Physiological Changes in QRS Fragmentation in Athletes and Nonathletes without Cardiac Disease.

Background/Objectives: QRS fragmentation has not been linked with increased mortality in individuals without known cardiac disease. We aimed to investigate the physiological determinants of QRS fragmentation in individuals without cardiac disease. Methods: Study participants were 163 (54 athletes, 109 nonathletes) asymptomatic individuals with QRS fragmentation but without cardiac disease. QRS fragmentation was assessed in the supine position after deep inspiration or standing up and during exercise. The changes in QRS fragmentation were evaluated over a median follow-up period of 2.3 (0.8-4.9) years. Results: The most common lead with QRS fragmentation was III (63.0% in athletes, 61.5% in nonathletes), immediately followed by V1 (50.0%) and aVF (42.6%) in athletes and aVF (55.0%) in nonathletes. QRS fragmentation in V1 was more frequent in athletes compared to nonathletes (p < 0.001). Among athletes, the presence of QRS fragmentation in V1 could be independently predicted by increased RVOTproxi (right ventricular outflow tract proximal diameter indexed to body surface area) (p < 0.001). Among individuals with QRS fragmentation in V1, deep inspiration resulted in disappearance of QRS fragmentation more frequently in nonathletes compared to athletes (100% vs. 20%, p = 0.003). Deep inspiration resulted in disappearance of QRS fragmentation in aVF (p < 0.001). The presence of QRS fragmentation in II or aVF was associated with increased body mass index (BMI) (p = 0.003). Among athletes without QRS fragmentation in V1 at baseline, the appearance of QRS fragmentation in V1 at the end of follow-up was associated with greater training age (p = 0.034). Among individuals with QRS fragmentation in aVF at baseline, the disappearance of QRS fragmentation in aVF at the end of follow-up was associated with greater reduction in BMI (p = 0.008). Conclusions: The characteristic feature of QRS fragmentation in athletes was the presence of QRS fragmentation in V1, which was associated with RVOTproxi. The persistence of QRS fragmentation in V1 after deep inspiration could serve as a specific marker of exercise-training-related cardiac adaptation. The presence of QRS fragmentation in the leads of the frontal plane was influenced by BMI and respiration phase.

Ergophysiological evaluation of heart failure patients with reduced ejection fraction undergoing exercise-based cardiac rehabilitation: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aims to explore in heart failure (HF) patients with reduced ejection fraction (EF) undergoing exercise-based cardiac rehabilitation the following: 1) the comparison of temporal changes between peak oxygen uptake (VO2peak) and first ventilatory threshold (VO2VT1), 2) the association of VO2peak and VO2VT1 changes with physiological factors, and 3) the differential effects of continuous aerobic exercise (CAE) and interval training (IT) on VO2peak and VO2VT1. METHODS: A systematic literature search was conducted in PubMed, CENTRAL, and Scopus. Inclusion criteria were 1) original research articles using exercise-based cardiac rehabilitation, 2) stable HF patients with reduced EF, 3) available values of VO2peak and VO2VT1 (in mL/kg/min) both at baseline and after exercise training with comparison between these time points. RESULTS: Among the 30 eligible trials, 24 used CAE, 5 IT, and one CAE and IT. Multivariable meta-regression with duration of exercise training and percentage of males as independent variables and the change in VO2peak as a dependent variable showed that the change in VO2peak was negatively associated with duration of exercise training (coefficient=-0.061, p=0.027), implying the possible existence of a waning effect of exercise training on VO2peak in the long term. Multivariable meta-regression demonstrated that both age (coefficient=-0.140, p<0.001) and EF (coefficient=-0.149, p<0.001) could predict the change in VO2VT1, whereas only age (coefficient=-0.095, p=0.022), but not EF (coefficient = 0.082, p = 0.100), could predict the change in VO2peak. The posttraining peak respiratory exchange ratio, as an index of maximum effort during exercise testing, correlated positively with the change in VO2peak (coefficient=-0.021, p=0.044). The exercise-induced changes of VO2peak (p = 0.438) and VO2VT1 (p = 0.474) did not differ between CAE and IT groups. CONCLUSIONS: Improvement of endurance capacity during cardiac rehabilitation may be detected more accurately with the assessment of VO2VT1 rather than VO2peak.

