Abnormal mitochondrial function in myocardium of dogs with chronic heart failure

Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria that include hyperplasia, reduced organelle size and compromised structural integrity. In the present study, we examined mitochondrial respiration in myocardium of 10 normal dogs and 10 dogs with chronic HF (LV ejection fraction 24+/-2%) produced by intracoronary micro-embolizations. Mitochondrial respiratory rates were determined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Basal respiratory rate (VO), respiratory rate after addition of substrates, glutamate and malate (VSUB) and state 3 respiratory rate (VADP, after addition of ADP), were measured in tissue samples from the subendocardial and subepicardial LV free wall, interventricular septum and right-ventricular free wall. No differences were observed in basal respiratory rates between normal and HF tissue, while VSUB was significantly lower in HF compared to normal. VADP was 50-60% lower in HF compared to normal tissue (P<0.001). The results indicate abnormal mitochondrial respiratory activity in myocardium of dogs with chronic HF. These findings support the concept of low myocardial energy production in HF that can contribute to the global cardiac dysfunction.     

Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure

It is often speculated that progressive deterioration of left ventricular function in heart failure is due to ongoing loss of viable cardiocytes. In this study, we examined the possibility that cardiocyte loss in heart failure may be due, in part, to apoptosis, an active process of gene-directed cellular self-destruction. Studies were performed in left ventricular tissue obtained from 10 dogs with chronic heart failure produced by multiple intracoronary microembolizations (left ventricular ejection fraction 27 +/- 1%) and from 5 normal dogs. Evidence for cardiocyte apoptosis was based on transmission electron microscopy criteria and on in situ immunohistochemical labeling of nuclear DNA fragmentation. There was no evidence of apoptotic cardiocytes in normal dogs. Features of cardiocyte apoptosis were observed in dogs with heart failure primarily in regions bordering old infarcts. Electron microscopic features of cardiocyte apoptosis included (1) intact sarcolemma and inner organelles in the presence of compaction and segregation of nuclear chromatin into sharply delineated masses that about the nuclear envelope, (2) intact sarcolemma in the presence of cytoplasm shrinkage, blebbing, and nuclear fragmentation, and (3) intact sarcolemma in the presence of complete disorganization of inner organelles and disappearance of nucleolemma. A count of all of the apoptotic bodies positively labeled for nuclear DNA fragments showed that 11% were of cardiocyte origin confirmed by positive labeling with striated muscle antimyosin antibody. We conclude that morphological and biochemical features of cardiocyte apoptosis exist in the left ventricular myocardium of dogs with chronic heart failure.     

Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure

OBJECTIVES: The aim of this study was to assess the potential acute benefit of multisite cardiac pacing with optimized atrioventricular synchrony and simultaneous biventricular pacing in patients with drug-refractory congestive heart failure (CHF). BACKGROUND: Prognosis and quality of life in severe CHF are poor. Various nonpharmacological therapies have been evaluated but are restricted in their effectiveness and applications. In the early 1990s, dual chamber pacing (DDD) pacing was proposed as primary treatment of refractory CHF but results were controversial. Recently, tests to evaluate the effect of simultaneous pacing of both ventricles have elicited a significant improvement of cardiac performance. METHODS: Acute hemodynamic study was conducted in 18 patients with severe CHF (New York Heart Association class III and IV) and major intraventricular conduction block (IVCB) (QRS duration = 170+/-37 ms). Using a Swan-Ganz catheter, pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were measured in different pacing configurations: atrial pacing (AAI) mode, used as reference, single-site right ventricular DDD pacing and biventricular pacing with the right ventricular lead placed either at the apex or at the outflow tract. RESULTS: The CI was significantly increased by biventricular pacing in comparison with AAI or right ventricular (RV). DDD pacing (2.7+/-0.7 vs. 2+/-0.5 and 2.4+/-0.6 l/min/m2, p < 0.001). The PCWP also decreased significantly during biventricular pacing, compared with AAI (22+/-8 vs. 27+/-9 mm Hg; p < 0.001). CONCLUSIONS: This acute hemodynamic study demonstrated that biventricular DDD pacing may significantly improve cardiac performance in patients with IVCB and with severe heart failure, in comparison with intrinsic conduction and single-site RV DDD pacing.     

Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure

BACKGROUND: The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown. METHODS AND RESULTS: Thirty-six men (mean age+/-SD, 55+/-8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4+/-4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (-24.2% [-28.1% to -20.3%]) and pulmonary (-19.9% [-28.4% to -11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15. 2% [10.8% to 19.6%]) and systemic (-9.3% [-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to -3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged. CONCLUSIONS: Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.     

Decreased proportion of type I myofibers in skeletal muscle of dogs with chronic heart failure

BACKGROUND: Whether biochemical and histological abnormalities of skeletal muscle (SM) develop in patients with chronic heart failure (HF) remains controversial. In the present study, dogs with chronic HF were used to examine potential alterations of SM fiber type, fiber size, number of capillaries per fiber (C/F), beta-adrenergic receptor density (Bmax), and fiber ultrastructural integrity. METHODS AND RESULTS: HF was produced in 17 dogs by sequential intracoronary microembolizations. Biopsies of the lateral head of the triceps muscle were used in all studies. Type I and type II fibers were differentiated by myofibrillar ATPase (pH 9.4 or 4.2). Bmax was assessed by radioligand binding and SM ultrastructure by transmission electron microscopy. Comparisons were made with biopsies obtained from nine control dogs. The percentage of SM type I fibers was reduced in HF dogs compared with control dogs (19 +/- 2% versus 32 +/- 5%) (p < 0.001), whereas the percentage of SM type II fibers was increased (81 +/- 2% versus 68 +/- 5%) (p < 0.001). The change in fiber type composition was not associated with a preferential atrophy or hypertrophy of either fiber type. There was no difference in SM Bmax (198.9 +/- 14.3 versus 186.8 +/- 17.3 fmol/mg protein) or in C/F (5.37 +/- 0.26 versus 5.84 +/- 0.21) between HF dogs and control dogs. No ultrastructural abnormalities were present in SM fibers of HF dogs. CONCLUSIONS: In dogs with HF, there is a decrease in the relative composition of the slow-twitch type I SM fibers and an increase in fast-twitch type II fibers. The shift in fiber type composition is not associated with preferential atrophy of either fiber type or with a reduction in C/F, beta-adrenergic receptor density, or structural abnormalities of the myofibers.     

Vascular and cardiac effects of amlodipine in acute heart failure in dogs

BACKGROUND: Amlodipine improves exercise capacity in patients with chronic congestive heart failure (HF), but the mechanisms of this effect are unknown. OBJECTIVE: To test the hypothesis, in a canine model of acute, ischemic HF, that amlodipine increases vascular capacitance and reduces cardiac filling pressures. METHODS: Amlodipine was given to 13 anesthetized, splenectomized dogs (six controls and seven with HF). Aortic, left ventricular end-diastolic (LVEDP) and portal venous (Pportal) pressures, cardiac output, portal flow (ultrasonic probe) and intestinal blood volume (IBV, 99mTc blood-pool scintigraphy) were measured. Intestinal vascular conductance (= 1/resistance) and vascular capacitance (CAP) were measured before and 15 mins after repetitive 150 micrograms/kg dosages of amlodipine (maximum cumulative dosage, 1000 micrograms/kg). Pportal-IBV curves were obtained by impeding portal flow (pneumatic cuff), and change in CAP was defined by the change in IBV at Pportal = 7.5 mmHg. HF was induced by microsphere embolization of the left coronary artery. RESULTS: CAP increased in the control group (+ 28%, P < 0.01) but decreased (-9%, P < 0.05) in the HF group. Left ventricular stroke work increased in the control group (P < 0.05), while it decreased (P < 0.05) in the HF group, suggesting a negative inotropic effect. In the control group, LVEDP increased after amlodipine was given (P < 0.05) but did not change significantly in the HF group. CONCLUSIONS: In the acute experimental HF model, amlodipine failed to increase intestinal vascular CAP or decrease filling pressures, and may have had a negative inotropic effect. The experiment failed to demonstrate a beneficial hemodynamic effect of amlodipine in acute HF, and the mechanism of benefit of this agent in chronic HF remains unclear.     

