Jyri Lommi

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.

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 bodys 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.

Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves

Objective—To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves. Methods and Results—Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V (P<0.05 for each) and a higher total cathepsin activity (P<0.001). In stenotic valves, cystatin C mRNA was increased (P<0.05), and cystatin C protein was found particularly in areas with infiltrates of inflammatory cells. Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization. Incubation of thin sections of aortic valves with cathepsins S, K, and V resulted in severe disruption of elastin fibers, and this cathepsin effect could be blocked by adding cystatin C to the incubation system. Conclusions—Stenotic aortic valves show increased expression and activity of elastolytic cathepsins S, K, and V. These cathepsins may accelerate the destruction of aortic valvular extracellular matrix, so promoting the progression of aortic stenosis.

Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression

Background— Giant-cell myocarditis often escapes diagnosis until autopsy or transplantation and has defied proper treatment trials for its rarity and deadly behavior. Current therapy rests on multiple-drug immunosuppression but its prognostic influence remains poorly known. We set out to analyze (1) our experience in diagnosing giant-cell myocarditis and (2) the outcome of patients on combined immunosuppression. Methods and Results— We reviewed the histories, diagnostic procedures, details of treatment, and outcome of 32 consecutive patients with histologically verified giant-cell myocarditis treated in our hospital since 1991. Twenty-six patients (81%) were diagnosed by endomyocardial or surgical biopsies and 6 at autopsy or post-transplantation. Twenty-eight (88%) patients underwent endomyocardial biopsy. The sensitivity of transvenous endomyocardial biopsy increased from 68% (19/28 patients) to 93% (26/28) after up to 2 repeat procedures. The 26 biopsy-diagnosed patients were treated with combined immunosuppression (2–4 drugs) including cyclosporine in 20 patients. The Kaplan-Meier estimates of transplant-free survival from symptom onset were 69% at 1 year, 58% at 2 years, and 52% at 5 years. Of the transplant-free survivors, 10/17 (59%) experienced sustained ventricular tachyarrhythmias during follow-up and 3 received intracardiac defibrillator shocks for ventricular tachycardia or fibrillation. Conclusions— Repeat endomyocardial biopsies are frequently needed to diagnose giant-cell myocarditis. On contemporary immunosuppession, two thirds of patients reach a partial clinical remission characterized by freedom from severe heart failure and need of transplantation but continuing proneness to ventricular tachyarrhythmias.

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.

Increased circulating concentrations and augmented myocardial extraction of osteoprotegerin in heart failure due to left ventricular pressure overload.

Osteoprotegerin (OPG) and the receptor activator of nuclear factor‐kB ligand (RANKL), two cytokines regulating bone remodeling, have recently been raised as potential pathogenetic factors in cardiovascular diseases. We have studied circulating and myocardial OPG and RANKL in patients having severe aortic stenosis (AS) with or without heart failure (HF).

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.

Is the pregnancy hormone relaxin an important player in human heart failure

The pregnancy hormone relaxin has been raised as a new compensatory mediator of cardiac origin in heart failure (HF). We set out to assess the role of relaxin in pressure overload‐induced human HF.

Heart failure ketosis

Lommi J, Koskinen P, Näveri M, Härkönen M, Kupari M (Helsinki University Central Hospital, Helsinki, Finland). Heart failure ketosis. J Intern Med 1997; 242: 231–8.

Natural course and risk factors for impaired renal function during the first year after heart transplantation

BACKGROUND Post-operative renal failure is a common and potentially hazardous complication after heart transplantation (HTx). In this study we characterized pre- and post-operative risk factors for acute renal failure requiring renal replacement therapy (RRT). METHODS Ninety-three patients underwent orthotopic HTx between 2000 and 2007. The risk factors for RRT during the early post-operative period and predictors contributing to impaired renal function within the first post-transplant year were analyzed by regression analysis. The impact of pre-operative renal failure and early post-operative RRT on renal function within 1 year were studied. RESULTS Before HTx, 55% of patients (51 of 93) had normal renal function or mild renal failure (glomerular filtration rate [GFR] >60 ml/min/1.73 m(2)). Before discharge from the hospital, 25% (23 of 93) developed acute renal failure and required RRT. Of these, 16% (8 of 51) had pre-operatively normal renal function or mild renal failure, and 36% (15 of 42) had moderate or severe renal failure (GFR <60 ml/min/1.73 m(2); p = 0.02). The prognosticators for early RRT were prolonged graft dysfunction, re-admission to the operating room due to post-operative bleeding, poor diuresis during surgery (<1,000 ml), pre-operative pacemaker implantation, intubation time >24 hours, pre-operative GFR <60 ml/min/1.73 m(2), post-operative troponin T >6 microg/liter and pre-operative use of angiotensin receptor blocker. CONCLUSIONS Pre-operative renal failure is a significant risk factor for RRT during the immediate post-operative period and requires aggressive treatment. Patients with pre-operative renal failure secondary to severe heart failure and acute post-operative renal failure requiring RRT tend to recover within the first year post-HTx.