Assessment of subclinical atherosclerosis and intraplaque neovascularization using quantitative contrast-enhanced ultrasound in patients with familial hypercholesterolemia

Objective

Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries.

Methods

The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software.

Results

Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface (p < 0.05).

Conclusion

Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface.     

Nonpharmacological Lipoprotein Apheresis Reduces Arterial Inflammation in Familial Hypercholesterolemia

Background

Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk.

Objectives

This study used ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients.

Methods

In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed.

Results

In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02).

Conclusions

The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B–containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.     

Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: A study of a cohort of 14,000 mutation carriers

Background

Some recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with ‘severe heterozygous FH (HeFH)’. However, no uniform definition of ‘severe HeFH’ exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients.

Methods and results

We analysed a cohort of 14,283 patients with molecularly defined HeFH, identified by the national FH screening programme in the Netherlands. Age and gender specific percentiles of untreated LDL-C were determined. The percentile corresponding to an LDL-C level of 8 mmol/L (309 mg/dL) in men aged 36–40 years (90^th percentile) was selected as the cut-off value for severe HeFH. By applying this percentile-criterion to the whole cohort, 11% of the HeFH patients could be considered as having severe HeFH. Combined with an estimated HeFH prevalence of 1:300 in the Netherlands, this would translate into a prevalence of approximately 1:3,000 for severe HeFH. CVD risk was significantly increased in severe HeFH patients compared to non-severe HeFH patients (adjusted hazard ratio: 1.25 [95% CI: 1.05–1.51], p = 0.015). In line, male gender, increased age, increased BMI, smoking, hypertension, diabetes, high LDL-C and low high-density lipoprotein cholesterol were independent CVD risk factors in HeFH per se.

Conclusions

We changed the commonly used static LDL-C level of 8 mmol/L for the identification of severe HeFH into an age and gender corrected percentile. This definition would theoretically result in a prevalence of 1:3,000 for severe HeFH. Patients with severe HeFH are at increased CVD risk compared to non-severe HeFH patients, which underscores the need for more aggressive LDL-C lowering these patients.     

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study

Background and aimsFamilial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy.Methods and resultsWe evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target.ConclusionsAfter 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations.Registration number for clinical trials: NCT04313270 extension.     

Health Consequences among Subjects Involved in Gulf Oil Spill Clean-up Activities

Background

Oil spills are known to affect human health through the exposure of inherent hazardous chemicals such as para-phenols and volatile benzene. This study assessed the adverse health effects of the Gulf oil spill exposure in subjects participating in the clean-up activity along the coast of Louisiana.

Methods

This retrospective study included subjects that had been exposed and unexposed to the oil spill and dispersant. Using medical charts, clinical data including white blood cell count, platelets count, hemoglobin, hematocrit, blood urea nitrogen, creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT), and somatic symptom complaints by the subjects were reviewed and analyzed.

Results

A total of 247 subjects (oil spill exposed, n = 117 and unexposed, n = 130) were included. Hematologic analysis showed that platelet counts (× 10³ per μL) were significantly decreased in the exposed group compared with those in the group unexposed to the oil spill (252.1 ± 51.8 vs 269.6 ± 77.3, P = .024). Conversely, the hemoglobin (g per dL) and hematocrit (%) levels were significantly increased among oil spill-exposed subjects compared with the unexposed subjects (P = .000). Similarly, oil spill-exposed subjects had significantly higher levels of ALP (76.3 ± 21.3 vs 61.2 ± 26.9 IU/L, P = .000), AST (31.0 ± 26.3 vs 22.8 ± 11.8 IU/L, P = .004), and ALT (34.8 ± 26.6 vs 29.8 ± 27 IU/L, P = .054) compared with the unexposed subjects.

Conclusion

The results of this study indicate that clean-up workers exposed to the oil spill and dispersant experienced significantly altered blood profiles, liver enzymes, and somatic symptoms.     

