Evaluation of Lipid Profile and Statin Therapy in Patients with Atrial Fibrillation: Real-Life Data from a Tertiary Hospital

AHA 2012: Prevention a key focus of meeting

A MET a Day Keeps Arrhythmia at Bay: The Association Between Exercise or Cardiorespiratory Fitness and Atrial Fibrillation

Optimal diabetes care and risk factor management are important to delay micro- and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. Cross-sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c) <53 mmol/mol, low-density lipoprotein-cholesterol (LDL-c) <2.6 mmoL/L (no cardiovascular disease [CVD] present) or <1.8 mmoL/L (CVD present), or blood pressure (BP) <140/90 mm Hg. Target achievement was compared for individuals with and without CVD. Data from 1737 individuals were included. Mean HbA1c was 63 mmol/mol (7.9%), LDL-c was 2.67 mmoL/L, and BP 131/76 mm Hg. In individuals with CVD, 24%, 33%, and 46% achieved HbA1c, LDL-c, and BP targets respectively. In individuals without CVD these percentages were 29%, 54%, and 77%, respectively. Individuals with CVD did not have any significant risk factors for HbA1c, LDL-c, and BP target achievement. In comparison, individuals without CVD were more likely to achieve glycemic targets if they were men and insulin pump users. Smoking, microvascular complications, and the prescription of lipid-lowering and antihypertensive medication were negatively associated with glycemic target achievement. No characteristics were associated with LDL-c target achievement. Microvascular complications and antihypertensive medication prescription were negatively associated with BP target attainment. Opportunities for improvement of diabetes management exist for the achievement of glycemic, lipid, and BP targets but may differ between individuals with and without CVD.

Improving Lipid Goal Attainment

Background:The most common risk factor for Atrial Fibrillation (AF) development is hypertension.Purpose:to explore patients’ characteristics associated with AF caused by hypertension.Methods:The sample of the study included 170 patients with AF caused by hypertension. Data collection was performed by the method of interview using a questionnaire developed by the researchers of the study for the collection of demographic, clinical and other patients’ characteristics.Results:Regarding type of AF, 21.9% of the patients had paroxysmal AF while 64.5% and 13.6% had persistent and permanent AF, respectively. Patients who had persistent AF were receiving anticoagulants and antiarrhythmics at a higher percentage (88.8% and 82.2%,respectively) than patients with paroxysmal (69.4% and 72.2%, respectively) or permanent AF (69.6% and 56.5%, respectively). Patients with persistent AF had at a lower percentage their blood pressure controlled than patients with paroxysmal or permanent AF (85.3% vs. 97.3% and 95.7%, respectively). Patients with permanent AF had at a higher percentage >5 years onset of their heart problem (47.8%) than patients with paroxysmal or persistent AF (10.8% and 8.3%, respectively). Patients with permanent AF had at a higher percentage previous hospitalization due to AF (69.6%) than patients with paroxysmal (40.5%) or persistent AF (62%). Lastly, patients with persistent AF were very informed about the state of their health at a higher percentage (33%) compared patients with paroxysmal or permanent AF (13.5% and 26,1%, respectively).Conclusions:The present study revealed patients’ characteristics that may be helpful when planning nursing interventions or guiding clinical decision-making.