An echocardiographic study of acute, progressive cardiac changes following a 246 km running race.

We describe the case of an ultra-marathon runner who finished first the "Spartathlon", a 246 km running race. The finishing time was the second fastest time ever in "Spartathlon". After finishing the race, the athlete suffered non-cardiac syncope and was administered intravenously 3 L of fluids for 5 hours. He underwent two echocardiographic assessments, one immediately after the finish of the race and the second 5 h later. Post-exercise fluid administration led to an increase in dimensions of all cardiac cavities, accompanied by a decrease in left ventricular (LV) end-diastolic interventricular septum thickness and posterior wall thickness of 0.1 cm. Dimensions and the respiratory profile of inferior vena cava improved after the race, reflecting alleviation of exercise-related hypovolaemia. Additionaly, LV global longitudinal strain improved, but right ventricular (RV) systolic function continued to deteriorate, mainly due to impairment of basal and medial RV free wall longitudinal strain. Study of this case offers a unique model for understanding the successive changes of cardiac structure and function following an ultra-marathon running race.

Prolonged QT Interval in Athletes: Distinguishing between Pathology and Physiology.

BACKGROUND: The physiological QT prolongation in athletes is expected to widen the gray zone between physiology and pathology of QT, increasing the diagnostic challenges encountered in athletes with QT prolongation. SUMMARY: According to international recommendations for electrocardiogram in athletes, further evaluation for long QT syndrome (LQTS) is indicated in male athletes with corrected QT (QTc) ≥470 ms and in female athletes with QTc ≥480 ms. Apart from QTc ≥500 ms, diagnostic challenges arise in borderline cases of QTc prolongation, where further clinical investigations are needed to be performed to clarify whether LQTS exists. Clinical diagnostic investigations, including exercise testing, are more readily available, convenient, and easily interpretable, as well as less costly than genetic testing for LQTS. The main findings on exercise testing that are suggestive of LQTS can be the paradoxical prolongation of QTc during exercise and QTc ≥480 ms at fourth min of recovery. KEY MESSAGES: Exercise testing appears to have an important role in the diagnostic evaluation of athletes with prolonged QT interval, when genetic testing is not available.

Impact of a 246 Km ultra-marathon running race on heart: Insights from advanced deformation analysis.

Although previous studies suggest that prolonged intense exercise such as marathon running transitorily alters cardiac function, there is little information regarding ultramarathon races. Aim of this study was to investigate the acute impact of ultra-endurance exercise (UEE) on heart, applying advanced strain imaging. Echocardiographic assessment was performed the day before and at the finish line of "Spartathlon": A 246 Km ultra-marathon running race. 2D speckle-tracking echocardiography was performed in all four chambers, evaluating longitudinal strain (LS) for both ventricles and atria. Peak strain values and temporal parameters adjusted for heart rate were extracted from the derived curves. Out of 60 participants initially screened, 27 athletes (19 male, age 45 ± 7 years) finished the race in 33:34:27(28:50:38-35:07:07) hours. Absolute values of right (RV) and left ventricular (LV) LS (RVLS -22.9 ± 3.6 pre- to -21.2 ± 3.0% post-, p=0.04 and LVLS -20.9 ± 2.3 pre- to -18.8 ± 2.0 post-, p=0.009) slightly decreased post-race, whereas atrial strain did not change. RV and LV LS decrease was caused mainly by strain impairment of basal regions with apical preservation. Inter-chamber relationships assessed through RV/LV, LV/LA, RV/RA and RA/LA peak values' ratios remained unchanged from pre to post-race. Finally, UEE caused an extension of the systolic phase of cardiac cycle with concomitant diastole reduction (p<0.001 for all strain curves). Conclusively, ventricular LS strain as well as effective diastolic period slightly decreased, whereas atrial strain and inter-chamber relationships remained unchanged after running a 246-km-ultra-marathon race. These changes may be attributed to concomitant pre- and afterload alterations following UEE.

