Amiodarone accumulates two cholesterol precursors in myocardium: A controlled clinical study.

BACKGROUND: Amiodarone is an effective antiarrhythmic drug, which interferes with cholesterol synthesis. In the human body, it inhibits two enzymes in the cholesterol-synthesis pathway, followed by increases especially in serum desmosterol and zymostenol concentrations and a decrease in that of serum lathosterol. OBJECTIVES: We explored whether desmosterol and zymostenol accumulate also in myocardial tissue during amiodarone treatment. METHODS: Thirty-three patients admitted for cardiac transplantation volunteered for the study. Ten patients were on amiodarone treatment (AD group) and 23 were not (control group). The groups were matched as regards demographic and clinical variables. Myocardial samples were obtained from the removed hearts from 31 patients. Cholesterol, non-cholesterol sterols and squalene were quantified by means of gas-liquid chromatography. RESULTS: In serum and myocardium, desmosterol was 19- and 18-fold higher and zymostenol 4- and 2-fold higher in the AD group versus the control group (p < 0.001 for all). In contrast, myocardial cholesterol, squalene and lathosterol levels were lower in the AD group than in the control group (p < 0.05 for all). Levels of phytosterols and cholestanol were similar in the serum and myocardium in the two groups. Levels of myocardial and serum desmosterol, zymostenol, lathosterol and phytosterols correlated with each other in both groups (p < 0.05 for all). CONCLUSION: Amiodarone treatment caused the accumulation of desmosterol and zymostenol in myocardium. In particular, myocardial desmosterol concentrations were substantially elevated, which may play a part in some of the therapeutic and adverse effects of amiodarone treatment.

Plant Stanol Esters Reduce LDL (Low-Density Lipoprotein) Aggregation by Altering LDL Surface Lipids: The BLOOD FLOW Randomized Intervention Study.

OBJECTIVE: Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. Approach and Results: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm, P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index<25 kg/m2. Decreased LDL aggregation susceptibility was associated with decreased proportion of LDL-sphingomyelins and increased proportion of LDL-triacylglycerols. LDL binding to proteoglycans was decreased in the plant stanol ester group, the decrease depending on decreased serum LDL-cholesterol concentration. CONCLUSIONS: Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01315964.

Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries.

AIMS: The present study was done to assess the role of sudden cardiac death (SCD) among the presenting manifestations of and fatalities from cardiac sarcoidosis (CS). METHODS AND RESULTS: We analysed altogether 351 cases of CS presenting from year 1998 through 2015 in Finland. There were 262 patients with a clinical diagnosis and treatment of CS, 27 patients with an initial lifetime diagnosis of giant cell myocarditis that was later converted to CS, and 62 cases detected at autopsy and identified by screening >820 000 death certificates from the national cause-of-death registry. The total case series comprised 253 females and 98 males aged on average 52 years at presentation. High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%), unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%). Severe coronary artery disease was found at autopsy concomitant with CS in four of the 38 cases presenting with fatal SCD. Of all deaths recorded till the end of 2015, 64% (n = 54/84) were unexpected SCDs from CS that had either been silent during life or defied all attempts at diagnosis. The Kaplan-Meier estimate (95% CI) of survival from symptom onset was 85% (80-90%) at 5 years and 76% (68-84%) at 10 years. CONCLUSION: Together fatal and aborted SCD constitute 14% of the presenting manifestations of CS. Nearly two-thirds of all fatalities from CS are caused by undiagnosed granulomas in the heart.