Cardiovascular disease in familial hypercholesterolaemia: influence of low-density lipoprotein receptor mutation type and classic risk factors

Aim

To determine the effect of the type of mutation in low-density lipoprotein receptor gene and the risk factors associated with the development of premature cardiovascular disease (PCVD) in a large cohort of heterozygous familial hypercholesterolemia (hFH) subjects with genetic diagnosis in Spain.

Methods and results

A cross-sectional study was conducted on 811 non-related FH patients (mean age 47.1 ± 14 years, 383 males and 428 females) with a molecular defect in the low-density lipoprotein receptor (LDLR) gene from the Spanish National FH Register. Prevalence of PCVD was 21.9% (30.2% in males and 14.5% in women, P < 0.001). Mean age of onset of cardiovascular event was 42.1 years in males and 50.8 years in females. Of those patients with PCVD, 59.5% of males and 27% of females suffered a second cardiovascular (CV) event. In multivariate analysis male gender, age, tobacco consumption (ever), and total cholesterol/HDL-cholesterol (TC/HDL-C) ratio were significantly associated with PCVD. Two hundred and twenty different mutations were found with a large heterogeneity. Patients carrying null-mutations had significantly higher frequency of PCVD and recurrence of CV events. No relationship with Lp(a) levels and genotype of Apo E were found.

Conclusions

This study confirms the importance of identifying some classic risk factors such as smoking and TC/HDL-C ratio, and also the type of mutation in LDLR gene in order to implement early detection and intensive treatment for the prevention of cardiovascular disease in FH patients.     

The Effect of Percutaneous Coronary Intervention of Chronically Totally Occluded Coronary Arteries on Left Ventricular Global and Regional Systolic Function

Background

Percutaneous coronary intervention (PCI) is frequently attempted to open chronic total occlusions (CTOs) and restore epicardial coronary flow. Data suggest adverse outcomes in the case of PCI failure. We hypothesized that failure to open a CTO might adversely affect regional cardiac function and promote deleterious cardiac remodelling, and success would improve global and regional cardiac function assessed using cardiac magnetic resonance and velocity vector imaging.

Methods

Thirty patients referred for PCI to a CTO underwent cardiac magnetic resonance examination before and after the procedure. Left ventricular function and transmural extent of infarction was assessed in these patients. Regional cardiac function using Velocity Vector Imaging version 3.0.0 (Siemens) was assessed in 20 patients.

Results

Successful CTO opening (thrombolysis in myocardial infarction 3 flow) occurred in 63% of patients. Left ventricular ejection fraction significantly increased after successful PCI (50 ± 13% to 54 ± 11%; P < 0.01). Global longitudinal strain (GLS) fell significantly in the failed group (Δ = −25 ± 17%; P = 0.02) in contrast with successful PCI in which GLS did not change (Δ 20 ± 32%; P = 0.17). GLS rate followed a pattern similar to GLS (failed, Δ −30 ± 17%; P < 0.01 vs success Δ 25 ± 48%; P = 0.34). In contrast, radial and circumferential strain/strain rate were not different between groups after success/failed PCI.

Conclusions

Regional cardiac function assessment using velocity vector imaging showed a significant decline in GLS and GLS rate in patients in whom PCI failed to open a CTO, with no change in global measures of cardiac function.     

Pacemaker-Detected Atrial Fibrillation in Patients With Pacemakers: Prevalence,Predictors, and Current Use of Oral Anticoagulation

Background

Dual-chamber pacemakers frequently document atrial fibrillation (AF) in patients without symptoms. Pacemaker-detected AF is associated with a 2.5-fold increased risk of stroke, although it is not established whether oral anticoagulation reduces this risk. This study sought to determine the prevalence and predictors of pacemaker-detected AF and to document current oral anticoagulant use.

Methods

A retrospective analysis included all patients from a single academic hospital who had pacemakers capable of documenting AF. Blinded evaluation of all echocardiograms conducted within 6 months of implantation was performed.