Arterial Function after a 246 km Ultra-marathon Running Race.

There is little research about the effects of ultra-endurance exercise on arterial morphological and functional properties. The aim was to assess the acute changes of the carotid-femoral pulse wave velocity and carotid doppler-derived parameters following an ultra-marathon race as well as the intima-media thickness of the carotid artery in ultra-marathon runners. Twenty athletes were examined at baseline and within 10 mins after a 246 km running race. Measurements included carotid-femoral pulse wave velocity, peak-systolic and end-diastolic velocities of carotid artery blood flow, pulsatility and resistivity indices and blood biochemical parameters. The intima-media thickness of the right and left carotid artery was measured before the race. Arterial stiffness and carotid artery intima media thickness at rest remained within known normal limits. The ultra-marathon race significantly increased carotid-femoral pulse wave velocity by 22.6% and pulsatility index by 10.2%. There was a decrease in body weight by 3.35% and an increase of all biochemical markers of muscle damage after the race. Additionally, C-reactive protein was correlated with both pulsatility and resistivity indices post-race. This study shows that immediately after a 246 km ultra-marathon running race, acute increase of arterial stiffness and vascular resistance were evident. The carotid artery thickness of ultra-marathon runners was within normal range.

The regulation of serum resistin levels in metabolically healthy and unhealthy obese individuals.

PURPOSE: We have recently demonstrated that absolute counts of circulating proinflammatory monocytes were lower in obese patients without metabolic syndrome (MS) (metabolically healthy obese, MHO) compared with those with MS (metabolically unhealthy obese, MUO), but higher compared with healthy lean controls (MHL). We hypothesized that circulating resistin, a cytokine secreted by white blood cells (WBC), is involved in obesity-related low-grade inflammation. The aim of this study was to (a) determine serum resistin levels among MUO and MHO subjects and (b) investigate the role of circulating WBC subsets as potential determinants of resistin. METHODS: Study participants were 58 obese (33 MUO, 25 MHO) and 25 MHL individuals. Serum levels of resistin, high-sensitivity C-reactive protein (hsCRP), and absolute counts of circulating WBC subpopulations were determined. Comparisons were sex- and age-adjusted. RESULTS: Serum resistin levels in MHL were lower compared with those of obese (p = 0.041), but similar to those of MHO (p = 0.856) individuals. Both resistin (p = 0.005) and absolute neutrophil count (NeuA) (p = 0.025) were higher in MUO compared with MHO. The difference in resistin levels between obese and MHL individuals disappeared after adjustment for NeuA. Resistin correlated positively with absolute total monocyte count (p = 0.037) in MHL and with body mass index (BMI) (p = 0.023), hsCRP (p = 0.022), and NeuA (p = 0.044) in obese subjects. Resistin association with ΒΜΙ disappeared after adjustment for hsCRP, while association with hsCRP disappeared after further adjustment for NeuA. CONCLUSION: Circulating resistin was higher in MUO compared with MHO. The increased secretion of resistin by the greater number of neutrophils in the former may have contributed to this regulation.

High Tolerability of Pitavastatin Therapy: A Case Report of Comparison with other Statins.