Low Childhood Cholesterol Absorption Predisposes to Gallstone Disease: The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: Unraveling pathogenesis of gallstones could help to diminish its enormous disease burden. We hypothesized that certain properties of childhood cholesterol metabolism predict gallstone disease in adulthood. METHODS: Childhood serum cholestanol and plant sterols (surrogates for cholesterol absorption), cholesterol precursors (surrogates for cholesterol synthesis), lipids, demographics, and dietary habits were compared between individuals diagnosed with gallstone disease subsequently in adulthood (n = 95) and control subjects (n = 190) matched for age, sex, and body mass index in 1980. Subjects were participants of prospective Cardiovascular Risk in Young Finns Study. RESULTS: In 1980, at mean age of 11.4 years gallstone cohort was characterized by 5.8% lower cholestanol (P = 0.038), and 11.2% to 12.2% (P range = 0.003-0.008) lower plant sterols campesterol, sitosterol, and avenasterol compared with controls. Mean lathosterol/sitosterol ratio was 16.3% higher in gallstone compared with control cohort (P = 0.028). Female gallstone group had 5.4% lower mean cholestanol compared with controls (P < 0.05), and, respectively, those of campesterol, sitosterol, and avenasterol were 12.7% to 14.0% lower (P < 0.05 for each). Body mass index was inversely related to cholestanol and sitosterol (r range = -0.161 to -0.208, P < 0.05 for each) in controls, but not among patients with gallstone. In whole study population, surrogates of cholesterol absorption (eg, campesterol, P = 0.018) and low dietary intake of vegetables (P = 0.009) were significant predictors of gallstones in logistic regression model. CONCLUSIONS: Cholesterol metabolism trait characterized by low serum levels of surrogate markers of cholesterol absorption precedes adult gallstone disease already in childhood. Low serum cholestanol and plant sterol ratios during normal Western diet may have role as predictive biomarkers for gallstones.

Mechanical compression devices for cardiac arrest: report of three cases.

Mechanical compression devices enable transportation of patients with cardiac arrest to the catheterization laboratory. Coronary angiography and coronary interventions can be performed while the patients are being resuscitated with these devices. In this report, we describe three cases in whom resuscitation with mechanical compression devices and rapid transportation to the catheterization laboratory resulted in favorable cardiac and neurological outcome.

A good start for scientific supervision.

Clinical research work is mostly supervised besides daily work. Good time management skills are in fact an essential prerequisite for success, also influenced by various qualities of the supervisor and the supervisee. One pattern will not work in all supervisory relationships. Functional communication plays a particularly central role. Attention should be paid on the regularity, quality and effectiveness of supervisory discussions. On the other hand, group supervision has proven to be effective and will also facilitate the continuity of supervision. Goals and desires set for the partners can be structured by applying supervision contracts.

Serum proprotein convertase subtilisin/kexin type 9 concentration is not increased by plant stanol ester consumption in normo- to moderately hypercholesterolaemic non-obese subjects. The BLOOD FLOW intervention study.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein (LDL) cholesterol (LDL-C) metabolism by targeting LDL receptors for degradation. Statins increase serum PCSK9 concentration limiting the potential of statins to reduce LDL-C, whereas ezetimibe, inhibitor of cholesterol absorption, has ambiguous effects on circulating PCSK9 levels. Plant stanols also reduce cholesterol absorption, but their effect on serum PCSK9 concentration is not known. Therefore, we performed a controlled, randomized, double-blind study, in which 92 normo- to moderately hypercholesterolaemic subjects (35 males and 57 females) consumed vegetable-oil spread 20 g/day enriched (plant stanol group, n=46) or not (control group, n=46) with plant stanols 3 g/day as ester for 6 months. Fasting blood samples were drawn at baseline and at the end of the study. Serum PCSK9 concentration was analysed with Quantikine Elisa Immunoassay, serum and lipoprotein lipids enzymatically and serum non-cholesterol sterols with GLC. At baseline, PCSK9 concentration varied from 91 to 716 ng/ml with a mean value of 278±11 (S.E.M.) ng/ml with no gender difference. It correlated with serum and LDL-C, serum triglycerides, age, body mass index (BMI) and plasma glucose concentration, but not with variables of cholesterol metabolism when adjusted to serum cholesterol. Plant stanols reduced LDL-C by 10% from controls (P<0.05), but PCSK9 levels were unchanged and did not differ between the groups. In conclusion, the present study demonstrated for the first time that inhibition of cholesterol absorption with plant stanol esters did not affect serum PCSK9 concentration. Thus, plant stanol esters provide an efficient dietary means to lower LDL-C without interfering with the PCSK9 metabolism and in this regard the LDL receptor-mediated cellular cholesterol uptake and removal.

Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions.

BACKGROUND: The efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non-cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols. METHODS: We collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas-liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method. RESULTS: The results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker. CONCLUSIONS: Serum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved. TRIAL REGISTRATION: Clinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111-117].

Comparative evaluation of microprobe versus conventional transoesophageal echocardiography for PFO closure guidance.

BACKGROUND: Patent foramen ovale (PFO) closure is traditionally guided by transoesophageal echocardiography (TEE) under general anaesthesia, which prolongs procedure duration and increases costs and risks. A transnasal echocardiography with a microTEE-probe (microTNE) is tolerated under conscious sedation and offers an effective alternative to TEE. The aim of this study was to compare the feasibility, safety and time expenditure of PFO closure using conventional TEE versus microTNE guidance. METHODS: Consecutive patients assigned for PFO losure in Helsinki University Hospital from 2003 to 2021 were included in the study (n=336). TEE with general anaesthesia was used until November 2018 (n=167) while microTNE-guided PFO closure (n=169) under conscious sedation was the principal method thereafter. Patients were followed for 3 months after PFO closure. RESULTS: The microTNE-route success rate was 97.2% vs TEE 100% (p=0.06) and procedure success rate was 97.7% with microTNE and 96.0% with TEE-guidance (p=0.54). The procedure time was significantly shorter with microTNE 21±7 min than with TEE 30±13 min (p<0.001). At the beginning of microTNE era, nasal bleeding complication was quite frequent; however, overall complication rates were equal between the groups. However, C reactive protein (CRP) increase was significantly milder with microTNE than TEE 1.0±2.9 vs 3.0±4.0 mg/L (p<0.001). An increase in CRP was independently associated with procedure type (p=0.004) and time (p=0.003). CONCLUSIONS: MicroTNE is a feasible and safe alternative for PFO closure guidance. MicroTNE under conscious sedation shortens procedure duration and induces a milder inflammatory reaction than conventional TEE under general anaesthesia.

The profile of cholesterol metabolism does not interfere with the cholesterol-lowering efficacy of phytostanol esters.

BACKGROUND & AIMS: Increasing evidence suggests that high cholesterol absorption efficiency enhances the risk of atherosclerotic cardiovascular diseases. It is not known whether inhibiting cholesterol absorption has different metabolic effects in high- vs. low cholesterol absorbers. We evaluated the effects of phytostanol esters on serum lipids and cholesterol metabolism in a post hoc study of three randomized, double-blind, controlled trials. The participants were classified into low (n = 20) and high (n = 21) cholesterol absorbers by median cholesterol absorption efficiency based on the plasma cholesterol absorption marker cholestanol at baseline. METHODS: The participants consumed mayonnaise or margarine without or with phytostanol esters for six to nine weeks without other changes in the diet or lifestyle. Serum cholesterol, cholestanol, lathosterol, and faecal neutral sterols and bile acids were analysed by gas-liquid chromatography. According to power calculations, the size of the study population (n = 41) was appropriate. RESULTS: During the control period, cholesterol synthesis, and faecal neutral sterols and bile acids were lower in high- vs. low absorbers (p < 0.05 for all). Phytostanol esters reduced low-density lipoprotein cholesterol by 10-13% in both groups, and directly measured cholesterol absorption efficiency by 41 ± 7% in low- and 47 ± 5% in high absorbers (p < 0.001 for all) without side effects. Cholesterol synthesis and faecal neutral sterols (p < 0.01) increased in both groups, more markedly in the high vs. low absorbers (p < 0.01). CONCLUSIONS: Low cholesterol absorption combined with high faecal neutral sterol excretion are components of reverse cholesterol transport. Thus, high- vs. low absorbers had a more disadvantageous metabolic profile at baseline. In both groups, phytostanol esters induced favourable changes in serum, lipoprotein, and metabolic variables known to help in prevention of the development of atherosclerotic cardiovascular diseases.