Results

Of 445 patients, pacemaker-detected AF was present in 246 (55.3%), who were older (74.3 ± 13.7 years vs 71.7 ± 14.4, P = 0.046), more likely to have a history of clinical AF (29.7% vs 19.1%, P = 0.01), and had a larger left atrial volume index (34.4 ± 11.8 mL/m² vs 30.0 ± 9.9 mL/m², P = 0.019) than the patients without pacemaker-detected AF. Among patients without a clinical history of AF, left atrial volume index was higher among those with pacemaker-detected AF (33.7 ± 11.3 mL/m² vs 29.0 ± 10.1 mL/m², P = 0.034). Anticoagulants were used in 35.3% of patients with pacemaker-detected AF, compared with 21.6% of patients without (P < 0.05). In patients with pacemaker-detected AF, anticoagulants were used more frequently among patients who also had clinical AF (58.9%) compared with those without (23.7%, P < 0.001).

Conclusions

Pacemaker-detected AF occurs in 50% of pacemaker patients and is treated with anticoagulants in less than 25% of patients who do not have a history of clinical AF. Clinical trials are needed to determine the role of anticoagulation in this population.     

The molecular basis of familial hypercholesterolemia in the Czech Republic: Spectrum of LDLR mutations and genotype-phenotype correlations

BackgroundFamilial hypercholesterolemia (FH), a major risk for coronary heart disease, is predominantly associated with mutations in the genes encoding the low-density lipoprotein receptor (LDLR) and its ligand apolipoprotein B (APOB).ResultsIn this study, we characterize the spectrum of mutations causing FH in 2239 Czech probands suspected to have FH. In this set, we found 265 patients (11.8%) with the APOB mutation p.(Arg3527Gln) and 535 patients (23.9%) with a LDLR mutation. In 535 probands carrying the LDLR mutation, 127 unique allelic variants were detected: 70.1% of these variants were DNA substitutions, 16.5% small DNA rearrangements, and 13.4% large DNA rearrangements. Fifty five variants were novel, not described in other FH populations. For lipid profile analyses, FH probands were divided into groups [patients with the LDLR mutation (LDLR+), with the APOB mutation (APOB+), and without a detected mutation (LDLR?/APOB?)], and each group into subgroups according to gender. The statistical analysis of lipid profiles was performed in 1722 probands adjusted for age in which biochemical data were obtained without FH treatment (480 LDLR+ patients, 222 APOB+ patients, and 1020 LDLR?/APOB? patients). Significant gradients in i) total cholesterol (LDLR+ patients > APOB+ patients = LDLR?/APOB? patients) ii) LDL cholesterol (LDLR+ patients > APOB+ patients = LDLR?/APOB? patients in men and LDLR+patients > APOB+ patients >LDLR?/APOB? patients in women), iii) triglycerides (LDLR?/APOB? patients > LDLR+ patients > APOB+ patients), and iv) HDL cholesterol (APOB+ patients > LDLR?/APOB? patients = LDLR+ patients) were shown.ConclusionOur study presents a large set of Czech patients with FH diagnosis in which DNA diagnostics was performed and which allowed statistical analysis of clinical and biochemical data.     

Comparison of cardiopulmonary exercise testing variables in COPD patients with and without coronary artery disease

Background

Coronary artery disease (CAD) is a common concomitant condition and an important cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Since COPD and CAD can both independently cause reduced exercise capacity, it is reasonable to hypothesize that the combination of these diseases may compound the abnormalities observed during cardiopulmonary exercise testing (CPET). However, little is known about the impact of CAD on the CPET response in COPD patients. The aim of this study is to compare exercise capacity and gas exchange variables in COPD patients with and without CAD.

Methods

Fifty-four COPD subjects without CAD (COPDnoCAD) were matched to 54 COPD subjects diagnosed with CAD (COPD/CAD) according to age, gender, body mass index and severity of COPD. All subjects underwent resting pulmonary function and symptom-limited CPET.