INTRODUCTION: Myopathy is possibly the most clinically relevant statin-induced side effect. CASE PRESENTATION: We report a case of a 63-year-old healthy male with mixed dyslipidemia. He developed bilateral myalgia of the forearms with fluvastatin 40 mg/day, pravastatin 20 mg/day, and combination of atorvastatin 10 mg and ezetimibe 10 mg/day. The only hypolipidemic treatment that was tolerable was the combination of pitavastatin 1 mg and ezetimibe 10 mg/day. DISCUSSION: Pitavastatin demonstrated less potential for the development of myalgia compared to the so far considered most tolerable statins (i.e., fluvastatin and pravastatin). All the tested statins were used at the lowest approved dose for clinical use. CONCLUSION: The combination of pitavastatin 1 mg and ezetimibe appears to be a promising treatment choice for individuals who are intolerant to statin therapy due to muscle complaints.

Exploring the determinants of the cardiac changes after ultra-long duration exercise: The echocardiographic Spartathlon study.

AIM: The investigation of the pathophysiological determinants of cardiac changes following ultra-long duration exercise. METHODS: Twenty-seven runners who finished a 246 km running race were examined both before and after the finish of the race. Examinations included echocardiography and measurement of body weight and blood biochemical parameters. RESULTS: Exercise increased left ventricular end-diastolic interventricular septum thickness (LVIVSd) (p < 0.001) and posterior wall thickness (LVPWTd) (p = 0.001) and right ventricular end-diastolic area (p = 0.005), while reduced tricuspid annular plane systolic excursion (TAPSE) (p = 0.004). A minor decrease in the peak absolute values of both left ventricular (from -20.9 ± 2.3% to -18.8 ± 2.0%, p = 0.009) and right ventricular (from -22.9 ± 3.6% to -21.2 ± 3.0%, p = 0.040) global longitudinal strains occurred. There was decrease in body weight (p < 0.001) and increase in both circulating high-sensitivity troponin I (p = 0.028) and amino-terminal pro-B type natriuretic peptide (NT-proBNP) (p = 0.018). The change in the sum of LVIVSd and LVPWTd correlated negatively with percentage change of body weight (r = -0.416, p = 0.049). The only independent determinant of post-exercise NT-proBNP was pulmonary artery systolic pressure (r = 0.797, p = 0.002). Post-exercise NT-proBNP correlated positively with percentage changes of basal (RVbas) (r = 0.582, p = 0.037) and mid-cavity (RVmid) (r = 0.618, p = 0.043) right ventricular diameters and negatively with percentage change of TAPSE (r = -0.720, p = 0.008). Similar correlations with RVbas, RVmid and TAPSE were found for pulmonary artery systolic pressure. Post-exercise high-sensitivity troponin I correlated negatively with percentage change of body weight (r = -0.601, p = 0.039), but was not associated with any cardiac parameter. CONCLUSION: The main cardiac effects of ultra-long duration exercise were the decrease in left ventricular end-diastolic dimensions and increase in left ventricular wall thickness, as well as minimal dilatation and alteration in systolic function of right ventricle, possibly due to the altered exercise-related right ventricular afterload.

Renovascular Hypertension: Novel Insights.

Renovascular hypertension (RVH) remains among the most prevalent and important, but also potentially reversible, causes of secondary hypertension. The predominant causes of renal artery stenosis (RAS) are atherosclerotic renovascular arterial stenosis (ARAS) and renal fibromuscular dysplasia. This condition can lead to progressive renal injury, cardiovascular complications and 'flash pulmonary edema'. Duplex Doppler ultrasonography, computed tomographic angiography and magnetic resonance angiography are the most commonly used diagnostic methods. There are three therapeutic options available: medical therapy including renin-angiotensin-aldosterone system antagonists, lipid-lowering agents, and antiplatelet therapy, percutaneous angioplasty with or without stent placement and surgical revascularization. Three large trials failed to demonstrate the superiority of renal artery revascularization over pharmaceutical therapy in controlling blood pressure and preserving renal function. For this reason, today revascularization is only recommended for patients with progressive worsening of renal function, recurrent 'flash pulmonary edema' and rapid increase in antihypertensive requirement in patients with previously well-controlled hypertension. However, more properly designed trials are needed in order to identify which patient populations would probably benefit from renal revascularization.