Hemodynamic and autonomic effects of intravenous saterinone in patients with chronic heart failure

In this study, the hemodynamic and neurohumoral/autonomic effects of intravenous saterinone (a selective phosphodiesterase type III inhibitor, with additional alpha 1-blocking properties) were evaluated. In a double-blind, placebo-controlled design, 36 patients with moderate to severe heart failure were studied (saterinone, n = 24; placebo, n = 12). Invasive hemodynamic measurements, by using right-heart catheterization, were performed, as well as measurement of plasma neurohormones and analysis of heart rate variability (HRV), to study drug influences on neurohumoral activation and autonomic tone. Systemic vascular resistance significantly decreased during saterinone infusion, accompanied by a decrease in systemic blood pressure (both p values < 0.05) and an increase in heart rate (p = 0.05). Filling pressures also decreased during saterinone, but this was statistically significant only for pulmonary capillary wedge pressure, whereas the cardiac index remained unaffected. Plasma neurohormones (norepinephrine, epinephrine, and renin activity) were not significantly influenced by saterinone. HRV analysis revealed no significant effect of saterinone on autonomic tone. These results suggest that intravenous saterinone has a significant vasodilating effect in patients with moderate to severe chronic heart failure (CHF), without exerting an adverse effect on the autonomic nervous system, as demonstrated by assessment of plasma neurohormones and HRV analysis.     

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure

Insulin-like growth factor I (IGF-I) enhances myofibrillar development in cardiomyocytes of rats in culture and in vivo. In addition, IGF-I has vasodilatory effects and improves cardiac function in healthy volunteers. This study was conducted to evaluate the acute hemodynamic effects of IGF-I in patients with chronic heart failure Eight patients with chronic heart failure were randomized to receive recombinant human IGF-I (60 micrograms/kg) or placebo, i.v., over 4 h in a cross-over, double blind study on 2 consecutive days. Electrocardiogram as well as systemic hemodynamics were continuously monitored over 7 h by flow-guided thermodilution and radial artery catheters. IGF-I was well tolerated by all patients, and no pathological changes on electrocardiogram were recorded. Compared with placebo, IGF-I increased the cardiac index by 27 +/- 3.7% (+/- SE; P < 0.0005) and the stroke volume index by 21 +/- 5.6% (P < 0.05), and decreased systemic vascular resistance by 28 +/- 4.4% (P < 0.0002), right atrial pressure by 33 +/- 9.0% (P < 0.003), and pulmonary artery wedge pressure by 25 +/- 6.1% (P < 0.03). Mean systemic and pulmonary artery pressure as well as heart rate and pulmonary vascular resistance were not significantly influenced by IGF-I treatment. Insulin and C peptide levels were decreased by IGF-I, whereas glucose and electrolyte levels remained unchanged. Urinary levels of norepinephrine decreased significantly (P < 0.05) during IGF-I infusion. Thus, acute administration of IGF-I in patients with chronic heart failure is safe and improves cardiac performance by afterload reduction and possibly by positive inotropic effects. Further investigations to establish whether the observed acute effects of IGF-I are maintained during chronic therapy appear to be warranted.     