Introduction An elevated level of low-density lipoprotein cholesterol (LDL-C) is associated with higher risk of atherosclerosis disease, and overwhelming evidence has demonstrated that lowering LDL-C reduces arteriosclerotic cardiovascular disease (ASCVD) events. However, many questions still remain regarding the use of LDL-C, such as “Are lower levels better?” and “How low is enough?” In this article, we discussed the optimal LDL-C level necessary to prevent atherosclerosis and cardiovascular events, reviewed the LDL-C level of newborns and adolescents, summarized the updated evidence of imaging and clinical benefits with lower LDL-C concentrations, and discussed the possible ways to reach lower levels of LDL-C and its safety. Atherosclerotic diseases were among the most important causes of death worldwide. Epidemiological, clinical, genetic, experimental, and pathological studies had clearly shown the role of lipoproteins in atherosclerosis. LD was the major atherogenic lipoprotein and many guidelines define it as the primary target of lipid-lowering treatment. Although the level of LDL, the primary target in the treatment of dyslipidemia, had been set to below 100 mg/dl in coronary heart diseases (CHDs) and CHD risk equivalents, it had been pulled down to below 70 mg/dl for the group defined as very high risk by guidelines following the new clinical studies. Was this target level low enough? Under intensive lipid-lowering therapy, even to the level as low as 55 mg/dL, the rate of cardiovascular events still remained at 0.77 and 1.36/100 person-years.[1] Hence, the optimal level of LDL-C may be lower than we had anticipated. As we already know, atherosclerosis begins in childhood as deposits of cholesterol and its esters, referred to as fatty streaks, in the intima of large muscular arteries. In adolescence, some fatty streaks accumulated more lipids and begin to develop a fibromuscular cap, forming the lesion termed a fibrous plaque. Further changes in fibrous plaques render them vulnerable to rupture, an event that precipitates occlusive thrombosis and clinically manifest diseases (sudden cardiac death, myocardial infarction, stroke, or peripheral arterial disease). In the neonatal stage, the progression of atherosclerosis was not yet initiated, so this suggests that the LDL levels should potentially be lowered to the levels at birth. Physical Low-density Lipoprotein Cholesterol Level in Newborn A sample of umbilical cord venous blood was obtained from 156 normal newborns (76 male) immediately after delivery: mean values of LDL-C in males, females, and in the total sample were 28.3, 32.4, and 30 mg/dl, respectively.[2] Cord blood mean (standard deviation [SD]) LDL-C values in 378 full-term Iranian newborns was 35.9 ± 22.4 in girls and 32.1 ± 16.3 in boys.[3] Another trial taken in Brazil showed that total cholesterol concentrations were 70.42 ± 1.63 mg/dl, and LDL-C level was 34.38 ± 1.29 mg/dl in the term group.[4] A study taken in china also determined the lipid profile in 242 healthy full-term newborn infants. The mean values of LDL-C in cord blood were 31.15 ± 8.08 mg/dL (mean ± SD).[5] A study was carried out in 137 healthy newborns (63 boys and 74 girls) coming from normal, physiological pregnancies, spontaneously born, and generally in good condition. The mean cholesterol LDL value was 34.12 ± 14.08 mg/dl. Recently, a cross-sectional study from Brazil tested the lipid profile of 435 parturient and their newborn babies. The mean LDL-C level in parturient and neonates were 112.7 mg/dL and 29.9 mg/dL, respectively. In addition, The LDL-C level in newborn is not influenced by change in the maternal lipid profile.[6] So according to the epidemiological studies, the natural cord blood and neonatal LDL level is about 30 mg/dL. Since atherosclerosis has not yet developed at birth, this may be the optimal physical cholesterol level for preventing atherosclerosis. Low-density Lipoprotein and Atherosclerosis in Children and Adolescent The LDL-C level and atherosclerosis both increase with aging. Many studies have investigated the LDL level in children ranging from 3 to 18 years old. The LDL level was 80-125 mg/dL.[7-14] It was normal according to the adult criteria in the practice guidelines, but much higher than in newborns. Meanwhile, studies showed that atherosclerosis also initiated at this period and progressed with age. A multicenter cooperative study,[15] Pathobiological Determinants of Atherosclerosis in Youth (PDAY) showed the extent of both fatty streaks and raised lesions (fibrous plaques and other advanced lesions) in the right coronary artery and in the abdominal aorta was associated positively with nonhigh-density lipoprotein -cholesterol (HDL-C) concentration. By 15-19 years of age, fatty streaks occupied ≈25% of the aortic intima in both the thoracic and abdominal aortas. By the age of 30-34 years, raised lesions occupied <0.5% of the thoracic aorta, but occupied ≈5% of the abdominal aortic surface. In