Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase

Background We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism. Objective Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies. Methods and Results We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity. Conclusion These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.Peer reviewe

Vasemman kammion mekaaninen tukihoito : siltahoito tai vaihtoehto sydämensiirrolle

Sydämen vajaatoiminnan osuus ihmisten sairastuvuudessa ja kuolleisuudessa on edelleen merkittävä lääke- ja muun hoidon kehityksestä huolimatta. Sydämensiirto on paras loppuvaiheen vaikeaa sydämen vajaatoimintaa sairastavan potilaan hoitomuoto, kun mikään muu hoito ei auta. Sydämensiirtojen määrää rajoittaa kuitenkin pula siirrännäisistä. Aikaisemmin verenkierron mekaanista tukihoitoa käytettiin lyhytaikaisena siltahoitona vajaatoiminnan ­loppuvaiheesta sydämensiirtoon. Viime vuosina tapahtunut kehitys on moninkertaistunut verenkierron mekaanisen tukihoidon käytön vaikeassa sydämen vajaatoiminnassa siltahoitona tai vaihtoehtona sydämensiirrolle. Mekaanisesti sydämen vasenta kammiota ja systeemiverenkiertoa tukevasta hoidosta saattaa tulla merkittävä vaihtoehto sydämensiirrolle, sillä tarkasti valikoiduilla potilailla kahden vuoden elinajan ennuste lähentelee sydämensiirtopotilaiden ennustetta.Peer reviewe

Outcomes after coronary artery bypass grafting and percutaneous coronary intervention in diabetic and non-diabetic patients

AimsTo assess the prognosis of patients with coronary heart disease (CHD) after first myocardial revascularisation procedure in real world practice and to compare the differences in outcomes of coronary artery by-pass grafting (CABG) and percutaneous coronary intervention (PCI) among diabetic and non-diabetic patients.Methods and resultsA database was compiled from the national hospital discharge register to collect data on all cardiac revascularisations performed in Finland in 2000-2015. The outcomes (all-cause deaths, cardiovascular (CV) deaths, major CV events and need for repeat revascularisation) after the first revascularisation were identified from the national registers at 28-day, 1-year and 3-year time points.A total of 139,242 first-time revascularisations (89,493 PCI and 49,749 CABG) were performed during the study period. Of all the revascularized patients, 24% had diabetes, and 76% were non-diabetic patients. At day 28 the risk of fatal outcomes was lower after PCI than after CABG among non-diabetic patients, whereas no difference was seen among diabetic patients. In long-term follow-up the situation was reversed with PCI showing higher risk compared with CABG for most of the outcomes. In particular, at three-year follow-up the risk of all-cause deaths was elevated among diabetic patients (HR 1.30 (95% CI 1.22-1.38) comparing PCI with CABG) more than among non-diabetic patients (HR 1.09 (1.04-1.15)). The same was true for CV deaths (HR 1.29 (1.20-1.38) among diabetic patients, and HR 1.03 (0.98-1.08) among non-diabetic patients).ConclusionAlthough PCI was associated with better 28-day prognosis, CABG seemed to produce better long-term prognosis especially among diabetic patients.</p

Assessment of Metabolic Phenotypes in Patients with Non-ischemic Dilated Cardiomyopathy Undergoing Cardiac Resynchronization Therapy

Studies of myocardial metabolism have reported that contractile performance at a given myocardial oxygen consumption (MVO2) can be lower when the heart is oxidizing fatty acids rather than glucose or lactate. The objective of this study is to assess the prognostic value of myocardial metabolic phenotypes in identifying non-responders among non-ischemic dilated cardiomyopathy (NIDCM) patients undergoing cardiac resynchronization therapy (CRT). Arterial and coronary sinus plasma concentrations of oxygen, glucose, lactate, pyruvate, free fatty acids (FFA), and 22 amino acids were obtained from 19 male and 2 female patients (mean age 56 ± 16) with NIDCM undergoing CRT. Metabolite fluxes/MVO2 and extraction fractions were calculated. Flux balance analysis (FBA) was performed with MetaFluxNet 1.8 on a metabolic network of the cardiac mitochondria (189 reactions, 230 metabolites) reconstructed from mitochondrial proteomic data (615 proteins) from human heart tissue. Non-responders based on left ventricular ejection fraction (LVEF) demonstrated a greater mean FFA extraction fraction (35% ± 17%) than responders [18 ± 10%, p = 0.0098, area under the estimated ROC curve (AUC) was 0.8238, S.E. 0.1115]. Calculated adenosine triphosphate (ATP)/MVO2 using FBA correlated with change in New York Heart Association (NYHA) class (rho = 0.63, p = 0.0298; AUC = 0.8381, S.E. 0.1316). Non-responders based on both LVEF and NYHA demonstrated a greater mean FFA uptake/MVO2 (0.115 ± 0.112) than responders (0.034 ± 0.030, p = 0.0171; AUC = 0.8593, S.E. 0.0965). Myocardial FFA flux and calculated maximal ATP synthesis flux using FBA may be helpful as biomarkers in identifying non-responders among NIDCM patients undergoing CRT

Acute coronary syndromes and acute heart failure:a diagnostic dilemma and high-risk combination. A statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology

Acute coronary syndrome is a precipitant of acute heart failure in a substantial proportion of cases, and the presence of both conditions is associated with a higher risk of short-term mortality compared to acute coronary syndrome alone. The diagnosis of acute coronary syndrome in the setting of acute heart failure can be challenging. Patients may present with atypical or absent chest pain, electrocardiograms can be confounded by pre-existing abnormalities, and cardiac biomarkers are frequently elevated in patients with chronic or acute heart failure, independently of acute coronary syndrome. It is important to distinguish transient or limited myocardial injury from primary myocardial infarction due to vascular events in patients presenting with acute heart failure. This paper outlines various clinical scenarios to help differentiate between these conditions and aims to provide clinicians with tools to aid in the recognition of acute coronary syndrome as a cause of acute heart failure. Interpretation of electrocardiogram and biomarker findings, and imaging techniques that may be helpful in the diagnostic work-up are described. Guidelines recommend an immediate invasive strategy for patients with acute heart failure and acute coronary syndrome, regardless of electrocardiographic or biomarker findings. Pharmacological management of patients with acute coronary syndrome and acute heart failure should follow guidelines for each of these syndromes, with priority given to time-sensitive therapies for both. Studies conducted specifically in patients with the combination of acute coronary syndrome and acute heart failure are needed to better define the management of these patients

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC

2016 ESC on Acute and Chronic H

Highlights of the 2009 scientific sessions of the European Society of Cardiology

The annual congress of the European Society of Cardiology (ESC) was held in Barcelona, Spain, August 29 to September 2, 2009. The total attendance was 31,323 participants from 136 different countries. Excellent congress facilities hosted 237 pre-arranged sessions in 30 meeting rooms running in parallel, including several joint sessions in collaboration with other societies (e.g., the American College of Cardiology, the American Heart Association, and the World Heart Federation). A total of 9,848 abstracts from 96 different countries was submitted, and 4,085 (42%) abstracts were selected for presentation