Beta blockade in congestive heart failure: persistent adverse haemodynamic effects during chronic treatment with subsequent doses

Widespread osteoporosis testing and diagnosis are currently limited due to the high capital cost and reduced portability of many existing bone densitometry techniques. In this study we evaluated an inexpensive, low radiation, X-ray-based technique for assessing bone density of the middle phalanx. The technique, termed computed digital absorptiometry (CDA), is similar to radiographic absorptiometry (RA), using a single-energy X-ray source, an aluminum alloy step-wedge, and a charge-coupled device (CCD) detector system to automatically compute bone mineral content (BMC, g) and bone mineral density (BMD, g/cm2) in the middle phalanx of the third finger. The potential advantage of CDA over current RA techniques is that by using a filmless detector system, no off-site processing of radiographs is required and bone density results are obtained immediately after the test. Using human cadaveric specimens we determined the accuracy and short-term precision of CDA as well as its correlation with other hand and forearm bone densitometry methods. We obtained 26 cadaveric forearms (50% female, mean age 78 years, range 52-96 years). BMC and BMD of the middle phalanx of the third finger were determined using CDA and using RA. We assessed forearm BMC and BMD using single-energy and dualenergy X-ray absorptiometry (SXA and DXA). Precision of CDA was assessed by measuring ten of the specimens five times each with repositioning between measurements. Finally, the middle phalanx was dissected and incinerated to determine ash weight. BMC estimates from CDA and from RA were strongly correlated with ash weight (r = 0.89, p < 0.001 and r = 0.93, p < 0.001, respectively). The mean coefficients of variation using CDA were 1.36% and 0.70% for phalanx BMC and BMD, respectively. BMC and BMD measured by CDA were strongly correlated with hand and forearm bone mineral measurements performed by SXA, DXA and RA (r = 0.74-0.91). These results indicate that CDA accurately and precisely predicts BMC of the middle phalanx. Thus, with further clinical verification, this technique may prove to be a useful tool for the widespread testing and assessment of osteoporotic fracture risk.     

Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure

OBJECTIVE: In isolated cardiac preparations of non-failing hearts from different species, including man, there is a positive force-frequency relation which is reversed into a negative relation in preparation from failing hearts. Whether or not such relations between ventricular function and heart rate hold true in the in situ heart is not clear at present. Mechanical restitution and postextrasystolic potentiation might serve as alternative measures of excitation-contraction coupling. METHODS: Eleven dogs were instrumented with a left ventricular micromanometer, ultrasonic crystals for the measurement of regional wall thickness, two hydraulic occluders around the descending aorta and the inferior caval vein, and left atrial and ventricular pacing leads with a subcutaneous pacemaker. Left ventricular dP/dtmax, as an isovolumic phase index, and systolic wall thickening, as an ejection phase index, were plotted versus heart rate, and heart rate was increased by left atrial pacing from rest to 200 min-1 in increments of 25 min-1. In a subset of dogs, left ventricular filling was controlled and the frequency range expanded by the bradycardic agent UL-FS 49. Measurements were performed in the presence and absence of autonomic blockade (hexamethonium, atropine). Mechanical restitution and postextrasystolic potentiation were determined as normalized dP/dtmax and systolic wall thickening, respectively, of the extra- and postextrasystolic beat versus defined variations of the extrasystolic time interval (250-550 ms). Following control studies, heart failure was induced by rapid left ventricular pacing at 250 min-1 for 20 days +/- 6 (SD) and measurements repeated. Isolated left ventricular trabeculae from non-failing and failing hearts were studied during stimulation at 0.2-4 Hz. RESULTS: Only with filling control and in the absence of autonomic blockade, was there a slightly positive relation between dP/dtmax and heart rate in the control state. Otherwise, the relation of dP/dtmax to heart rate was flat both in the control state and in heart failure. The relation between systolic wall thickening and heart rate in the control state was negative, unless filling was controlled, and it was flat in heart failure. In contrast, the time constants of mechanical restitution and postextrasystolic potentiation were increased significantly with heart failure from 91 +/- 25 (SD) to 164 +/- 13 ms and from 107 +/- 18 to 156 +/- 4 ms, respectively, for dP/dtmax and from 76 +/- 22 to 162 +/- 10 ms and from 101 +/- 17 to 160 +/- 17 ms, respectively, for systolic wall thickening. These time constants were, however, insensitive to UL-FS 49 and autonomic blockade. There was a negative force-frequency relation in left ventricular trabeculae from non-failing hearts at higher calcium concentrations, where it was flat in trabeculae from failing hearts. CONCLUSION: Time constants of mechanical restitution and postextrasystolic potentiation are more sensitive than the steady state relation of ventricular function and heart rate to characterize the impairment of excitation-contraction coupling in heart failure.     