the right coronary artery, fatty streaks increased in extent from ≈2% of the intimal surface at the age of 15-19 years to ≈8% at the age of 30-34 years and were equal in men and women. Raised lesions increased from ≈0.5% at the age of 15-19 years to >2% at the age of 30-34 years. The same phenomenon was observed in the Bogalusa Heart Study. Another study[10] related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9-11 years. A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. The mean LDL in the population was 110 [SD 25.4] mg/dL. There was a significant, inverse relation between LDL-C and distension of the artery across this range (linear regression P < 0.005). Hence LDL-C levels had an impact on arterial distensibility in the first decade of life. Although the LDL-C seems to be normal at in children and during the adolescent period, it still initiates damage to the vessel and progression of atherosclerosis. The fatty steak and small plaque develop with age. Low-density Lipoprotein Cholesterol Lowering and Atherosclerosis Progression and Regression Abundant data from many prospective trials revealed a strong and direct relationship between LDL levels and rates of atherosclerotic progression. Recently, trials showed that intensive lipid-lowering with statins or other drugs can halt or even reverse atherosclerosis. These randomized controlled trials showed that the atherosclerosis progression or regression was closely related to the on-treat LDL level. Intima-Media Thickness Evaluation Clinical sequelae, however, are preceded by silent changes. It has been now widely endorsed and standardized for measurement of intima-media thickness (IMT). Nowadays, carotid IMT changes over time have become an important surrogate endpoint in clinical intervention trials. Some studies demonstrated the relationship between LDL-C value and IMT. The effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia was studied using a randomized, double-blind clinical trial in 325 patients.[16] After 2-year therapy, IMT decreased by 0.031 mm in the atorvastatin 80 mg group, whereas in the simvastatin 40 mg group, it increased by 0.036 mm. The LDL-C level was reduced from 307.69 mg/dl to 149.23 mg/dl and 320.38 mg/dl to 185 mg/dl, respectively. At the end of the ENHANCE[17] study, the mean (± SD) LDL-C level was 192.7 ± 60.3 mg/dl in the simvastatin group and 141.3 ± 52.6 mg/dl in the combined therapy group. The primary outcome, the mean (± SE) change in IMT, was 0.0058 ± 0.0037 mm in the simvastatin-only group and 0.0111 ± 0.0038 mm in the simvastatin plus ezetimibe group (P = 0.29). The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial[18] used 80 mg/d atorvastatin or 40 mg/d pravastatin in 161 patients with a mean baseline LDL of 150 mg/d. Atorvastatin reduced LDL to mean levels as well as to 76 mg/dl and 110 mg/dl in pravastatin. The IMT regressed 0.038 mm in atorvastatin compared with a mean progression of 0.026 mm in the pravastatin group. Another 984 patients were enrolled in Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR).[19] Among the patients who took rosuvastatin 40 mg, the LDL-C level of 155 mg/dl was reduced to 78 mg/dl. The change was −0.0014 mm/y and 0.0131 mm/y in rosuvastatin and in the placebo. Thus, rosuvastatin resulted in LDL-C levels as low to 78 mg/dl and induced statistically significant reductions in the rate of progression of maximum CIMT over 2 years versus placebo. Mean IMT measures (0.83 ± 0.13 mm vs. 0.87 ± 0.16 mm) were also significantly lower among those with Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene variant when compared with the noncarriers with lower LDL-C level (95.5 ± 32.1 mg/dL vs. 109.6 ± 32.0 mg/dL) in a recent study.[20] These trials have further supported that decreasing LDL-C levels can delay thickening of IMT and intensive medication therapy can even stop or regress the progression of atherosclerosis, with LDL-C level around the 70-80 mg/dl. However, since the regression was very small, it seems that we should induce a greater reduction of LDL levels. Intravascular Ultrasound Evaluation Intravascular ultrasound (IVUS) imaging had emerged as the predominant approach for evaluating coronary atherosclerosis. IVUS provided a precise and reproducible method for determining the change in atheroma burden. The early trial used minimal lumen diameter change as endpoints. Recent trials measured atheroma volume, especially percent atheroma volume (PAV), the most rigorous IVUS parameter of disease progression and regression. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study[21] was an 18-month trial comparing the effects of intensive versus moderate lipid-lowering therapy on plaque progression in patients. A total of 253 patients were randomized to atorvastatin 80 mg/d and 249 patients were randomized to pravastatin 40 mg/d. LDL-C levels decreased from a baseline mean of 150 mg/dL in both groups to 79 mg/dL in the atorvastatin group and 110 mg/dL in the pravastatin group. For the primary end-point of percent change in total atheroma volume, a significantly lower rate of progression from baseline was observed with atorvastatin (−0.4%) than with pravastatin (2.7%) (P = 0.02). More recently, prospective, open-label blinded trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) enrolled 507 patients,[22] and 40 mg/d rosuvastatin were administered for 24 months. The LDL-C was reduced by 53.2%, from 130.4 mg/dL to 60.8 mg/dL (P < 0.01). The mean (SD) change in PAV was −0.98% (3.15%), with a median of −0.79% (97.5% confidence interval [CI] -1.21% to −0.53%) (both P < 0.01 vs. baseline). The investigator suggested that very high-intensive statin therapy with lower LDL-C level can regress atherosclerosis in CHD patients. The results of Multicenter Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound In Japanese Subjects (COSMOS) was published last year.[23] This 76-week open-label trial was performed in Japan. A total of 126 patients were given 2.5-20 mg/d rosuvastatin and had baseline and follow-up IVUS measurement. The mean (SD) LDL-C was reduced from 140.2 (31.5) mg/dl to 82.9 (18.7) mg/dl. The mean (SD) plaque volume was decreased from 72.1 (38.1) mm3 to 66.8 (34.0) mm3. Rosuvastatin also exerted significant regression of coronary plaque volume in Japanese patients with stable CAD. PRECISE-IVUS Trial[24] in Japanese patients who underwent percutaneous coronary intervention showed that the combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 vs. 73.3 mg/dl; P < 0.001). For the absolute change in PAV, the mean difference in ezetimibe combination group was noninferior compared with atorvastatin group. However, the absolute change in PAV did show superiority for the dual lipid-lowering strategy (−1.4%; 95% [CI]: −3.4% to −0.1% vs. −0.3%; 95% CI: −1.9% to 0.9% with atorvastatin alone; P < 0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; P < 0.004). If the LDL-C level reduced to about 80 mg/dl, progression of atherosclerosis was halted in REVERSAL. When LDL level further decreased to 60-80 mg/dl, as low as 60.8 mg/dl in ASTEROID trial with intensive statin therapy and 63.2 mg/dl in PRECISE-IVUS trial with combination therapy, atherosclerosis was regressed [Figure 1]. Although the extent of regression was just about 0.2%-1.4%, it still supported the hypothesis that we should reduce LDL to newborn levels.Figure 1:: Relationship between low-density lipoprotein and change of atheroma (both percent atheroma volume and minimal lumen diameter change). Use Pearson correlation test. (PRECISE-IVUS study is not included)Low-density Lipoprotein and Clinical Events Many trials and meta-analyses had demonstrated the relationship between LDL level and coronary heart disease, including WOSCOPS, AFCAPS, ASCOT, and JUPITER in primary prevention and 4S, LIPID, CARE, HPS, IDEAL, TNT, and PROVIT-IT in secondary prevention. In a previous aggregated analysis, results indicated[25] that the LDL level at which the CHD rate predicated to approach 0 is 57 mg/dl for primary prevention and 30 mg/dl for secondary prevention. All these data support the theory “the lower the better.” In recent famous trial - Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),[1] after rosuvastatin 20 mg/d treatment, LDL can be further reduced to 55 mg/dl, the lowest level in large clinical trial. The mean baseline LDL-C level was at 108 mg/dl. The combined primary end-point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes can also be reduced, 1.60% versus 2.82%. Recently, IMPROVE-IT study caught attention and discussion worldwide since its main results published not only because it is a mega trial in CV area but also because of its scientific significance. IMPROVE-IT study was an international, multicenter, randomized, double-blind active comparator trial of 18,144 patients with high-risk acute coronary syndromes (ACS).[26] At 7 years, 32.7% of patients taking ezetimibe plus simvastatin experienced a first primary end-point event (major cardiovascular event) compared to 34.7% of patients taking simvastatin alone, corresponding to a 6.4% relative risk reduction (absolute risk reduction 2%, hazard ratio of 0.936, 95% CI: 0.887-0.988, P = 0.016). The mean LDL-C in the study at 1 year was 53 mg/dL in the ezetimibe plus simvastatin arm and 70 mg/dL in the simvastatin arm. The conclusion from this study could be summarized as: Even lower is even better (achieved mean LDL-C 53 vs. 70 mg/dL at 1 year) to further reduce cardiovascular events in ACS patients. However, even with LDL levels at 53 mg/dL, cardiovascular risk still remained. Either in primary or secondary prevention, it seemed that we should reduce LDL even more. The results of IMPROVE-IT also supported that the extent of the benefit was consistent with that seen in previous trials, with a similar reduction in cardiovascular events according to the degree of LDL-C lowering in lower LDL-C levels. Thus, maybe we could have more clinical benefits by decreasing LDL-C to about 20-30 mg/dL as in newborns [Figures 2 and 3].Figure 2:: Relationship between low-density lipoprotein and coronary heart disease events (%) in primary prevention. Composite cardiovascular events for JUPITER trial. Use Pearson correlation testFigure 3:: Relationship between low-density lipoprotein and coronary heart disease events (%) in secondary prevention. Composite cardiovascular events for TNT trial. Use Pearson correlation testPCSK9 inhibitors are a new class of drugs that have shown to further decrease LDL-C by 50%-70% when administered as a monotherapy or in combination with statins.