200 arbitrary U/ml. The mean time to the first hospitalization was 25.8 ± 17.0 months. The mortality rate was 44.1%. Combined mortality and hospitalization rate was 58.8%. Adjusted hazard ratios of OxLDL-Ab for hospitalization were 3.16, p <0.001, 95% confidence interval 1.740 to 5.736 and for composite outcome 2.67, p <0.001, 95% confidence interval 1.580 to 4.518. In conclusion, OxLDL-Ab level was the best predictor for both hospitalization and composite outcome. It may, thus, serve as a useful clue for early and more accurate detection of poorly controlled HF and as a marker for imminent exacerbations of thereof.

Low molecular weight heparin-induced increase in chylomicron-remnants clearance, is associated with decreased plasma TNF-α level and increased hepatic lipase activity.

OBJECTIVE: The acute effect of heparin on lipoprotein clearance is well characterized. Yet, the effect of prolonged low-molecular-weight-heparin (LMWH) administration on post-prandial lipemia has remained so far unexplored. Recent reports suggest that LMWH could modify lipid and carbohydrate metabolism by diminishing TNFα-mediated inflammatory response. This, together with the known negative effect of TNF-α on insulin sensitivity, prompted us to hypothesize that LMWH would favorably affect post-prandial lipoprotein disposal. METHODS: Twenty four patients were given a vitamin A-fat loading meal at the end of 6-week enoxaparin treatment and after 3-month washout period. Post-prandial lipemia was assessed by measuring retinyl-palmitate (RP) during 8hours following the meal. Insulin sensitivity index (ISI), plasma lipolytic activity and plasma TNF-α were measured. RESULTS: Enoxaparin did not impact fasting plasma lipids and lipoproteins levels. Enoxaparin increased RP clearance in the chylomicron remnant (CMR) fraction by 32% (P<0.01). Additionally, enoxaparin decreased plasma TNF-α by 22% (P<0.01), increased hepatic lipase (HL) activity by 81% (P<0.01), along with a 2-fold increase in ISI (P<0.01). The decrease in CMR correlated with the reduction in TNFα and the increase in ISI and HL activity (R=0.48, -0.68, -0.56, respectively, p<0.05). Significant correlations were also found between the reduction in TNFα and both the increase in ISI and increase in HL activity (R=-0.43, -0.54, respectively, P<0.05). CONCLUSIONS: The association of the effect on post-prandial metabolism, plasma TNFα level and HL activity during prolonged enoxaparin treatment may support the hypothesis that the beneficial outcome of enoxaparin may possibly be linked to anti-inflammatory and lipase-potentiating impact.

Apolipoprotein A-V modulates multiple atherogenic mechanisms in a mouse model of disturbed clearance of triglyceride-rich lipoproteins.

OBJECTIVE: Apolipoprotein A-V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA-V would inhibit atherogenesis in apoE(-/-) mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. METHODS AND RESULTS: ApoA-V(+/+)ApoE(-/-) mice expressing human apolipoprotein A-V (hapoA-V) were generated and compared to apoE(-/-) mice. Atherosclerotic aortic sinus lesion area was 70% smaller in hapoA-V(+/+)apoE(-/-). This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in hapoA-V(+/+)apoE(-/-) mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in hapoA-V(+/+)apoE(-/-) mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in hapoA-V(+/+)apoE(-/-) mice. In addition, hapoA-V(+/+)apoE(-/-) mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, hapoA-V(+/+)apoE(-/-) displayed a milder systemic inflammatory response compared to apoE(-/-) mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1ß and IL-6, respectively. CONCLUSIONS: We showed that human apolipoprotein A-V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA-V as a potential therapeutic target for treatment of atherosclerosis.