Replacement of reduced highly unsaturated fatty acids (HUFA deficiency) in dilative heart failure: dosage of EPA/DHA and variability of adverse peroxides and aldehydes in dietary supplement fish oils.

OBJECTIVES: To explore the rationale for ω-3 fatty acids in heart failure treatment, the dosage of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) for replacing low levels of highly unsaturated fatty acids (HUFA deficiency) was examined. To judge the usefulness of various EPA/DHA preparations, their content of peroxides and aldehydes was determined. METHODS: In 298 patients with dilative heart failure, the serum HUFA level was assessed by gas chromatography. In ω-3-acid ethyl esters 90 (Omacor/Lovaza, approved by the Food and Drug Administration and the European Medicines Agency) and 63 dietary supplement fish oils, oxidation products were determined by photometry. RESULTS: Increasing serum HUFA from the lower (4.3 ± 1.0%) to the upper (9.5 ± 1.5%) tertile would be associated with an increased left ventricular (LV) ejection fraction (34.1 ± 9.9 vs. 28.3 ± 9.5%, p < 0.01) and reduced LV enddiastolic diameter (63.5 ± 7.1 vs. 66.9 ± 7.4 mm) requiring at least 2 g EPA/DHA daily. In fish oils, the peroxide and alkenal level varied greatly, i.e. peroxide value ≤ 5 mEq/kg in only 7 and ≤ 10 mEq/kg in 38 fish oils. Compared with equivalent doses of ω-3-acid ethyl esters 90, the mean peroxide intake would be 8.6 ± 6.1 and the alkenal intake 10.9 ± 4.4 times higher in fish oils. CONCLUSIONS: Levels of adverse oxidation products should be considered when targeting HUFA deficiency or treating patients with myocardial infarction or high triglycerides.

MR, CT, and PET imaging in pericardial disease.

Although echocardiography remains the standard diagnostic tool for identifying pericardial diseases, procedures with better delineation of morphology and heart function are often required. The pericardium consists of an inner visceral (epicardium) and outer parietal layer (pericardium), which constitute for the pericardial cavity. Pericardial effusion can occur as transudate, exudate, pyopneumopericardium, or hemopericardium. Potential causes are inflammatory processes, that is, pericarditis due to autoimmune or infective reasons, neoplasms, irradiation, or systemic disorders, chronic renal failure, endocrine, or metabolic diseases. Pericardial fat can mimic pericardial effusion. Using various image-acquisition sequences, MRI allows identifying and separating fluid and solid structures. Fast spin-echo T1-weighted sequences with black-blood preparation are favourably used for morphological evaluation. Fast spin-echo T2-weighted sequences, particularly with fat saturation, and short-tau inversion-recovery sequences are useful to visualize oedema and inflammation. For further tissue characterization, delayed inversion-recovery imaging is used. Therefore, image acquisition is performed at 5-20 min subsequent to contrast agent administration, the so-called technique of late gadolinium enhancement. Ventricular volumes and myocardial mass can be assessed accurately by steady-state free-precession sequences, which is required to measure cardiac function and ventricular wall stress. Constrictive pericarditis usually results from chronic inflammatory processes leading to increased stiffness, which impedes the slippage of both pericardial layers and thereby the normal cardiac filling. CT imaging can favourably assess pericardial calcification. Thus, MR and CT imaging allow a comprehensive delineation of the pericardium. Superior to echocardiography, both methods provide a larger field of view and depiction of the complete chest including abnormalities of the surrounding mediastinum and lungs. PET provides unique information on the in vivo metabolism of 18-fluorodeoxyglucose that can be superimposed on CT findings and is useful for identifying inflammatory processes or masses, for example neoplasms. These imaging techniques provide advanced information of anatomy and cardiac function to optimize the pericardial access, for example by the AttachLifter system, for diagnosis and treatment.

Mechanisms involved in the differential reduction of omega-3 and omega-6 highly unsaturated fatty acids by structural heart disease resulting in "HUFA deficiency".