[27] The ongoing trials, such as ODYSSEY OUTCOMES, SPIRE-1, and SPIRE-2, will provide evidence for “the lower the better.” We will see whether the cardiovascular events can be further decreased with very-low LDL-C level by PCSK9 inhibitor. Too Low To Go? And How To Go There? The safety concerns stem from two different questions: A. Are very-low LDL-C levels safe? B. Are drugs leading to very-low LDL-C safe? First of all, cholesterol is an essential component of cell membranes and is a necessary precursor for bile acid, steroid hormone, and Vitamin D synthesis. The newborn LDL-C levels were enough for physical need. When human fibroblasts were grown in cell culture, they took up media LDL through the LDL receptor pathway until sufficient cholesterol was internalized to meet cellular needs, leading to the downregulation of LDL receptors. The amount of LDL-C that was needed in such cultures was only 2.5 mg/dl. Because there was a 10:1 gradient between plasma and interstitial fluid LDL levels, this implied that a plasma level of 25 mg/dl LDL-C would be sufficient to supply peripheral cholesterol needs.[28] People with heterozygous hypobetalipoproteinemia had LDL-C levels as low as 30 mg/dl. These patients were always free of atherosclerosis with longevity. There was also lack of other adverse effects that might have been caused by such a low LDL level.[29] In healthy persons with a nonsense mutation in each PCSK9 gene, LDL-C concentrations were reported as low as 14-16 mg/dl.[30,31] Thus, it seemed that a very-low level of LDL-C, as low as newborns, was safe. Second, clinical trials showed that the intensive statin therapy could decrease LDL-C value safely. The cumulative data with statin therapy showed impressive cardiovascular benefits without a corresponding increase in adverse events such as malignancy or noncardiovascular mortality. In the JUPITER trial[1] in which LDL-C levels were as low as 55 mg/dl, there was no difference between rosuvastatin (40 mg) and placebo in any serious adverse events, including muscular weakness/stiffness/pain, myopathy, rhabdomyolysis, newly diagnosis cancer, death from cancer, gastrointestinal disorder, renal disorder, and hepatic disorder. Hence, high-intensive statin therapy is recommended as first-line (Class I, A) for patients <75 years old with clinical ASCVD.[32] However, many meta-analysis also showed that the side effects of statins such as liver dysfunction, myopathy,[33] or newly diagnosed diabetes[34] were dose-dependent and more common in high intensive statins, where high dose of statins are usually needed for reaching lower LDL-C targets. Furthermore, it should be noticed that the safety of high doses of statins in the Chinese population is not yet confirmed. In 2013 American Heart Association and American Stroke Association guidelines,[32] evidence among Asian populations was not included, therefore, it is recommended that moderate intensive statins could be used in Asian ancestry, to avoid statin-associated side effects. The most common side effects of statin, liver, and muscle toxicity, was seen with high dose of statins, but not in relationship to the on-treatment LDL level. Therefore, combination therapy or a new potent drug might be an alternative to reach the much lower LDL-C level. IMPROVE-IT study[26] had confirmed the safety of intensive LDL-C lowering by combining ezetimibe with simvastatin. The mean LDL-C was 53 mg/dL in the combination group. There were no significant differences between the two study groups in any of the prespecified safety end-points or in the rate of discontinuation of study medication owing to adverse events including the incidence of rhabdomyolysis or myopathy, alanine aminotransferase and aspartate aminotransferase ≥3×, ULN, and cancer, etc. Add-on ezetimibe to statins did not show significant increase of adverse event. PCSK9 could reduce LDL-C dramatically as monotherapy and combination with statin, and the reduction is not affected by the dose of background statins. In published phase 3 trial, the rate of serious adverse events was 2%-6%. Adverse events causing discontinuation of the drug occurred in 2%-10%. Elevation of liver aminotransferase >3 times of upper normal limit was observed in >2% of the patients. Elevation of creatinine was similarly rare.