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.

Leakage of cardiac troponin I in aortic valve stenosis.

OBJECTIVE: Degeneration and death of cardiomyocytes contribute to the genesis of heart failure (HF) in aortic valve stenosis (AS). We studied whether the ongoing myocyte damage in AS can be detected from circulating cardiac troponin I (cTnI) concentrations. DESIGN AND SETTING: A cross-sectional cohort study in a university hospital. SUBJECTS AND METHODS: We examined 131 adult patients undergoing echocardiography and cardiac catheterization for isolated AS. Blood was sampled from the aortic root and, in a subset of 49 patients, also from the coronary sinus for the determination of cTnI using a sensitive immunoanalysis. RESULTS: Seventy-three patients (56%) had detectable aortic cTnI (> or =5 ng L(-1)) with 30 of them (23% of the total group) having cTnI above the reference limit in healthy subjects (>14 ng L(-1)). Patients with detectable cTnI had a higher prevalence of HF than those with undetectable cTnI (42% vs. 19%, P = 0.004). Plasma cTnI rose from the aorta to the coronary sinus by > or =5 ng L(-1) in 13 of 49 patients with AS (27%) versus in none of 12 control patients free of structural heart disease (P = 0.044). AS patients with transcardiac cTnI gradients > or =5 ng L(-1) had lower left ventricular (LV) ejection fractions than AS patients with gradients <5 ng L(-1) (mean +/- SD, 52 +/- 14% vs. 61 +/- 11%; P = 0.011). CONCLUSIONS: Detectable circulating cTnI is not uncommon in AS and shows a moderate association with the presence of HF. Leakage of cTnI into the coronary sinus associates with impairment of LV systolic function. Monitoring cTnI could provide a means to expose incipient clinical deterioration in AS.

Diagnosing heart failure in aortic valve stenosis.

OBJECTIVE: In aortic valve stenosis (AS), heart failure (HF) omens a high risk of death and is an indication for prompt valve replacement. We studied whether its detection can be facilitated by measuring plasma N-terminal B-type natriuretic peptide (Nt-BNP) or by estimating pulmonary capillary wedge pressure (PCWP) using echocardiography. DESIGN AND SETTING: A cross-sectional cohort study in a university hospital. SUBJECTS AND METHODS: We studied 137 consecutive adult patients referred to our unit for invasive evaluation of isolated AS. All patients underwent cardiac catheterization, measurement of plasma Nt-BNP and estimation of PCWP by Doppler echocardiography of transmitral and pulmonary venous flow velocities. The final diagnosis of HF was based on the combined criteria of dyspnoea on ordinary effort and PCWP >14 mmHg at cardiac catheterization. The performance of Nt-BNP and the PCWP estimate in the detection of HF were studied using receiver operating characteristic (ROC) analysis. RESULTS: Totally 42 patients had HF. A cardiologist's clinical diagnosis of HF had high specificity (94%) but poor sensitivity (66%). With an optimized cut-off point, plasma Nt-BNP had moderate sensitivity (77%) and specificity (79%) for HF; the ROC area was 0.83. The echocardiographic PCWP estimate classified 90% of patients correctly as having normal or truly elevated (>14 mmHg) PCWP. Its sensitivity and specificity for the diagnosis of HF were 80 and 95% respectively; the ROC area was 0.88. With a cut-off point of 12 mmHg, the sensitivity of the PCWP estimate was 85% and specificity, 88%. CONCLUSION: The recognition of HF in patients with AS can be improved by estimating PCWP using Doppler echocardiography of transmitral and pulmonary venous flow velocities.

Free fatty acid kinetics and oxidation in congestive heart failure.