Factors associated with delayed presentation at the emergency department in patients with acute ischemic stroke.

Background and aims: Pre-hospital delay is a crucial factor that determines the eligibility for intravenous thrombolysis in patients with acute ischemic stroke. We aimed to evaluate the time to presentation at the emergency department (ED) and the factors that affect this time. Patients and methods: We prospectively studied 682 patients who were admitted with acute ischemic stroke (43.3% men, age 79.9 ± 6.6 years). Results: The median time to presentation at the ED was 2.1 h (range 0.15 to 168 h); 68.8% of the patients arrived within 4.5 h and 56.5% arrived within 3 h from the onset of symptoms. Independent predictors of presentation within 4.5 h were the use of emergency medical services (EMS) for transportation to the hospital (OR 2.61, 95% CI 1.38-4.94, p = .003), family history of cardiovascular disease (CVD)(OR 4.0 0,95%CI 1.61-12.23, p = .006) and the absence of history of smoking (OR 2.49, 95% CI 1.13-5.42, p = .021). Independent predictors of presentation within 3 h were the use of EMS for transportation to the hospital (OR 6.24, 95% CI 2.52-16.63, p = .0001), family history of CVD (OR 3.07, 95% CI 1.14-9.43, p = .03), and a moderately severe stroke at admission (OR vs. minor stroke 0.38, 95% CI 0.16-0.87, p = .02). Conclusions: A considerable proportion of patients with acute ischemic stroke arrives at the ED after the 4.5-h threshold for performing intravenous thrombolysis. Non-smokers, patients with a family history of CVD, with moderately severe stroke and those who use the EMS are more likely to arrive on time.

Impaired antioxidative activity of high-density lipoprotein is associated with more severe acute ischemic stroke.

BACKGROUND/AIMS: High-density lipoprotein (HDL) has important anti-atherogenic functions, including antioxidant effects. However, it is unclear whether the antioxidative activity of HDL is associated with the severity and outcome of acute ischemic stroke. We aimed to evaluate this association. METHODS: We prospectively studied 199 consecutive patients admitted with acute ischemic stroke and followed them up until discharge. We measured HDL antioxidant capacity, HDL-associated paraoxonase-1 (PON1) activity and HDL-associated myeloperoxidase (MPO) levels. Severe stroke was defined as National Institutes of Health Stroke Scale (NIHSS) at admission ≥5. Dependency was defined as modified Rankin scale at discharge between 2 and 5. RESULTS: Patients with severe stroke had lower HDL antioxidant capacity, higher MPO levels and higher MPO/PON1 ratio. Independent risk factors for severe stroke were female gender (RR 2.80, 95% CI 1.37-5.70, p = 0.005), glucose levels (RR 1.01, 95% CI 1.0-1.02, p < 0.01) and HDL antioxidant capacity (RR 1.03, 95% CI 1.01-1.06, p < 0.05). Patients who were dependent at discharge had lower HDL antioxidant capacity, higher MPO levels and higher MPO/PON1 ratio. Independent predictors of dependency at discharge were lack of lipid-lowering treatment (RR 6.86, 95% CI 1.83-25.67, p < 0.005) and NIHSS (RR 1.56, 95% CI 1.29-1.88, p < 0.0001). The HDL antioxidant capacity did not differ between patients who died during hospitalization and those who were discharged. The only independent predictor of in-hospital mortality was NIHSS (RR 1.16, 95% CI 1.06-1.27, p < 0.005). CONCLUSIONS: Impaired antioxidative activity of HDL is associated with more severe acute ischemic stroke and might also predict a worse functional outcome in these patients.

Metabolically Healthy Obesity Is Characterized by a Proinflammatory Phenotype of Circulating Monocyte Subsets.