Results

Comparing COPDnoCAD patients with COPD/CAD patients revealed that exercise capacity, as measured by % peak oxygen consumption (42 ± 16% vs 53 ± 19%, p = 0.002) and % peak wattage (23 ± 13% vs 32 ± 16%, p = 0.001), was significantly lower in COPD/CAD. Ventilatory response, as measured by VE/VCO₂ nadir (36 ± 9 vs 32 ± 5, p = 0.001), was significantly higher in COPD/CAD, with % peak VO₂ and VE/VCO₂ nadir correlating to % FEV₁ and inversely correlating with %DLCO.

Conclusion

COPD patients with CAD have significantly impaired CPET responses with lower exercise capacity and impaired gas exchange compared to COPD patients without CAD. These findings may affect the clinical interpretation of CPET data in COPD patients who have concomitant CAD.     

Left Ventricular Torsion Abnormalities in Septic Shock and Corrective Effect of Volume Loading: A Pilot Study

Background

Ventricular torsion is an important component of cardiac function. The effect of septic shock on left ventricular torsion is not known. Because torsion is influenced by changes in preload, we compared the effect of fluid loading on left ventricular torsion in septic shock with the response in matched healthy control subjects.

Methods

We assessed left ventricular torsion parameters using transthoracic echocardiography in 11 patients during early septic shock and in 11 age- and sex-matched healthy volunteers before and after rapid volume loading with 250 mL of a Ringer's lactate solution.

Results

Peak torsion and peak apical rotation were reduced in septic shock (10.2 ± 5.2° and 5.6 ± 5.4°) compared with healthy volunteers (16.3 ± 4.5° and 9.6 ± 1.5°; P = 0.009 and P = 0.006 respectively). Basal rotation was delayed and diastolic untwisting velocity reached its maximum later during diastole in septic shock patients than in healthy volunteers (104 ± 16% vs 111 ± 14% and 13 ± 5% vs 21 ± 10%; P = 0.03 and P = 0.034, respectively). Fluid challenge increased peak torsion in both groups (septic shock, 10.2 ± 5.3° vs 12.6 ± 3.9°; healthy volunteers, 16.3 ± 4.5° vs 18.1 ± 6°; P = 0.01). Fluid challenge increased left ventricular stroke volume in septic shock patients (P = 0.003).

Conclusions

Compared with healthy volunteers, left ventricular torsion is impaired in septic shock patients. Fluid loading attenuates torsion abnormalities in parallel with increasing stroke volume. Reduced torsional motion might constitute a relevant component of septic cardiomyopathy, a notion that merits further testing in larger populations.     

Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) in Acute Coronary Syndrome: Relationship With Low-Density Lipoprotein Cholesterol

Background

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) might play a role in the formation of vulnerable atherosclerotic plaques. Its plasma distribution and mass in subjects with acute coronary syndrome (ACS) has yet to be characterized.

Methods

We compared plasma levels of Lp-PLA₂ in 24 patients within 48 hours of an ACS (acute) and 12 weeks after (recovery), in 26 patients with stable coronary artery disease and in 10 normal healthy control subjects. Lp-PLA₂ mass was determined using enzyme-linked immunosorbent assay.

