Handrean Soran

Influence of diabetes on the maintenance of sinus rhythm after a successful direct current cardioversion in patients with atrial fibrillation

AIM To determine independent risk factors for recurrence of atrial fibrillation (AF) after a successful direct current (DC) cardioversion in patients with and without diabetes. DESIGN We retrospectively analysed the outcome in patients recently diagnosed with persistent AF. METHODS Of 364 patients included, 289 had a successful direct current (DC) cardioversion. We compared 42 (14.5%) patients known to have diabetes to 247 (85.5%) without. Patients were reviewed in outpatient clinic with assessment of heart rhythm clinically and by electrocardiogram. Median follow-up after DC cardioversion was 74 days [interquartile range (IQR) 69-78 days]. RESULTS When reviewed in outpatient clinic, only 63.7% (185 of 289) were still in sinus rhythm (SR). Of the group without diabetes, 66.8% (165 of 247) remained in SR vs. 45.2% (19 of 42) of the group with diabetes (P = 0.005). Binary logistic regression analysis showed duration of AF (P < 0.0001) and the presence of diabetes (P = 0.019) have been independent risk factors for recurrence of AF. DISCUSSION Presence of diabetes and the longer duration of AF were independent risk factors for the recurrence of AF after a successful DC cardioversion.

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BACKGROUND Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low‐density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow‐up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of ‐56.0% in the bococizumab group and +2.9% in the placebo group, for a between‐group difference of –59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower‐risk, shorter‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow‐up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher‐risk, longer‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow‐up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection‐site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower‐risk patients but did have a significant benefit in the trial involving higher‐risk patients. (Funded by Pfizer; SPIRE‐1 and SPIRE‐2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389.)

Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy.

Objectives Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated. Methods and Results Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n  = 58) were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n  = 39) or placebo (n  = 19) were added to lipid-lowering therapy for 26 weeks. Main outcome: percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27) reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18) from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001). Mipomersen produced statistically significant (p<0.001) reductions in apolipoprotein B and lipoprotein(a), with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%), 39(100%); serious adverse events, 0(0%), 6(15.4%); discontinuations due to adverse events, 1(5.3%), 8(20.5%) and cardiac adverse events, 1(5.3%), 5(12.8%). Conclusion Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a). Mounting evidence suggests it may be a potential pharmacologic option for lowering LDL-C in patients with severe hypercholesterolemia not adequately controlled using existing therapies. Future studies will explore alternative dosing schedules aimed at minimizing side effects. Trial Registration ClinicalTrials.gov NCT00794664.

Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.

Variation in paraoxonase-1 activity and atherosclerosis.

Purpose of review Paraoxonase-1 (PON1) is an HDL-associated protein of 354 amino acids with a molecular mass of 43 000 Da. It is synthesized in the liver, and in serum it is almost exclusively associated with HDL. PON1 has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL. PON1 impedes oxidative modification of LDL. PON1 serum activity is related to systemic lipid peroxidation stress and prospective cardiovascular risk. In this review, we discuss the relationship between PON1 activity and atherosclerotic diseases and various factors modulating PON1 activity including genes, age, lifestyle factors and medical conditions. Finally, evidence that pharmacological agents may affect PON1 activity is summarized. Recent findings There is increasing evidence from both animal and human studies linking low PON1 activity to an increased likelihood of cardiovascular diseases. Two prospective studies reported a significantly lower incidence of major cardiovascular events in participants with the highest systemic PON1 activity, compared with those with the lowest activity. Summary PON1 is a potentially antiatherogenic HDL-associated enzyme that protects LDL from oxidative modification. Enhancing PON1 activity could be an important target for future pharmacological agents aimed at decreasing cardiovascular risk.

Hypercholesterolaemia and its management.