[27] Summary Atherosclerosis develops progressively with age and is closely related to the LDL-C levels. It was not initiated in healthy newborns with LDL levels around 30 mg/Dl but had begun in children and adolescents with normal LDL-C values. Clinical trials had shown that reducing LDL could retard or even reverse atherosclerosis in much lower LDL levels (53-80 mg/dL) with intensive medication therapy, evaluated by IMT, IVUS, or clinical end-points. However, the extent of the regression was small and the risk of cardiovascular events remained. So maybe we should lower LDL to the safe levels that you are born with, which are around 30 mg/dL, to prevent the development of atherosclerosis or provide the best treatment effects. More well-designed trials (combination therapy or with new drugs) are needed to support this hypothesis and confirm its safety. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Atrial fibrillation frequently develops in patients with sepsis and is associated with increased morbidity and mortality. Unfortunately, risk factors for new-onset atrial fibrillation in sepsis have not been clearly elucidated. Clarification of the risk factors for atrial fibrillation during sepsis may improve our understanding of the mechanisms of arrhythmia development and help guide clinical practice. Medline, Embase, Web of Science, and Cochrane CENTRAL. We conducted a systematic review and meta-analysis to identify risk factors for new-onset atrial fibrillation during sepsis. We extracted the adjusted odds ratio for each risk factor associated with new-onset atrial fibrillation during sepsis. For risk factors present in more than one study, we calculated pooled odds ratios (meta-analysis). We classified risk factors according to type and quantified the factor effect sizes. We then compared sepsis-associated atrial fibrillation risk factors with risk factors for community-associated atrial fibrillation. Forty-four factors were examined as possible risk factors for new-onset atrial fibrillation in sepsis, 18 of which were included in meta-analyses. Risk factors for new-onset atrial fibrillation included demographic factors, comorbid conditions, and most strongly, sepsis-related factors. Sepsis-related factors with a greater than 50% change in odds of new-onset atrial fibrillation included corticosteroid use, right heart catheterization, fungal infection, vasopressor use, and a mean arterial pressure target of 80-85 mm Hg. Several cardiovascular conditions that are known risk factors for community-associated atrial fibrillation were not identified as risk factors for new-onset atrial fibrillation in sepsis. Our study shows that risk factors for new-onset atrial fibrillation during sepsis are mainly factors that are associated with the acute sepsis event and are not synonymous with risk factors for community-associated atrial fibrillation. Our results provide targets for future studies focused on atrial fibrillation prevention and have implications for several key areas in the management of patients with sepsis such as glucocorticoid administration, vasopressor selection, and blood pressure targets.

Since its market launch in the early 2000s, ezetimibe has had a stormy history of acceptance and use by the clinical community. Ezetimibe’s initial approval by regulatory bodies was based primarily on its low side effect profile together with its ability to consistently reduce low-density lipoprotein (LDL) cholesterol by ≈20% either as monotherapy or as an additive to statin therapy. Notably, approval was granted despite the absence from ezetimibe’s portfolio of studies, demonstrating reductions in hard clinical cardiovascular outcomes, such as myocardial infarction or stroke. By 2006, ezetimibe accounted for >15% of all prescriptions for lipid-lowering medications in the United States,1 reflecting that era’s stout faith in the reliability of LDL cholesterol as a surrogate marker for clinical end points, together with practitioners’ positive real-world experiences with ezetimibe’s biochemical efficacy and good tolerability. It was tacitly anticipated that the pending cardiovascular outcome studies would be positive, eventually vindicating the early confidence that clinicians placed in the drug. However, the waters grew rough for ezetimibe in 2008. First, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial conducted for 24 months in 720 patients with familial hypercholesterolemia showed that combined therapy with ezetimibe and simvastatin did not significantly change carotid intima–media thickness when compared with simvastatin alone, despite decreased levels of LDL cholesterol.2 Next, the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial conducted for 52 months in 1873 elderly nondiabetic patients with aortic stenosis showed that ezetimibe plus simvastatin did not reduce the composite outcome of combined aortic valve events and ischemic events.3 To add insult to injury, the 2009 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6-HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study demonstrated that when combined with a statin, extended-release niacin caused a significant …