Results

The ACS patients (mean age 57 ± 8.7 years) had high-sensitivity C-reactive protein (hsCRP) levels of 30.46 ± 57.57 mg/L (ACS acute) vs 1.69 ± 1.32 mg/L (ACS recovery). Plasma Lp-PLA₂ levels were significantly higher in ACS acute subjects than in ACS recovery subjects (143.13 ± 60.88 ng/mL vs 88.74 ± 39.12 ng/mL; P < 0.0001). Interestingly, stable coronary artery disease patients had higher Lp-PLA₂ levels than ACS recovery patients (121.72 ± 31.11 ng/mL vs 88.74 ± 39.12 ng/mL; P = 0.0018). There was a strong correlation between Lp-PLA₂ and low-density lipoprotein (LDL) cholesterol (LDL-C) (r = 0.709; P < 0.0001) or changes in LDL (r = 0.449; P = 0.027), suggesting that the major determinant of plasma Lp-PLA₂ is LDL-C. No significant correlations were observed between Lp-PLA₂ and hsCRP or high-density lipoprotein (HDL) cholesterol. When separated using high-performance liquid chromatography, > 65%-70% of Lp-PLA₂ mass was within the apolipoprotein B-containing lipoprotein fraction, with approximately 30%-35% on HDL fraction, with no significant change in distribution between ACS acute and recovery.

Conclusions

Subjects with an ACS have markedly increased Lp-PLA₂ levels acutely related to LDL-C levels.     

Inverse correlation between coronary and retinal blood flows in patients with normal coronary arteries and slow coronary blood flow

Background

The “Slow Coronary Flow” (SCF) phenomenon in the presence of angiographically normal coronaries is attributed to microvascular and endothelial dysfunction. The microcirculation can be non-invasively assessed by measuring retinal blood flow velocity.The aim of the present study was to evaluate the efficacy of the “Retinal Functional Imager” (RFI) device as a noninvasive method of diagnosing patients with slow coronary flow.

Methods

Coronary blood flow velocity assessed by corrected TIMI Frame Count and retinal arterioles blood flow assessed by RFI were measured in 28 consecutive patients with normal coronary arteries. The patients were divided into 2 groups: a slow coronary flow (SCF) and a normal coronary flow (NCF) groups.

Results

Inverse correlation was found between retinal and coronary blood flows so that higher retinal arterial flow velocity was observed in the SCF group (3.8 ± 1.1 mm/s vs. 2.9 ± 0.61 mm/s, respectively, p = 0.022). RFI provided 73% sensitivity and 77% specificity for diagnosing SCF using ROC analysis. Additionally, patients with SCF had higher values of serum LDL cholesterol (104.7 ± 18.93 mg/dl vs. 81.55 ± 14.62 mg/dl in NCF, p = 0.005), Glucose (96.9 ± 23.0 mg/dl vs. 83.55 ± 9.7 mg/dl in NCF, p = 0.024), and lower percentage of statin consumption (40.0% vs. 76.9% in NCF, p = 0.049).

Conclusions

Slow coronary blood flow can be non-invasively diagnosed with Retinal Functional Imager. Patients with normal coronary arteries and slow coronary blood flow have high retinal arteriolar blood flow. Early non-invasive diagnosis of SCF might help detect individuals who are at higher risk to develop coronary atherosclerosis, and to provide them with early preventive measures.     

Markers of atherosclerotic development in children with familial hypercholesterolemia: A literature review

Objective

Atherosclerosis is a multi-step process, where lipids, inflammatory and hemostatic mediators orchestrate plaque formation and progression, which subsequently may lead to myocardial infarction and ischemic stroke. Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis due to the genetically determined elevated low density lipoprotein (LDL)-cholesterol seen in these individuals. Children with FH are suitable to investigate the isolated effect of elevated LDL-cholesterol on early markers of atherosclerosis. The aim of the present paper was to review the literature to summarize the findings of atherosclerotic markers in children with FH to better understand how elevated LDL-cholesterol per se promotes atherogenesis.

Methods

We conducted a systematic literature search from the years 1990–2013, resulting in identification of 903 articles. In order to investigate whether intima-media thickness (IMT) is different in children with and without FH, we conducted a meta-analysis of the studies comparing FH children with a control group.

Results

37 original articles were included. Among these, 24 reported subclinical measurements, whereas other articles reported measurements of atherogenic lipids (n = 9), inflammatory markers (n = 10), hemostatic markers (n = 6) and other surrogate markers of atherosclerosis (n = 7). In the meta-analysis (n = 8), IMT was significantly thicker in children with FH than in control children (weighted mean difference 0.06, 95% confidence interval [0.01, 0.11]).

