Volume control in treatment-resistant congestive heart failure: role for peritoneal dialysis.

Chronic congestive heart failure (HF) has a rising prevalence and increasing impact on health care systems. Current treatment consists of diuretics, renin-angiotensin-aldosterone system blockers, and restriction of salt and fluids. This strategy is often hampered by a drop in effective circulating volume and hence renal perfusion and function, triggering harmful counter regulatory mechanisms. Slow ultrafiltration by peritoneal dialysis (PD) might be an effective treatment strategy to relieve fluid overload without compromising cardiac output and thereby renal function. In this review, we discuss the (patho)physiological mechanisms of the cardiorenal interaction and the current literature on PD strategies in congestive HF.

Validation and clinical use of a novel diagnostic device for screening of atrial fibrillation.

AIMS: Patients with asymptomatic and undiagnosed atrial fibrillation (AF) are at increased risk of heart failure and ischaemic stroke. In this study, we validated a new diagnostic device, the MyDiagnostick, for detection of AF by general practitioners and patients. It records and stores a Lead I electrocardiogram (ECG) which is automatically analysed for the presence of AF. METHODS AND RESULTS: In total, 192 patients (age 69.4 ± 12.6 years) were asked to hold the MyDiagnostick for 1 min, immediately before a routine 12-lead ECG was recorded. Atrial fibrillation detection and ECGs stored by the MyDiagnostick were compared with the cardiac rhythm on the 12-lead ECG. In a second part of the study, the MyDiagnostick was used to screen for AF during influenza vaccination in the general practitioner's office. Atrial fibrillation was present in 53 out of the 192 patients (27.6%). All AF patients were correctly detected by the MyDiagnostick (sensitivity 100%; 95% confidence interval 93-100%). MyDiagnostick AF classification in 6 out of 139 patients in sinus rhythm was considered false positive (specificity 95.9%; 95% confidence interval 91.3-98.1%). During 4 h of influenza vaccination in 676 patients (age 74 ± 7.1 years), the MyDiagnostick correctly diagnosed AF in all 55 patients (prevalence 8.1%). In 11 patients (1.6%), AF was not diagnosed before, all with a CHA2DS2VASc score of >1. CONCLUSION: The high AF detection performance of the MyDiagnostick, combined with the ease of use of the device, enables large screening programmes for detection of undiagnosed AF.

Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris.

To identify the effect of L-propionylcarnitine (LPC) on ischemia, 31 fasting, untreated male patients with left coronary artery disease were studied during 2 identical pacing stress tests 45 minutes before (atrial pacing test I [APST I]) and 15 minutes after (APST II) administration of 15 mg/kg of LPC or placebo. Hemodynamic, metabolic, and nuclear angiographic variables were studied before, during, and for 10 minutes after pacing. After LPC administration, arterial total carnitine levels increased from 47 +/- 1.7 mumol/liter (control) to 730 +/- 30 mumol/liter. Hemodynamic and metabolic variables were comparable in LPC and placebo during APSI I, and reproducible in placebo during both tests. Although LPC did not affect myocardial oxygen demand and supply, it diminished myocardial ischemia, indicated by a significant 12% and 50% reduction in ST-segment depression and left ventricular end-diastolic pressure, respectively, during APST II. Moreover, during APST II, left ventricular ejection fraction increased by 18% (p < 0.05 vs APST I). Furthermore, LPC improved recovery of myocardial function after pacing, with a reduction in the time to peak filling and a 21% increase in both peak ejection and filling rates 10 minutes after pacing (all p < 0.05). Thus, LPC prevents ischemia-induced ventricular dysfunction, not by affecting the myocardial oxygen supply-demand ratio but as a result of its intrinsic metabolic actions, increasing pyruvate dehydrogenase activity and flux through the citric acid cycle. Because it is well tolerated, it may be a valuable alternative or addition to available antiischemic therapy.

Acute anti-ischemic effects of perindoprilat in men with coronary artery disease and their relation with left ventricular function.