The effect of hydroxychloroquine on cholesterol synthesis depends on the profile of cholesterol metabolism. A controlled clinical study.

Background and aims: Hydroxychloroquine (HCQ) has a variable effect on cholesterol synthesis. To clarify this, we assessed the effect of HCQ on the cholesterol-synthesis pathway in individuals with low and high cholesterol absorption efficiency. Method: A total of 53 acute myocardial infarction patients with a constant statin dose randomized to receive HCQ or placebo for six months in a double-blind manner, were classified further into low (n = 26) and high (n = 27) cholesterol absorbers based on the median baseline serum cholestanol level. Serum lipids and biomarkers of cholesterol synthesis (squalene, lanosterol, zymostenol, desmosterol, and lathosterol) and absorption efficiency (sitosterol and cholestanol), were measured at baseline and one-, six-, and 12-month follow-up visits. Results: In low cholesterol absorbers, serum cholesterol concentration and cholesterol synthesis and absorption biomarkers did not differ between the HCQ and placebo groups. At one month, high cholesterol absorbers with HCQ had lower serum cholesterol concentration and serum lanosterol to cholesterol ratio in comparison to the placebo group (HCQ 3.18 ± 0.62 vs. placebo 3.71 ± 0.65, p = 0.042, and HCQ 10.4 ± 2.55 vs. placebo 13.1 ± 2.36, p = 0.008, respectively). At 12 months, serum desmosterol to cholesterol ratio was lower in HCQ users (HCQ 47.1 ± 7.08 vs. placebo 59.0 ± 13.1, p = 0.011). Conclusions: HCQ affects the cholesterol-synthesis pathway in high cholesterol absorbers. It reduces serum lanosterol and desmosterol ratios and consequently serum cholesterol concentration possibly by inhibiting the activity of lanosterol synthase as described earlier in vitro studies. Trial registration: ClinicalTrials.gov Identifier: NCT02648464.

Smartphone-Based Recognition of Heart Failure by Means of Microelectromechanical Sensors.

BACKGROUND: Heart failure (HF) is the leading cause of hospitalization in individuals over 65 years of age. Identifying noninvasive methods to detect HF may address the epidemic of HF. Seismocardiography which measures cardiac vibrations transmitted to the chest wall has recently emerged as a promising technology to detect HF. OBJECTIVES: In this multicenter study, the authors examined whether seismocardiography using commercially available smartphones can differentiate control subjects from patients with stage C HF. METHODS: Both inpatients and outpatients with HF were enrolled from Finland and the United States. Inpatients with HF were assessed within 2 days of admission, and outpatients were assessed in the ambulatory setting. In a prespecified pooled data analysis, algorithms were derived using logistic regression and then validated using a bootstrap aggregation method. RESULTS: A total of 217 participants with HF (174 inpatients and 172 outpatients) and 786 control subjects from cardiovascular clinics were enrolled. The mean age of participants with acute HF was 64 ± 13 years, 64.9% were male, left ventricular ejection fraction was 39% ± 15%, and median N-terminal pro-B-type natriuretic peptide was 5,778 ng/L (Q1-Q3: 1,933-6,703). The majority (74%) of participants with HF had reduced EF, and 38% had atrial fibrillation. Across both HF cohorts, the algorithms had an area under the receiver operating characteristic curve of 0.95 with a sensitivity of 85%, specificity of 90%, and accuracy of 89% for the detection of HF, with a decision threshold of 0.5. The positive and negative likelihood ratios were 8.50 and 0.17, respectively. The accuracy of the algorithms was not significantly different in subgroups based on age, sex, body mass index, and atrial fibrillation. CONCLUSIONS: Smartphone-based assessment of cardiac function using seismocardiography is feasible and differentiates patients with HF from control subjects with high diagnostic accuracy. (Recognition of Heart Failure With Micro Electro-mechanical Sensors FI; NCT04444583; Recognition of Heart Failure With Micro Electro-mechanical Sensors [NCT04378179]; Detection of Coronary Artery Disease With Micro Electro-mechanical Sensors; NCT04290091).