To observe the clinical features of atrial fibrillation (AF) patients, and to explore the correlation between the routine detection index and the new-onset AF and to find out risk factors for new AF in critically ill patients. A prospective observational study was conducted. The patients with AF admitted to intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from March 2016 to June 2017 were enrolled. The patients were divided into new-onset AF group and past-existed AF group according to their past history of AF (including persistent AF, paroxysmal AF or permanent AF). In addition, patients in ICU without history of AF and new-onset AF were selected as the control group (no AF group). The general epidemiological characteristics of patients in three groups, and the blood biochemical, coagulation and other related indicators at the time of AF occurred (new-onset AF group) or 48 hours after ICU admission (AF group and no AF group) were analyzed; the difference of laboratory indexes between patients in new-onset AF group with AF within 48 hours before occurred and patients in no AF group within 48 hours after admission to ICU was compared. The relationship between each index and new-onset AF were analyzed. Pearson or Spearman rank correlation was used for analysis. Risk factors of new-onset AF were analyzed by Logistic regression analysis. 1 673 patients were admitted to ICU, including 179 cases of AF (10.70%), and 106 males and 73 females, with an average age of (71.73±23.22) years. There was 75 new-onset AF (morbidity 4.48%), and had a 28-day mortality of 45.33% (34/75). There were differences in age, previous heart disease and heart failure (HF) among new-onset AF group (n = 75), past-existed AF group (n = 104) and no AF group (n = 75). Compared with other two groups, renal insufficiency rates, troponin, serum sodium, calcium and procalcitonin levels were higher, mechanical ventilation time and the length of ICU stay were significantly prolonged, ICU and hospitalization costs were higher in new-onset AF group. Compared with no AF group, new-onset AF patients with the higher percentage of septic shock, the accumulation of vascular contraction drugs within 24 hours after AF usage were higher, and used more anti-arrhythmic drugs, has higher brain natriuretic peptide (pro-BNP), serum creatinine, blood lactic acid levels, and lower albumin, oxygenation index, and serum potassium levels, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score and 28-day mortality were higher. Correlation analysis showed that age, APACHE II score, septic shock, HF, cardiovascular disease, renal insufficiency were positively correlated with new-onset AF (r values were 0.393, 0.270, 0.386, 0.251, 0.194, 0.170; P values were 0.000, 0.001, 0.000, 0.002, 0.017, 0.037, respectively). The age [odds ratio (OR) = 0.962, P = 0.046], basic oxygenation index (OR = 1.005, P = 0.028) and serum potassium levels (OR = 1.638, P = 0.022) were the risk factors for new-onset AF. Critical patients with a high incidence of AF, new-onset AF significantly prolong the length of ICU stay; age, APACHE II score, septic shock, cardiovascular disease, and renal insufficiency are related to new-onset AF; age, basic oxygenation index and serum potassium levels are risk factors for new-onset AF.

ObjectiveAssess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines.DesignSystematic literature review.Data SourcesMedline, EMBASE, Cumulated Index to Nursing and Allied Health Literature.Eligibility CriteriaObservational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]).Data Extraction and SynthesisTwo reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies–Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test.ResultsAcross 81 eligible studies (303,534 patients), achievement of LDL-C < 1.8 mmol/L was poor among patients with established CVD (16%; range 9–56%) and at very high risk of CVD (SCORE ≥ 10% [18%; 14–25%]). In individuals with FH, SCORE 5–10%, or diabetes and target organ damage, LDL-C < 2.5 mmol/L was achieved by 15% (9–22%), 46% (21–55%) and 13% (6–34%), respectively. Comparing the 5 years before/after publication of the 2011 guidelines, target achievement increased significantly over time but remained suboptimal (LDL-C < 1.8, 22% versus 15%; LDL-C < 2.5, 68% versus 61%; both p < 0.001; established CVD group only).ConclusionsThese data show suboptimal LDL-C control among European patients at high risk of CVD. Those at greatest overall risk (clinically established CVD or at least a 10% 10-year risk of fatal CVD) had the lowest achievement of 2011/2016 EAS/ESC LDL-C targets. With lower LDL-C targets advocated in 2019 ESC/EAS guidelines, this unmet need will increase.Protocol RegistrationPROSPERO registration number; CRD77844Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01285-2) contains supplementary material, which is available to authorized users.

Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment. This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included. Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks. The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy. In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone. ClinicalTrials.gov Identifier: NCT04806893.

IntroductionWe evaluated the prevalence and control of dyslipidemia in a wide sample of patients referred to our ESH “Hypertension Excellence Centre” for high blood pressure (BP). Furthermore, we evaluated the role of adiposity on the serum lipid profile.MethodsObservational study on 1219 consecutive outpatients with valid ambulatory BP monitoring (ABPM) referred for high BP. Patients with body mass index (BMI) ≥ 25 kg/m2 were defined as overweight/obese (OW/OB). Dyslipidemia and the control rates of low-density lipoprotein cholesterol (LDLc) were defined according to the 2016 ESC/EAS Guidelines.ResultsMean age: 56.5 ± 13.7 years. Male prevalence: 55.6%. OW/OB patients were 70.2%. The prevalence of dyslipidemia was 91.1%. Lipid-lowering drugs were taken by 23.1% of patients. Patients with controlled LDLc comprised 28.5%, while BP was controlled in 41.6% of patients. Only 12.4% of patients had both 24-h BP and LDLc controlled at the same time. The higher the cardiovascular (CV) risk was, the lower was the rate of LDLc control (p < 0.001). Patients in secondary prevention had worse LDLc control than patients in primary prevention (OR 3.5 for uncontrolled LDLc, p < 0.001). OW/OB showed a more atherogenic lipid profile, characterized by lower high-density lipoprotein cholesterol (HDLc) (p < 0.001), higher non-HDLc (p = 0.006), higher triglycerides (p < 0.001), higher non-HDLc/HDLc (p < 0.001) and higher (non-HDLc + non-LDLc) (p < 0.001).ConclusionDyslipidemia is still too often neglected in hypertensives, especially in patients at higher CV risk. OW/OB hypertensives have a “double-trouble” atherogenic lipid pattern likely driven by adiposity. We encourage a comprehensive evaluation of the lipid profile in all hypertensives, especially if they are OW/OB, to correctly assess their CV risk and improve their management.FundingArticle processing charges funded by Servier SpA.

Thyroid Heart Disease Should Include the Coincidental Association of Hypothyroidism and Atrial Fibrillation

Background While severe mitral regurgitation is a well-established risk factor for atrial fibrillation (AF), it is less known whether atrial fibrillation induces mitral/tricuspid valve regurgitation (MR/TR). The present study aims to identify the long-term effects of permanent or non-permanent AF on atrial remodelling and on the progression of MR/TR. Methods The severity of MR/TR was assessed at baseline and after a period of 65±10 months in 37 patients with permanent AF, in 80 patients with non-permanent AF (of whom 43 were treated with ablation) and in 53 control patients with persistent sinus rhythm. MR/TR was qualitatively assessed by the multi-integrative approach, and quantitatively by measurement of the colour jet area. Results At baseline, AF patients had larger MR jet areas than control patients. At follow up, progression of MR, expressed as delta MR jet area, was 0.05±1.3 cm2 in the control group, 0.73±2.1 cm2 in the non-permanent AF group and 1.95±3.6 cm2 in the permanent AF group (p=0.001). Severe MR at follow up was observed in 0%, 2.5%, 8%, respectively. After adjustment for baseline clinical and echocardiographic parameters, permanent AF remained independently associated with the progression of MR. There was a significant positive correlation between a progression of MR and an increase in left atrial volume index (r=0.31, p&lt;0.001). Although rhythm control in non-permanent AF patients was better with AF ablation than with medical treatment only, the MR evolution was similar (delta MR jet area: 0.85±2.05 cm2 vs 0.61±2.12 cm2, p=0.6). Comparable findings, albeit less pronounced, were observed for the association between of AF and TR progression. MR jet area Conclusions The presence of longstanding AF is associated with a significant progression of MR/TR mainly due to atrial remodelling. Our data showed a beneficial effect of sustained rhythm control, either medically or by ablation, on MR/TR progression.

<i>Circulation</i> : Clinical Summaries