Background: Obesity is associated with macrophage infiltration in adipose tissue that induces insulin resistance and contributes to the development of metabolic syndrome (MS). The aim of this study was to investigate whether circulating monocyte subsets (macrophage precursors) differ among obese subjects with MS [metabolically unhealthy obese (MUO)], obese subjects without MS [metabolically healthy obese (MHO)], and metabolically healthy lean (MHL) individuals. Methods: Fifty-eight obese (33 MUO, 25 MHO) and 25 MHL individuals participated in the study. Absolute blood counts of classical (Mon1A), intermediate (Mon2A), and nonclassical (Mon3A) monocyte subsets were measured by flow cytometry. Results: Increased proinflammatory monocyte counts (Mon2A, Mon3A) were observed in obese compared with MHL individuals (P = 0.001 and P = 0.017 respectively). Mon2A count in MHO was lower compared with that in MUO subjects (P = 0.036) but higher compared with MHL controls (P = 0.032). Mon2A was positively associated with serum triglyceride levels (r = 0.328, P = 0.023) and mean blood pressure (BP) (r = 0.457, P = 0.001) in obese subjects. Among MS components, only the presence of elevated BP (≥130/85 mmHg) was independently associated with increased Mon2A in obese subjects (P < 0.001). Conclusions: Absolute counts of proinflammatory monocytes were lower in metabolically healthy compared with MUO individuals, but higher compared with healthy lean controls. The presence of low-grade inflammation suggests that "metabolically healthy" obesity is not a benign condition. ClinicalTrials.gov identifier: NCT03241394.

Indirect clinical markers for the detection of anabolic steroid abuse beyond the conventional doping control in athletes.

Growing analytical challenges have arisen for the detection of misuse of androgenic anabolic steroids (AAS) in athletes the last years. Therefore, consideration of additional indirect markers can substantially aid the efforts to detect AAS abuse in athletes. Moreover, this approach can also help physicians to suspect AAS abuse when treating athletes. Laboratory markers highly indicative of AAS abuse in athletes include the considerable downregulation of high density lipoprotein-cholesterol, elevation of haematocrit or serum γ-glutamyl transpeptidase levels and for males reduced serum levels of both luteinizing hormone and follicle-stimulating hormone. Moreover, physical signs suggestive of current AAS abuse are hypertension, apparent changes in behaviour making the athlete more irritable and aggressive and the sudden appearance of acne vulgaris in an adult athlete with no recent history of acne, while testicular atrophy and gynecomastia raise suspicion of current or past AAS abuse in male athletes.

Association between age at menopause and fracture risk: a systematic review and meta-analysis.

PURPOSE: Early menopause (EM, age at menopause < 45 years) and premature ovarian insufficiency (POI, age at menopause < 40 years) are associated with an increased risk of osteoporosis. However, their association with increased fracture risk has not been established, with studies yielding conflicting results. The primary aim of this systematic review and meta-analysis was to synthesize studies evaluating the association between age at menopause and fracture risk. The secondary aim was to evaluate this effect concerning the site of fractures. METHODS: A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to 31 January 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). The I2 index was employed for quantifying heterogeneity. RESULTS: Eighteen studies were included in the qualitative and quantitative analysis (462,393 postmenopausal women, 12,130 fractures). Compared with women with age at menopause > 45 years, women with EM demonstrated higher fracture risk (OR 1.36, 95% CI 1.11-1.66, p < 0.002, I² 81.5%). Women with POI did not display any difference in fracture risk compared either with women with age at menopause > 40 (OR 1.23, 95% CI 0.72-2.09, p = 0.436, I² 62.5%) or >45 years (OR 0.54, 95% CI 0.22-1.29, p = 0.17, I2 0%). No difference was evident when a separate analysis was performed for vertebral, non-vertebral and hip fractures. CONCLUSIONS: This is the first meta-analysis showing that EM is associated with increased fracture risk compared with normal age at menopause, without any distinct effect on the site of the fracture.

Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis.