The effects of plant stanol ester consumption on arterial stiffness and endothelial function in adults: a randomised controlled clinical trial.

BACKGROUND: The hypocholesterolemic effect of plant stanol ester consumption has been studied extensively, but its effect on cardiovascular health has been less frequently investigated. We studied the effects of plant stanol esters (staest) on arterial stiffness and endothelial function in adults without lipid medication. METHODS: Ninety-two asymptomatic subjects, 35 men and 57 women, mean age of 50.8±1.0 years (SEM) were recruited from different commercial companies. It was randomized, controlled, double-blind, parallel trial and lasted 6 months. The staest group (n=46) consumed rapeseed oil-based spread enriched with staest (3.0 g of plant stanols/d), and controls (n=46) the same spread without staest. Arterial stiffness was assessed via the cardio-ankle vascular index (CAVI) in large and as an augmentation index (AI) in peripheral arteries, and endothelial function as reactive hyperemia index (RHI). Lipids and vascular endpoints were tested using analysis of variance for repeated measurements. RESULTS: At baseline, 28% of subjects had a normal LDL cholesterol level (≤3.0 mmol/l) and normal arterial stiffness (<8). After the intervention, in the staest group, serum total, LDL, and non-HDL cholesterol concentrations declined by 6.6, 10.2, and 10.6% compared with controls (p<0.001 for all). CAVI was unchanged in the whole study group, but in control men, CAVI tended to increase by 3.1% (p=0.06) but was unchanged in the staest men, thus the difference in the changes between groups was statistically significant (p=0.023). AI was unchanged in staest (1.96±2.47, NS) but increased by 3.30±1.83 in controls (p=0.034) i.e. the groups differed from each other (p=0.046). The reduction in LDL and non-HDL cholesterol levels achieved by staest was related to the improvement in RHI (r=-0.452, p=0.006 and -0.436, p=0.008). CONCLUSIONS: Lowering LDL and non-HDL cholesterol by 10% with staest for 6 months reduced arterial stiffness in small arteries. In subgroup analyses, staest also had a beneficial effect on arterial stiffness in large arteries in men and on endothelial function. Further research will be needed to confirm these results in different populations. TRIAL REGISTRATION: Clinical Trials Register # NCT01315964.

High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases?

Lowering elevated low-density lipoprotein cholesterol (LDL-C) concentrations reduces the risk of atherosclerotic cardiovascular diseases (ASCVDs). However, increasing evidence suggests that cholesterol metabolism may also be involved in the risk reduction of ASCVD events. In this review, we discuss if the different profiles of cholesterol metabolism, with a focus on high cholesterol absorption, are atherogenic, and what could be the possible mechanisms. The potential associations of cholesterol metabolism and the risk of ASCVDs are evaluated from genetic, metabolic, and population-based studies and lipid-lowering interventions. According to these studies, loss-of-function genetic variations in the small intestinal sterol transporters ABCG5 and ABCG8 result in high cholesterol absorption associated with low cholesterol synthesis, low cholesterol elimination from the body, and a high risk of ASCVDs. In contrast, loss-of-function genetic variations in another intestinal sterol transporter, NPC1L1 result in low cholesterol absorption associated with high cholesterol synthesis, elevated cholesterol elimination from the body, and low risk of ASCVDs. Statin monotherapy is not sufficient to reduce the ASCVD risk in cases of high cholesterol absorption, and these individuals need combination therapy of statin with cholesterol absorption inhibition. High cholesterol absorption, i.e., >60%, is estimated to occur in approximately one third of a population, so taking it into consideration is important to optimise lipid-lowering therapy to prevent atherosclerosis and reduce the risk of ASCVD events.