Conclusion

Elevated LDL-cholesterol distinguishes children with and without FH, but these groups of children also differ in several other ways. In particular, children with FH display a variety of changes reflecting both the lipid and the inflammatory arm of atherosclerosis. The IMT-meta-analysis result strengthens the evidence of early atherosclerotic development in children with FH. In a clinical perspective, early diagnosing and treatment of children with FH is of high importance to attenuate development of the potential ongoing early atherosclerotic process in these individuals.     

More Favorable Outcomes with Peptic Ulcer Bleeding Due to Helicobacter Pylori

Background

Acute upper gastrointestinal bleeding is a common complication of peptic ulcer disease, often caused by Helicobacter pylori and nonsteroidal anti-inflammatory drug (NSAID) use. The purpose of this study was to determine whether the cause and biologic behavior of ulcers associated with acute upper gastrointestinal bleeding might lead to divergent patient outcomes.

Methods

In this Institutional Review Board-approved study, we compared clinical features and outcomes of patients with acute upper gastrointestinal bleeding due to ulcers categorized into 4 groups: Helicobacter pylori positive or negative combined with NSAID usage positive or negative. Likelihood chi-squared analyses were utilized for group comparisons and stepwise multiple logistic regression models were utilized to determine which factors were related to bleeding outcomes.

Results

Of 2242 patients with upper gastrointestinal bleeding, 575 (26%) had gastroduodenal ulcer disease, and of those with appropriate diagnostic testing, approximately half (228, 10% overall) had evidence of Helicobacter pylori infection and half (216, 10% overall) had no evidence of Helicobacter pylori infection. Patients without Helicobacter pylori infection had significantly more comorbid conditions than those with Helicobacter pylori and higher Charlson Index comorbidity scores (2.6 ± 2.6 [mean and SD] vs 1.9 ± 2.3, P = .003). Hospital length of stay was significantly longer for Helicobacter pylori-negative patients (mean 11.4 ± 21.7 vs 6 ± 8.5 days and median 5.5 vs 3 days, P <.001 and <.001, respectively). Rebleeding events within 30 days were more frequent in Helicobacter pylori-negative patients than Helicobacter pylori-positive patients (11% vs 5%, P = .009). Rebleeding was most frequent in patients without Helicobacter pylori and with no reported use of NSAIDS (18%, P = .01).

Conclusions

Helicobacter pylori-negative ulcers were associated with poorer outcomes regardless of use of NSAIDs. Patients with ulcers negative for Helicobacter pylori and no history of NSAID use had the worst outcomes and had more severe systemic disease.     

Contrast Volume Use in Manual vs Automated Contrast Injection Systems for Diagnostic Coronary Angiography and Percutaneous Coronary Interventions

Background

Contrast-induced nephropathy (CIN) is an important cause of iatrogenic morbidity and mortality. The amount of contrast delivered has a major effect on CIN and is operator-dependent. A few studies suggested that the use of automated contrast injection systems is associated with reduced contrast volume. It is unknown whether this is true when smaller amounts of contrast are used and how this is affected by training.

Methods

Volume of contrast media was measured in 1358 consecutive patients undergoing diagnostic catheterization and percutaneous coronary intervention (PCI) from January 31 to May 31, 2011. Patients were allocated to manual stopcock-manifold contrast injection (1052 patients) or automated contrast injection (306 patients).