The causes of reduced levels of omega-3 and omega-6 highly unsaturated fatty acids ("HUFA deficiency") in heart failure remain unresolved. HUFA profiles were examined in the serum of 331 patients with failing versus nonfailing heart disease. Arachidonic acid was positively correlated (P < 0.001) with eicosapentaenoic acid (EPA) (r = 0.40) and docosahexaenoic acid (DHA) (r = 0.53) and negatively with palmitic (r = 0.42), palmitoleic (r = 0.38), and oleic acid (r = 0.48). Delta-5 desaturase activity was reduced (P < 0.01) in heart failure patients with low ejection fraction, dilatation, increased wall stress, and reduced heart rate variability (SDNN). In these patients, the reduced (P < 0.01) HUFA and increased palmitic (P < 0.01) and oleic acid (P = 0.05) arose from separate influences involving reduced cardiac contractility (arachidonic acid and palmitic acid predicted by ejection fraction) and chamber dilatation (DHA and oleic acid predicted by end-diastolic diameter). A low DHA (0.2%-0.9% versus 1.4%-3.1%) was associated (P < 0.025) with atrial dilatation (44 ± 8 mm versus 40 ± 8 mm). Equidirectional but less pronounced effects on HUFA were induced by sympathetic activation and (or) insulin resistance (fat and sugar fed to deoxycorticosterone acetate (DOCA)-salt rats) but not by compensated cardiac overload alone (DOCA-salt or aortic constriction), or reduced fatty acid oxidation (CPT-1 inhibition). Based on administration of omega-3 HUFA (OMACOR), dilatation is identified as a target for 1-2 g omega-3 HUFA·day(-1). Interventions for reduced arachidonic acid remain to be explored.

Acute heart failure--basic pathomechanism and new drug targets.

In view of the high incidence of heart failure and sudden cardiac death, efforts in the development of compounds which target-specific mechanisms such as a reduced expression of SERCA2, the Ca2+ pump of sarcoplasmic reticulum, of hypertrophied cardiomyocytes of pressure-overloaded or infarcted hearts should be strengthened. Lead compounds for correcting a dysregulated gene expression are the carnitine palmitoyltransferase-1 (CPT-1) inhibitors etomoxir and oxfenicine. Since bypassing the CPT-1 inhibition by a medium-chain fatty acid diet had a lesser effect on myosin V1 proportion than on lipid droplet number, one has to infer also other mechanisms such as PPARalpha activation (FOXIB/PPARalpha). In view of the intricate interrelationship between depressed pump function and malignant arrhythmias, stimulation of endogenous antiarrhythmogenic mechanisms linked to an enhanced production of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could potentially provide alternatives to the administration of 1 g EPA and DHA ethyl esters (minimum 84% EPA + DHA) for secondary prevention of myocardial infarction. The apparently greater efficacy of omega-3 fatty acids in post-myocardial infarction patients (GISSI-Prevention study) compared with ICD patients (SOFA study) can be attributed to the greater ischemia-induced release of membrane-bound EPA and DHA and a better compliance (one vs. four capsules daily).

Microdetermination of fatty acids by gas chromatography and cardiovascular risk stratification by the "EPA+DHA level".

The therapeutic options for interfering with the electrical instability of a pathologically remodeled or ischaemic heart remain limited. Of increasing importance become interventions which target the fatty acid composition of blood and membrane lipids. In particular, the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide parameters for stratification of risks associated with severe arrhythmia disorders and sudden cardiac death. Since EPA and DHA appear to have their anti-arrhythmogenic actions when present as free fatty acids, the parameters which determine a critical free fatty acid concentration are of great interest. In the present study, conclusions on EPA and DHA incorporation in blood lipids are derived from the administration of Omacor which contains highly purified (84%) EPA and DHA ethyl esters and reduced the risk of sudden cardiac death by 45% in post-myocardial infarction patients (GISSI-Prevention study). The "EPA+DHA level" is described as risk identifying parameter for severe arrhythmia disorders, particularly if they are associated with myocardial ischaemia. It appears essential not only to build up body stores for release of EPA and DHA but to provide also a sustained uptake of EPA and DHA in the form of ethyl esters. In contrast to more rapidly absorbed triacylglycerols from fish, ethyl esters are taken up slowly within 24 h. For the administration of 1 g/day Omacor to healthy volunteers, it is shown that in whole blood EPA is increased from 0.6% to 1.4% within 10 days while DHA is increased from 2.9% to 4.3%. After withdrawal, the EPA and DHA levels approach baseline values within 10 days. A gas chromatographic procedure was established which requires only 10 microl of whole blood for the identification of more than 30 fatty acids. Evidence is summarized strengthening the concept that a low "EPA+DHA level" presents a risk for severe arrhythmia disorders and sudden cardiac death. The administration of 840 mg/day of EPA and DHA ethyl esters raises the "EPA+DHA level" to approximately 6% that is associated with protection from sudden cardiac death. The pharmacological effects of ethyl esters are compared with the naturally occurring EPA and DHA triacylglycerols present in fish or fish oils which are of interest in primary prevention of cardiovascular disorders.