Objective/Design Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause <45 years) or premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with increased risk of type 2 diabetes mellitus (T2DM). To systematically investigate and meta-analyze the best evidence regarding the association of age at menopause with the risk of T2DM. Methods A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to January 31, 2018. Data are expressed as odds ratio (OR) with 95% confidence intervals (CI). The I 2 index was employed for heterogeneity. Results Thirteen studies were included in the qualitative and quantitative analysis (191 762 postmenopausal women, 21 664 cases with T2DM). Both women with EM and POI were at higher risk of T2DM compared with those of age at menopause of 45-55 years (OR: 1.15, 95% CI: 1.04-1.26, P = 0.003; I 2: 61%, P < 0.002 and OR: 1.50, 95% CI: 1.03-2.19, P = 0.033; I 2: 75.2%, P < 0.003), respectively). Similar associations emerged when women with EM and POI were compared with those of age at menopause >45 years (OR: 1.12, 95% CI: 1.01-1.20, P < 0.02; I 2: 78%, P < 0.001 and OR: 1.53, 95% CI: 1.03-2.27, P = 0.035; I 2: 78%, P < 0.001), respectively). Conclusions Both EM and POI are associated with increased risk of T2DM.

Multimodal Treatment of Homozygous Familial Hypercholesterolemia.

BACKGROUND: Familial Hypercholesterolemia (FH) is an autosomal-dominant genetic disease, associated with premature atherosclerotic Cardiovascular Disease (CVD), especially in its homozygous type (HoFH). OBJECTIVE: The aim of this review is to discuss the safety and efficacy of combination treatments (procedures and drugs) for HoFH. RESULTS: Historically, liver transplantation was used first; however, it is currently considered only as a last resort for some patients. In the mid 70's, LDL aphaeresis was introduced and remains up today the treatment of choice for patients of any age, despite its significant cost. The use of Ezetimibe results in additive 15-20% reductions in LDL-C regardless of the therapeutic approach, while statins are modestly effective in patients with class 4 or 5 mutations, in which LDL Receptors (LDLR) are present. One of the novel drugs for HoFH is Lomitapide, which is a highly effective oral agent, but is also exceedingly expensive ($350, 000/year). Mipomersen is administered every week subcutaneously, is also effective but has been approved only in the US mainly due to injection site reactions up to 80%. Both Lomitapide (mainly) and Mipomersen have been found to promote fat accumulation in the liver, resulting in subsequent serum transaminases elevations. PCSK9 inhibitors are effective in those with partial LDLR presence and function by reducing frequency of LDL apheresis, improve cost effectiveness of treatment. CONCLUSION: Pediatric and adult HoFH treatment needs combination of procedures and drugs. The main treatment is LDL-C apheresis aided by ezetimibe and PCSK9 inhibitors. Lomitapide needs caution, and liver transplantation is an alternative as the last resort.

Atypical anastomotic malignancies of small bowel after subtotal gastrectomy with Billorth II gastroenterostomy for peptic ulcer: Report of three cases and review of the literature.

AIM: To present patients who developed small-bowel malignancy at the level of the gastrointestinal anastomosis decades after a subtotal gastrectomy for ulcer, to review relevant literature, and to attempt to interpret the reasons those cancers developed to these postsurgical non-gastric sights. METHODS: For the current retrospective study and review of literature, the surgical and histopathological records dated from January 1, 1993 to December 31, 2017 of our department were examined, searching for patients who have undergone surgical treatment of small-bowel malignancy to identify those who have undergone subtotal gastrectomy for benign peptic ulcer. A systematic literature search was also conducted using PubMed, EMBASE, and Cochrane Library to identify similar cases. RESULTS: We identified three patients who had developed small-intestine malignancy at the level of the gastrointestinal anastomosis decades after a subtotal gastrectomy with Billroth II gastroenterostomy for benign peptic ulcer-two patients with adenocarcinoma originated in the Braun anastomosis and one patient with lymphoma of the efferent loop. All three patients were submitted to surgical resection of the tumor with Roux-en-Y reconstruction of the digestive tract. In the literature review, we only found one case of primary small-intestinal cancer that originated in the efferent loop after Billroth II gastrectomy because of duodenal ulcer but none reporting Braun anastomosis adenocarcinoma following partial gastrectomy for benign disease. We also did not find any case of efferent loop lymphoma following gastrectomy. CONCLUSION: Anastomotic gastric cancer following distal gastrectomy for peptic ulcer is a well-established clinical entity. However, malignancies of the afferent or efferent loop of the gastrointestinal anastomosis are extremely uncommon. The substantial diversion of the potent carcinogenic pancreaticobiliary secretions through the Braun anastomosis and the stomach hypochlorhydria, allowing the formation of carcinogenic factors from food, are the two most prominent pathogenetic mechanisms for those tumors.