The effect of hydroxychloroquine on cholesterol metabolism in statin treated patients after myocardial infarction.

Background and aims: To evaluate the effect of hydroxychloroquine (HCQ) on serum and lipoprotein lipids and serum biomarkers of cholesterol synthesis and absorption in myocardial infarction patients with a high-dose statin. Methods: Myocardial infarction patients (n = 59) with a constant statin dose were randomized to receive hydroxychloroquine 300 mg (n = 31) or placebo (n = 28) daily for six months and followed up for one year. Results: Statin reduced total-c (-26 ± 22% in hydroxychloroquine and -28 ± 19% in placebo group, P = 0.931), LDL-c (-38 ± 26% vs. -44 ± 23%, respectively, P = 0.299), and cholesterol synthesis biomarkers zymostenol, desmosterol, and lathosterol ratios from baseline to one year (e.g., serum lathosterol ratio -17 ± 45% vs. -15 ± 41%, respectively, P < 0.001 for both, P = 0.623 between groups). Compensatorily, cholesterol absorption increased during the intervention (e.g., serum campesterol ratio 125 ± 90% vs. 113 ± 72%, respectively, P < 0.001 for both, P = 0.488 between groups). Hydroxychloroquine did not affect cholesterol concentrations or cholesterol absorption. It prevented the statin-induced increase in cholesterol precursor, desmosterol ratio, from six months to one year in the hydroxychloroquine group (P = 0.007 at one year compared to placebo). Conclusions: Combined with a high-dose statin, hydroxychloroquine had no additional effect on serum cholesterol concentration or cholesterol absorption. However, the findings suggest that hydroxychloroquine interferes with lanosterol synthesis, and thereafter, it temporarily interferes with the cholesterol synthesis pathway, best seen in halting the increase of the desmosterol ratio.Trial Registration ClinicalTrials.gov Identifier: NCT02648464.

Arterial function, biomarkers, carcinoid syndrome and carcinoid heart disease in patients with small intestinal neuroendocrine tumours.

PURPOSE: Carcinoid heart disease (CHD) is a life-threatening complication of carcinoid syndrome (CS) characterised by tricuspid regurgitation (TR). However, there is an unmet need for earlier diagnosis of CHD. We cross-sectionally assessed the prevalence and potential predictive or diagnostic markers for CS and CHD in a contemporary cohort of patients with small intestinal neuroendocrine tumours (SI-NETs). METHODS: Biochemical characteristics, hepatic tumour load, measures of arterial and endothelial function, atherosclerosis, and transthoracic echocardiography were analysed in a prospective cross-sectional setting. RESULTS: Among the 65 patients studied, 29 (45%) had CS (CS+ ), and 3 (5%) CHD. CS+ was characterised by significantly higher hepatic tumour load, S-5-HIAA and fP-CgA, higher frequency of diarrhoea and flushing, and more frequent PRRT compared to CS- (for all, P < 0.05). Central systolic, central mean, and central end-systolic blood pressures were significantly higher in CS+ than in CS- (for all, P < 0.05). Subjects with grades 2-4 TR had higher hepatic tumour burden, fP-CgA, and S-5-HIAA compared to those with grades 0-1 TR, but measures of vascular function did not differ. fP-CgA (P = 0.017) and S-5-HIAA (P = 0.019) but not proBNP increased significantly according to the severity of TR. CONCLUSION: Although CS is common, the prevalence of CHD was found to be lower in a contemporary cohort of SI-NET patients than previously anticipated. Measures of arterial or endothelial function or carotid atherosclerosis do not identify subjects with mild TR. Echocardiography remains the most sensitive means to diagnose CHD in CS patients with high tumour burden and elevated CgA and 5-HIAA.

Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose and lipoprotein metabolism. However, the metabolism of cholesterol in NAFLD remains unexplored. We investigated how fatty liver influences cholesterol metabolism in 242 non-diabetic subjects. METHODS: Liver fat content was measured with proton magnetic resonance spectroscopy. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of cholesterol synthesis and absorption. The analyses were performed with gas-liquid chromatography. RESULTS: A total of 114 subjects had NAFLD and 128 subjects had normal liver fat content. Non-cholesterol sterols reflecting cholesterol synthesis (cholestenol, desmosterol, and lathosterol) were higher, and those reflecting cholesterol absorption (cholestanol and plant sterols) were lower in subjects with NAFLD than in controls, independent of body mass index. Liver fat content was positively associated with markers of cholesterol synthesis (r = from 0.262 to 0.344, p < 0.001 for all) and inversely associated with markers of cholesterol absorption (r = from -0.299 to -0.336, p < 0.001 for all). In the entire study group, synthesis and absorption markers were interrelated, indicating that the homeostasis of cholesterol metabolism was maintained. LDL cholesterol was similar in the two groups. CONCLUSIONS: We demonstrated that although LDL cholesterol concentrations are unchanged, cholesterol metabolism in NAFLD is characterized by increased synthesis and diminished absorption of cholesterol. These changes are associated with liver fat content independent of body weight.

Obesity Does Not Interfere with the Cholesterol-Lowering Effect of Plant Stanol Ester Consumption (as Part of a Heart-Healthy Diet).

Dietary modifications including plant stanol ester consumption are recommended measures to control serum and low-density lipoprotein (LDL)-cholesterol concentrations, but obesity can affect their responses. We investigated whether body mass index (BMI) affects serum cholesterol levels during plant stanol (mainly sitostanol) ester consumption. This ad hoc analysis was based on earlier results of a cross-over, randomized controlled trial of postmenopausal women consuming rapeseed oil-based margarine without or with plant stanol ester (3 g plant stanols/day) for seven weeks. We classified the subjects as normal-weight (BMI ≤ 25 kg/m2, n = 9, mean 22.6 kg/m2) or overweight/obese (BMI > 25 kg/m2, n = 11, mean 28.4 kg/m2), and recalculated the results, focusing on cholesterol absorption, cholesterol synthesis, and fecal steroid outputs. Serum cholesterol levels were similar in the groups during the control diet. Plant stanol ester reduced serum cholesterol by 0.63 ± 0.19 mmol/L (11%) in normal-weight and by 0.75 ± 0.13 mmol/L (12%) in overweight/obese subjects (p < 0.05 for both), and cholesterol absorption was reduced in both groups. However, relative and dietary cholesterol absorption were more effectively reduced in normal-weight subjects. In conclusion, overweight/obesity did not interfere with the serum cholesterol response to plant stanol ester consumption despite substantial differences in cholesterol metabolism between the groups.

Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study.

Cholesterol synthesis is upregulated and absorption downregulated in insulin resistance and in type 2 diabetes. We investigated whether alterations in cholesterol metabolism are observed across the glucose tolerance status, from normoglycemia through impaired glucose tolerance to type 2 diabetes, in 781 randomly selected men 45 to 70 years of age from a population-based Metabolic Syndrome in Men Study. Cholesterol metabolism was assayed using surrogate serum markers, squalene, and noncholesterol sterols. The study population was classified into subgroups according to glucose tolerance as follows: normoglycemia, impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes. LDL cholesterol did not differ between the groups. Cholesterol synthesis markers were lowest and absorption markers highest in normoglycemia. Sitosterol was lower in subjects with impaired fasting glucose compared with normoglycemic subjects (113 +/- 7 vs. 136 +/- 3 10(2) mumol/mmol of cholesterol, P < 0.05). LDL cholesterol was not associated with lathosterol/sitosterol ratio, a marker of cholesterol metabolism. Peripheral insulin sensitivity evaluated by the Matsuda index was associated with the lathosterol/sitosterol ratio in the entire population (r = -0.457, P < 0.001) and with that of lathosterol/cholestanol independently of obesity. In conclusion, cholesterol metabolism was altered already from subjects with impaired fasting glucose. Upregulated cholesterol synthesis was associated with peripheral insulin resistance independent of obesity.