Hypercholesterolaemia is one of the major causes of atherosclerosis. Although there are many causes, hypercholesterolaemia is the permissive factor that allows other risk factors to operate.1 The incidence of coronary heart disease is usually low where population plasma cholesterol concentrations are low.2 In Britain coronary heart disease is a major cause of mortality, and a recent Department of Health survey suggested that the average plasma cholesterol concentration in the United Kingdom was 5.9 mmol/l, much higher than the 4 mmol/l seen in rural China and Japan, where heart disease is uncommon.3 Many studies before and after the introduction of statins have indicated that reducing the prevalence of hypercholesterolaemia is an important means of decreasing coronary risk. Cholesterol plays an important role as the precursor for steroid hormones and bile acids and it is essential for the structural integrity of cell membranes. It is transported in the body in lipoproteins. Figure 1⇓ shows the role of cholesterol in lipoprotein metabolism. Fig 1 The role of cholesterol in the metabolism of lipoprotein. Adapted from Charlton-Menys4 Conventionally the upper limit for laboratory reference ranges is based on the 95th or 90th centile for a healthy population. This does not apply to plasma cholesterol, however, as several studies show that the epidemiological relation between plasma cholesterol and risk of coronary heart disease extends to the lower end of the cholesterol distribution. Although the relation becomes progressively steeper, there is no obvious threshold below which it ceases to exist.5 Therefore, it is more rational to base a desirable or healthy concentration of plasma cholesterol on the value at which coronary risk is considered unacceptably high. Most patients developing coronary heart disease have plasma cholesterol concentrations that are likely to be between the 30th and 90th centile for their population …

Effects of Bariatric Surgery on Human Small Artery Function: Evidence for Reduction in Perivascular Adipocyte Inflammation, and the Restoration of Normal Anticontractile Activity Despite Persistent Obesity

Objectives The aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this. Background In lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity-associated conditions such as the metabolic syndrome and type II diabetes where there is evidence of adipocyte inflammation and increased oxidative stress. Methods Segments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in vitro with wire myography, and perivascular adipose tissue (PVAT) morphology was assessed with immunohistochemistry. Results The anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers and was restored 6 months after bariatric surgery. In vitro protocols with superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals before surgery. The improvement in anticontractile function after surgery was accompanied by improvements in insulin sensitivity, serum glycemic indexes, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese. Conclusions Bariatric surgery and its attendant improvements in weight, blood pressure, inflammation, and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability.

Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile-associated disease.

BACKGROUND Clostridium difficile is the most common infectious cause of colitis and has been increasingly diagnosed in hospitalized patients. The number of prescriptions for proton pump inhibitors (PPIs) has also increased significantly over time. Few studies have reported an association between C. difficile-associated disease (CDAD) and PPI use. AIM To assess the extent and appropriateness of PPI prescribing in patients diagnosed with C. difficile infection. METHODS We prospectively studied PPI prescriptions in 138 hospitalized patients diagnosed with C. difficile infection over a 4-month period. Clostridium difficile infections were diagnosed by the presence of C. difficile toxin in the stools. The appropriateness of prescriptions and relevant investigations were assessed by interview of patients and review of patient records. RESULTS Sixty-four percent (88 of 138) of all patients who developed C. difficile infections were on PPIs. A valid indication for PPIs therapy was not apparent in 63% of the patients. CONCLUSION There appears to be a widespread and inappropriate use of PPIs in hospital practice. Reduction of unnecessary PPIs use may be an additional strategy to reduce the incidence of this infection.

Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro

OBJECTIVE LDL atherogenicity is frequently attributed to oxidative modification, but glycated LDL, which can participate in many of the cellular processes leading to atherosclerosis, generally circulates at higher concentration even in non-diabetic people. We tested the hypothesis that small-dense LDL, known to be most closely associated with coronary heart disease, undergoes more glycation than other LDL sub-fractions. METHODS AND RESULTS The concentration of glycated apolipoprotein B (apo B) was measured in serum, LDL and its sub-fractions from 44 non-diabetic subjects. By ELISA serum glycated apoB concentration was 3.0+/-1.1mg/dl (mean+/-S.D.) of which 84.6+/-13.6% was in LDL. Of the glycated apo B in LDL 67.8+/-21.9% was in small dense LDL (LDL3; D1.044-1.063g/ml) whereas only 32.2+/-21.9% was in more buoyant LDL subfractions (LDL1 and 2; D1.019-1.044g/ml). The percentage of apo B present in LDL1 and 2 which was glycated was 1.8+/-1.8% whereas in LDL3 it was 17.4+/-18.5% (P<0.001). Furthermore when LDL sub-fractions from non-diabetics (n=29) were incubated with glucose (30-80mmol/l) glycation of apo B in the denser LDL3 subfraction was significantly more pronounced than in less dense LDL subfractions. CONCLUSION Small-dense LDL is more susceptible to glycation and this may contribute to the atherogenicity of small-dense LDL, even in non-diabetic people.

Familial hypercholesterolaemia: A global call to arms.

Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDL-receptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDL-cholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1], [2] and [3]. If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years [2], [3], [4] and [5]. Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated [1], thereby representing a major global public health challenge.