Results

No significant difference in contrast volume use was found between manual and automated contrast injection systems, respectively: diagnostic catheterization, 72 ± 40 mL vs 96 ± 63 mL (P = 0.08); diagnostic catheterization with left ventricular angiography, 98 ± 40 mL vs 95 ± 35 mL (P = 0.51); PCI, 206 ± 82 mL vs 205 ± 90 mL (P = 0.84); diagnostic catheterization and PCI, 264 ± 83 mL vs 253 ± 93 mL (P = 0.51). No significant difference in CIN incidence, according to contrast injection systems, was found among patients receiving PCI (manual 9.8% vs automated 7.4%, P = 0.43). Using smaller sized catheters during diagnostic procedures was associated with injection of smaller amounts of contrast (P < 0.0001).

Conclusions

The use of automated contrast injection for diagnostic catheterization and PCI is not associated with reduced contrast volume as compared with manual injection. The use of smaller calibre catheters might reduce contrast volume.     

Randomized Trial of Nordic Walking in Patients With Moderate to Severe Heart Failure

Background

Patients with heart failure are a growing population within cardiac rehabilitation. The purpose of this study was to compare, through a single-centre, parallel-group, randomized controlled trial, the effects of Nordic walking and standard cardiac rehabilitation care on functional capacity and other outcomes in patients with moderate to severe heart failure.

Methods

Between 2008 and 2009, 54 patients (aged 62.4 ± 11.4 years) with heart failure (mean ejection fraction = 26.9% ± 5.0%) were randomly assigned to standard cardiac rehabilitation care (n = 27) or Nordic walking (n = 27); both groups performed 200 to 400 minutes of exercise per week for 12 weeks. The primary outcome, measured after 12 weeks, was functional capacity assessed by a 6-minute walk test (6MWT).

Results

Compared with standard care, Nordic walking led to higher functional capacity (Δ 125.6 ± 59.4 m vs Δ 57.0 ± 71.3 m travelled during 6MWT; P = 0.001), greater self-reported physical activity (Δ 158.5 ± 118.5 minutes vs Δ 155.5 ± 125.6 minutes; P = 0.049), increased right grip strength (Δ 2.3 ± 3.5 kg vs Δ 0.3 ± 3.1 kg; P = 0.026), and fewer depressive symptoms (Hospital Anxiety and Depression Scale score = Δ −1.7 ± 2.4 vs Δ −0.8 ± 3.1; P = 0.014). No significant differences were found for peak aerobic capacity, left-hand grip strength, body weight, waist circumference, or symptoms of anxiety.

Conclusions

Nordic walking was superior to standard cardiac rehabilitation care in improving functional capacity and other important outcomes in patients with heart failure. This exercise modality is a promising alternative for this population.     

Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: Randomized controlled trial (PioRAGE)

Objective

The receptor for advanced glycation end-products (RAGE) is involved in vascular complications in diabetic patients. Pioglitazone, in contrast to glimepiride, has been shown to be protective against atherosclerotic disorders. In this study, we directly compared the effects of those drugs on RAGE system.

Methods

Sixty-three type 2 diabetic patients (age 20–80 years, hemoglobin A1c 6.4–10.3%) being treated with sulfonylurea (glimepiride 0.5–2.0 mg/day, glyclazide 20–80 mg/day, glibenclamide 1.25–5.0 mg/day), or with nateglinide or metiglynide were randomly assigned to receive either pioglitazone (n = 31) or glimepiride (n = 32). Levels in plasma of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE), and RAGE expression in peripheral mononuclear cells were determined at 0, 12, and 24 weeks.

Results

Twenty-seven patients in the pioglitazone group (15–30 mg) and 30 in the glimepiride group (0.5–4 mg) completed the 24-week trial. Increases in plasma esRAGE were significantly greater in the pioglitazone group (12 weeks: 55 ± 15 pg/mL, p = 0.018; 24 weeks: 90 ± 14 pg/mL, p = 0.003) as compared to the glimepiride group (12 weeks: 12 ± 9 pg/mL; 24 weeks: 29 ± 14 pg/mL). Increases in plasma sRAGE were also significantly (p = 0.037) higher in the pioglitazone group at 24 weeks (170 ± 166 vs.74 ± 171 pg/mL). Furthermore, RAGE expression in mononuclear cells was significantly (p = 0.008) decreased to a greater degree in the pioglitazone group at 24 weeks (−7.39 ± 5.18 vs. −3.39 ± 5.72 MFI). Changes in HbA1c, IRI, and insulin resistance index (HOMA) at 24 weeks were not significantly different between the groups.