The effect of antidiabetic medications on the cardiovascular system: a critical appraisal of current data.

Both type 1 and type 2 diabetes are associated with increased risk for cardiovascular disease (CVD) events. This risk seems to be reduced by achievement of euglycemia. However, after the withdrawal of rosiglitazone from the market, the question arose as to whether this risk concerns simply a matter of euglycemia or the distinct role played by each antidiabetic drug with respect to its effect on CVD risk. To address this issue, many studies have been published during the last decade involving old and new antidiabetic agents, which however yielded contradictory results. Briefly, metformin is still considered safe and confers a beneficial effect on CVD risk. Conflicting data exist as concerns sulfonylureas, although the second and third generation representatives are regarded as relatively safe. Pioglitazone use seems to be associated with a reduction in CVD risk, whereas the dipeptidyl-dipeptidase-4 inhibitors (DPP-4i), lixisenatide and exenatide-LAR [from the category of glucagon-like-peptide-1 receptor (GLP-1R) agonists], confer a neutral effect. Two other GLP-1R agonists, liraglutide and semaglutide, as well as the sodium-glucose transporter-2 (SGLT2)-inhibitors, empagliflozin and cangliflozin, have shown an additional effect on CVD risk reduction, although their safety is in doubt. Insulin analogues and newer long-acting compounds are also safe for the cadiovascular system. The aim of this narrative review is to present and critically analyse the current data for each antidiabetic drug category with regard to their effect on CVD risk.

Treatment with Mannitol is Associated with Increased Risk for In-Hospital Mortality in Patients with Acute Ischemic Stroke and Cerebral Edema.

BACKGROUND: Current guidelines state that osmotic therapy is reasonable in patients with clinical deterioration from cerebral infarction-related cerebral edema. However, there are limited data on the safety and efficacy of this therapy. We aimed to evaluate the effect of mannitol on the outcome of ischemic stroke-related cerebral edema. METHODS AND RESULTS: We prospectively studied 922 consecutive patients admitted with acute ischemic stroke. Patients who showed space-occupying brain edema with tissue shifts compressing the midline structures received mannitol. The outcome was assessed with dependency rates at discharge (modified Rankin Scale grade 2-5) and in-hospital mortality. Rates of dependency were higher in patients treated with mannitol (n = 86) than in those who were not (97.7 and 58.5%, respectively; p < 0.001). Independent predictors of dependency were age, history of ischemic stroke and National Institutes of Health Stroke Scale (NIHSS) score at admission. Rates of mortality were higher in patients treated with mannitol than in those who were not (46.5 and 5.6%, respectively; p < 0.001). Independent predictors of in-hospital mortality were diastolic blood pressure [relative risk (RR) 1.05, 95% confidence interval (CI) 1.02-1.08, p < 0.001], NIHSS score at admission (RR 1.19, 95% CI 1.14-1.23, p < 0.001) and treatment with mannitol (RR 3.45, 95% CI 1.55-7.69, p < 0.005). CONCLUSIONS: Administration of mannitol to patients with ischemic stroke-related cerebral edema does not appear to affect the functional outcome and might increase mortality, independently of stroke severity.