To characterize fuel utilization of patients with congestive heart failure (CHF), we measured serum free fatty acid (FFA), counterregulatory hormone concentrations, whole body substrate oxidation rates (indirect calorimetry), and the turnover and oxidation rates of FFA ([1-(14)C]-palmitate infusion) in 7 patients with CHF and in 7 cardiac patients without CHF after an overnight fast. Plasma glucose and serum insulin concentrations were comparable, whereas serum FFA, blood ketone body, and fasting blood lactate (p <0.05 for all) concentrations were significantly increased in patients with CHF compared to those without CHF. Fasting plasma norepinephrine (p <0.05), serum cortisol (p <0.01), and growth hormone (p <0.01) concentrations were also higher in patients with CHF than in those without CHF. Rates of energy expenditure at rest (62 +/- 2 vs 56 +/- 1 J x kg(-1) x min(-1), p <0.05), FFA turnover (6.5 +/- 0.5 vs 5.0 +/- 0.4 micromol x kg(-1) x min(-1), p <0.05), and oxidation (2.0 +/- 0.2 vs 1.5 +/- 0.1 micromol x kg(-1) x min(-1)], p <0.05) were significantly higher in patients with CHF than in control subjects. In univariate analysis, the left ventricular ejection fraction was inversely correlated and the plasma norepinephrine concentration positively correlated with both energy expenditure at rest, FFA turnover, and the FFA oxidation rate. In multivariate analysis, the plasma norepinephrine concentration was the most significant predictor of increased FFA oxidation rate. We conclude that release of FFAs to the circulation and their subsequent oxidation are increased in patients with severe CHF after an overnight fast. These changes might reflect stress hormone-induced lipolysis and accompanying stimulation of serum FFA oxidation via mass action.

Heart failure ketosis.

OBJECTIVE: To assess whether blood ketone bodies are increased in congestive heart failure (CHF). METHODS: Thirteen patients with CHF and 11 cardiac patients without CHF took part in the study. Blood acetoacetate and b-hydroxybutyrate levels and the pertinent metabolic and hormonal milieu were measured during 20 h fast and after 2 h glucose infusion. RESULTS: The averaged blood ketone body and free fatty acid levels were significantly higher during the fast and also remained higher after glucose infusion in patients with CHF than in the control group. The areas under ketone body concentration time curve over the last 8 h of the fast were 3522 +/- 662 mumol L-1 h-1 (SE) and 1789 +/- 192 mumol L-1 h-1 in patients with and without CHF, respectively (P = 0.022). Circulating noradrenaline and growth hormone were higher but glucagon lower in patients with CHF than in the controls (P < 0.05 for all differences) whereas the glucose and insulin concentrations were comparable in the study groups. At the time of peak ketonaemia the glucagon-to-insulin ratio was lower in patients with CHF than in patients without CHF (P = 0.04). CONCLUSIONS: These data suggest that severe CHF is a ketosis-prone state. Augmented supply of free fatty acids for ketogenesis due to increased stress hormone-related lipolysis is one likely mechanism.

Haemodynamic, neuroendocrine and metabolic correlates of circulating cytokine concentrations in congestive heart failure.

OBJECTIVES: Increased activity of pro-inflammatory cytokines in the circulation has been observed in many, though not all, patients with congestive heart failure. To identify the predictors of cytokine activation in congestive heart failure, we assessed the relationship of peripheral and hepatic venous cytokines to central haemodynamics, neuroendocrine status and intermediary metabolism in patients with moderate or severe congestive heart failure. PATIENTS AND METHODS: Concentrations of tumour necrosis factor-alpha, soluble tumour necrosis factor-receptor II and interleukin 6 were measured from peripheral and hepatic venous plasma in 58 adult cardiac patients, of whom 44 had congestive heart failure, undergoing heart catheterization, echocardiography and assessment of selected neuroendocrine and metabolic characteristics. RESULTS: Peripheral venous soluble tumour necrosis factor-receptor II was directly related to NYHA class (rs = 0.46, P < 0.001) and inversely to 6-min walking distance (rs = -0.46, P < 0.001). Peripheral venous tumour necrosis factor-alpha was related to 6-min walking distance (rs = -0.37, P < 0.01), but like soluble tumour necrosis factor-receptor II, was unrelated to other haemodynamic and neuroendocrine measurements. Peripheral venous interleukin 6 correlated with NYHA class (rs = 0.66, P < 0.001) and 6-min walking distance (rs = -0.52, P < 0.001). In addition, interleukin 6 was related to right atrial pressure (rs = 0.55, P < 0.001), pulmonary artery wedge pressure (rs = 0.50, P < 0.001) and left ventricular ejection fraction (rs = -0.39, P < 0.01); in multivariate analysis, only right atrial pressure was an independent predictor of interleukin 6 concentration (P < 0.001). Comparisons between patients with and without congestive heart failure showed significantly higher hepatic venous tumour necrosis factor-alpha, soluble tumour necrosis factor-receptor II and interleukin 6 in the heart failure group; the differences in peripheral venous cytokines were less consistent. CONCLUSIONS: In cardiac patients, increased plasma tumour necrosis factor-alpha and soluble tumour necrosis factor-receptor II are associated with symptoms of heart failure and poor exercise capacity, while the most important predictor of increased interleukin 6 is elevated systemic venous pressure. Different but still unknown mechanisms may be responsible for the increased release of cytokines in congestive heart failure.