Conclusion

Pioglitazone suppresses RAGE expression and increases circulating sRAGE/esRAGE, and those activities are not necessarily dependent on plasma glucose or insulin resistance levels.

Clinical trial No

UMIN000002055.     

Dificultades en el diagnóstico de los pacientes con enfermedad de Wilson en la práctica clínica: experiencia de 15 casos

Background

Wilson disease (WD) is an inherited disorder that causes copper (Cu) accumulation, leading to mainly liver, neurological and/or psychiatric manifestations. In the absence of some of the typical features, diagnosis of WD is difficult and is based on the combination of clinical, biochemical and genetic testing. The aim of this study was to illustrate the complexity of the approach to WD in daily clinical practice.

Methods

We retrospectively analyzed the medical records of patients with WD, including the clinical presentation, histological and biochemical findings, and follow up after treatment. We also carried out genetic testing, and the Leipzig diagnostic score was applied.

Results

We included 15 patients. Four were symptomatic, with liver (n = 1), neurological (n = 1), psychiatric (n = 1) and mixed clinical manifestations (n = 1), and 11 were presymptomatic, with elevated transaminases (n = 8) and family study (n = 3).We observed Kayser-Fleischer ring in 2 patients, both without neurologic symptoms.Ceruloplasmin ≤5 mg/dL was present in 73%, and 24-hour urinary Cu > 100 μg in 40%. Liver Cu was > 250 μg/g.d.t. in 85% of the patients. The final diagnosis of WD was given by genetic testing (ATP7B gene mutations) in 5 patients with minimal disease features, including one symptomatic patient (psychiatric symptoms). We identified 5 previously reported mutations (p.M645R, p.R827W, p.H1069Q, p.P768L and p.G869R) and 3 unpublished mutations (p.L1313R, p.I1311T and p.A1179D); the most frequent mutation was p.M645R.After treatment, biochemical parameters (transaminases, urinary cooper) and symptoms improved, except in patients with neurological and psychiatric manifestations.

Conclusions

Our series illustrates the important role of genetic testing in the diagnosis of WD. The identification of the p.M645R mutation in most of our patients should be kept in mind in the molecular analysis of the ATP7B gene in our region.     

Lamin A/C mutation is independently associated with an increased risk of arterial and venous thromboembolic complications

Background

Lamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications.

Methods

We compared a cohort of 76 LMNA mutation carriers with a cohort of 224 idiopathic DCM patients without a LMNA mutation, with respect to the prevalence of arterial and venous thromboembolic complications. Furthermore, we carried out a case–control study to explore whether a prothrombotic phenotype was present in LMNA mutation carriers without DCM or atrial tachyarrhythmias (n = 14) and compared this with mutation negative relatives (n = 13).

Results

The prevalence of thromboembolic complications was higher in the cohort of LMNA mutation carriers than in DCM patients (22 vs 11%; p < 0.05), after respectively mean follow-up of 42 ± 12 and 49 ± 12 years. After adjustment for possible confounders, including atrial tachyarrhythmias and left ventricular ejection fraction, LMNA mutation carriership was independently associated with an increased risk of thromboembolic complications (HR 4.8, 95% CI: 2.2–10.6). The results of the case–control study suggested a prothrombotic phenotype in LMNA mutation carriers, as reflected by an altered platelet function and increased thrombin generation.

Conclusions

LMNA mutation is independently associated with an increased risk of arterial and venous thromboembolic complications. Laboratory research in LMNA mutation carriers without severe cardiac abnormalities suggests a prothrombotic phenotype.