Pharmacokinetics and hypotensive effect of diltiazem in rabbits: comparison of diltiazem with its major metabolites

To assess the contribution of its metabolites to the antihypertensive effects of diltiazem, a previously established rabbit model has been used to compare the pharmacokinetics and haemodynamic effects of the drug with those of its major metabolites deacetyldiltiazem (M1) and deacetyl-N-monodemethyldiltiazem (M2). Diltiazem, M1 and M2 were administered separately to each animal (n = 5 or 6 per study group) as a single 5 mg kg(-1) intravenous dose. Blood samples, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to 8 h, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites were determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vdss) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SBP and DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P > 0.05). These results indicate that diltiazem is a more potent hypotensive agent than M1 or M2, possibly because of the higher plasma concentrations secondary to the smaller CL and Vdss of diltiazem compared with the metabolites. The effects of the metabolites might, however, be more sustained.     

Management of chronic heart failure

Throughout the last years the concept and methods of treatment of chronic heart failure have considerably changed. The objective of the treatment is not only the relief of the symptoms, but also prevention of the onset and progression of the disease. The emphasis of treatment aims to moderate the increased neuroendocrine activity and thus to prevent myocardial damage. This review summarizes our knowledge concerning the treatment of chronic heart failure due to left ventricular dysfunction. It is based on former American guidelines and especially on the guideline of the Task Force of the European Society of Cardiology. The treatment of systolic and diastolic dysfunction of left ventricle are separately discussed. Emphasis is laid on the non pharmacologic treatment of heart failure. The treatment with ACE-inhibitors, diuretics, betablockers, digitalis, calcium antagonists and other drugs as well as the invasive procedures are also discussed.     

Uric acid in chronic heart failure: a marker of chronic inflammation

BACKGROUND: Chronic heart failure is associated with hyperuricaemia and elevations in circulating markers of inflammation. Activation of xanthine oxidase, through free radical release, causes leukocyte and endothelial cell activation. Associations could therefore be expected between serum uric acid level, as a marker of increased xanthine oxidase activity, and markers of inflammation. We have explored these associations in patients with chronic heart failure, taking into account the hyperuricaemic effects of diuretic therapy and insulin resistance. METHODS AND RESULTS: Circulating uric acid and markers of inflammation were measured in 39 male patients with chronic heart failure and 16 healthy controls. All patients underwent a metabolic assessment, which provided a measure of insulin sensitivity (intravenous glucose tolerance tests and minimal modelling analysis). Compared to controls, patients with chronic heart failure had significantly higher levels of circulating uric acid, interleukin-6, soluble tumour necrosis factor receptor (sTNFR)-1, soluble intercellular adhesion molecule-1 (ICAM-1, all P<0.001), E-selectin and sTNFR2 (both P<0.05). In patients with chronic heart failure, serum uric acid concentrations correlated with circulating levels of sTNFR1 (r=0.74), interleukin-6 (r=0.66), sTNFR2 (r=0.63), TNFa (r=0.60) (all P<0.001), and ICAM-1 (r=0.41, P<0.01). In stepwise regression analyses, serum uric acid emerged as the strongest predictor of ICAM-1, interleukin-6, TNF, sTNFR1 and sTNFR2, independent of diuretic dose, age, body mass index, alcohol intake, serum creatinine, plasma insulin and glucose, and insulin sensitivity. CONCLUSIONS: Serum uric acid is strongly related to circulating markers of inflammation in patients with chronic heart failure. This is consistent with a role for increased xanthine oxidase activity in the inflammatory response in patients with chronic heart failure.     