Blood ketone bodies in congestive heart failure.

OBJECTIVES: The present study was designed to assess whether blood ketone bodies are elevated in congestive heart failure (CHF) and whether ketonemia is related to the hemodynamic and neurohumoral abnormalities of CHF. BACKGROUND: In CHF, consumption of the body's fat stores may become abnormally high, contributing to the development of cardiac cachexia. Increased mobilization of free fatty acids could, in theory, augment ketogenesis, but whether patients with CHF are prone to ketosis remains unknown. METHODS: Forty-five patients with chronic CHF (mean age [+/- SD] 57 +/- 13 years) and 14 control subjects free of CHF (mean age 53 +/- 13 years) underwent invasive and noninvasive cardiac studies and determination of blood ketone bodies (acetoacetate plus beta-hydroxybutyrate), circulating free fatty acids, glucose, lactate, insulin, glucagon, growth hormone, cortisol, norepinephrine, N-terminal proatrial natriuretic peptide, tumor necrosis factor-alpha and interleukin-6 after an overnight fast. RESULTS: Patients with CHF had elevated blood ketone bodies (median 267 mumol/liter, range 44 to 952) compared with control subjects (median 150 mumol/liter, range 31 to 299, p < 0.05). In the total study group, blood ketone bodies were related to pulmonary artery wedge pressure (r5 = 0.45, p < 0.001), left ventricular ejection fraction (r3 = -0.37, p < 0.01), right atrial pressure (r3 = 0.36, p < 0.01) and circulating concentrations of free fatty acids (r5 = 0.52, p < 0.001), glucose (r5 = -0.39, p < 0.001), norepinephrine (r3 = 0.45, p < 0.001), growth hormone (r5 = 0.30, p < 0.05) and interleukin-6 (r3 = 0.27, p < 0.05). In multivariate analysis, left ventricular ejection fraction, serum free fatty acids and serum glucose were independent predictors of ketonemia. CONCLUSIONS: Blood ketone bodies are elevated in CHF in proportion to the severity of cardiac dysfunction and neurohormonal activation. This may be at least partly attributable to increased free fatty acid mobilization in response to augmented neurohormonal stimulation. Additional studies are needed to identify the detailed mechanisms and clinical implications of CHF ketosis.

Dependence of atrial sensing function on posture in a single-lead atrial triggered ventricular (VDD) pacemaker.

The influence of body posture on atrial sensing was examined in a single-lead VDD pacemaker in 16 patients. At implantation, a position was searched for the floating atrial bipolar sensor to obtain an adequate atrial signal amplitude. After 1-12 months the atrial signals were measured by programming the sensitivity in five postures: supine, sitting, and standing and lying on the right and left sides. The group mean amplitudes of the atrial signal were equal in all postures, and comparable to the supine value (1.01 +/- 0.51 mV). However, the values within each individual varied considerably according to position, by a range of 0.46 +/- 0.41 mV on average. Testing only supine did not always predict decent sensing when upright, e.g., in 3 patients the atrial signal decreased more than 0.5 mV. In 24-hour ambulatory electrocardiography, with the sensitivity (0.15-0.30 mV) set to cover all postures, atrial beats were undersensed not at all in 4 patients, < 0.01% in 6 patients, and < 0.1% in the remaining 6 patients. Thus, with a floating atrial electrode, sensitivity testing in various postures is advisable to ascertain proper sensing function.

Breath acetone in congestive heart failure.

To summarize, CHF predisposes to postabsorptive ketosis in relation to the severity of venous congestion. A simple and fully noninvasive measurement of breath acetone may add to the diagnostic assessment of patients with CHF.