Outpatient management program of patients with chronic heart failure

Hospitalization of patients with heart failure is often caused by poor adherence to drug therapy, by suboptimal utilization of ACE inhibitors and beta-blockers, and by the lack of systematic monitoring of patients after discharge. The aim of the study is to verify the impact of an outpatient management program on the hospitalization rate and functional status of patients with chronic heart failure. Over a five-year period, 435 patients entered our outpatient management program, which includes adjustment in medical therapy, patient education and visits timed according to the patient's status. Fifty-six percent of the patients were in New York Heart functional class I-II; 74% were male; mean age was 62 +/- 11 years. Heart failure was due to coronary heart disease in 42%, dilated cardiomyopathy in 35%, hypertensive heart disease in 13%, other etiologies in 10%. The following changes in medical therapy were made compared to the period before referral: ACE inhibitors in 88% of the patients vs 70% (p < 0.05), mean dose of enalapril and captopril respectively 18 +/- 6 mg vs 11 +/- 4 mg (p < 0.05) and 89 +/- 28 mg vs 61 +/- 34 mg (p < 0.05); digoxin in 71 vs 70% (NS); furosemide in 90 vs 87%; beta-blockers in 16 vs 6% (p < 0.05); amiodarone in 24 vs 16% (p < 0.05); oral anticoagulants in 22 vs 12% (p < 0.05); calcium channel blockers in 10 vs 16% (p < 0.05). During the follow-up period (35 +/- 11 months), there were 111 hospital admissions compared to 518 during the year before recruitment (p < 0.05). Seventy-two patients died (65 for cardiac causes) and four patients underwent cardiac transplantation. Functional status improved (301 patients in I-II functional class and 56 in III-IV after referral compared to 225 and 132 before referral, respectively). Our results were obtained through adjustment in pharmacological therapy, intensive patient education and therapeutic continuity made possible by our outpatient heart-failure clinic organization. It is likely that the increase in costs due to therapeutic adjustment and to the increase in the number of visits is counterbalanced by the reduced rate of hospital admissions.     

Cardiovascular effects of mibefradil in hypertensive patients with obstructive sleep apnea

OBJECTIVE: Hypertension is often seen in obstructive sleep apnea (OSA) and is characterized by increased sympathetic activity, depressed baroreflex and accentuated vascular responsiveness. The objective of this study was to investigate the effects of the new T-selective calcium channel blocker mibefradil on invasively measured blood pressure (BP) and heart rate in hypertensive patients with OSA. METHODS: The present study was a double-blind, randomized and placebo-controlled before and after trial in two parallel groups. Fifty-three men aged 23 69 years with systemic hypertension and OSA were recruited from the Outpatient Department of the Marburg University Sleep Laboratory and hospitalized for 10 days. Mibefradil (50 mg) or placebo were given orally in the morning for 8 days. The main outcome measure was the mean arterial (radial) BP monitored continuously during nocturnal sleep and during standardized daytime physical and psychological performance testing. RESULTS: Mibefradil lowered mean arterial BP and heart rate with (SD) during the entire measurement period compared with placebo: -7.25 (9.59) vs -2.11 (8.43) mmHg (P=0.039) and -4.83 (5.94) vs -1.34 (4.13) bpm (P=0.022), respectively. Both effects were observed during nocturnal sleep and performance testing, including graded exercise. Adverse events did not differ compared with placebo. CONCLUSION: Mibefradil is an effective but well-tolerated antihypertensive that also lowers heart rate over 24 h in OSA, in conditions known to increase BP.