Long-term angiotensin-converting enzyme (ACE) inhibition may reduce ischemic events in patients with coronary artery disease, but whether it protects against acute ischemia or the effects of preexisting left ventricular (LV) dysfunction on potential anti-ischemic properties is unknown. We performed a double-blind trial in 25 patients with exercise-induced ischemia. The effects of perindoprilat on pacing-induced myocardial ischemia were examined. Fourteen patients received perindoprilat and 11 patients received placebo. Based on LV function, 2 subgroups were formed in the perindoprilat group: 7 patients with LV dysfunction (LV ejection fraction <0.40), and 7 patients with normal LV function. After receiving the study medication, the pacing test was repeated. During the first pacing test both groups developed ischemia. After perindoprilat administration, the increase in systemic vascular resistance and LV end-diastolic pressure were significantly blunted (p <0.05). Further, the ischemia-induced increase in arterial and cardiac uptake of norepinephrine was inhibited by perindoprilat, and the increase in atrial natriuretic peptide was less pronounced; also, ST-segment depression was reduced by 32% compared with placebo (all p <0.05). In the group with LV dysfunction, perindoprilat reduced LV end-diastolic pressure significantly by 67% and myocardial lactate production was prevented, but this did not happen in the group with normal LV function. In addition, the increase in arterial norepinephrine was reduced by 74% and 33%, respectively (p <0.05). These results indicate that perindoprilat reduced acute, pacing-induced ischemia in normotensive patients. In patients with (asymptomatic) LV dysfunction these effects were more pronounced than in patients with normal LV function.

Anti-ischaemic effects of converting enzyme inhibitors: underlying mechanisms and future prospects.

ACE inhibitors have the potential to affect myocardial ischaemia in patients with asymptomatic ventricular dysfunction and ischaemic cardiomyopathy after long-term treatment. However, anti-ischaemic effects are virtually absent in stable effort angina during short-term therapy, which suggests different mechanisms of action in different patient subtypes. Long-term treatment in left ventricular dysfunction may lead to a reduction in myocardial oxygen demand and ischaemia as a result of ventricular remodelling, possibly supported by structural coronary vascular effects, i.e., an improved endothelial function and vasodilator capacity. An alternative mechanism by which ACE inhibitors may affect ischaemia, is through modulation of ischaemia-induced neurohormonal activation and subsequent systemic vasoconstriction. Depending on the severity of ischaemia, pronounced catecholamine activation and stimulation of the circulating renin-angiotensin system occur, accompanied by systemic vasoconstriction and an increase in afterload. These changes are marked in patients with left ventricular dysfunction. Moreover, a change from net catecholamine release to uptake in the ischaemic area is observed. Although the clinical significance of the latter observation is still unclear, sympathetic activation may lead to coronary vasoconstriction in stenotic areas where normal endothelium-dependent coronary vasodilatation has become impaired. In the resting patient, enalaprilat and perindoprilat significantly reduce myocardial ischaemia, not by a direct effect on the oxygen supply-demand ratio, but through modulation of neurohormonal activation, in particular of sympathetic activation during ischaemia, and, subsequently, by preventing systemic vasoconstriction. These effects are pronounced in left ventricular dysfunction, at least where perindoprilat is concerned. The possibility that ACE inhibitors improve endothelial function in concert with their modulating effects on ischaemia-induced neurohormonal activation and hence influence the occurrence of myocardial ischemia during long-term treatment needs further evaluation.

Acute myocardial ischaemia induces cardiac carnitine release in man.

In animal studies, prolonged periods of ischaemia decrease the cardiac carnitine content. However, whether in humans the heart loses carnitine during short-term ischaemia, and whether this is related to ischaemia-induced cardiac dysfunction, is as yet unknown. Carnitine kinetics were investigated in 28 normotensive patients with significant left coronary artery disease, during and after incremental atrial pacing. To evaluate carnitine kinetics from the ischaemic area, patients were grouped as those with (n = 22) or without (n = 6) myocardial lactate production. Atrial pacing resulted in a comparable maximal heart rate and ST depression in both groups. Carnitine kinetics did not change in those without lactate production. In contrast, coronary venous free carnitine levels increased significantly by 9% during pacing in those with lactate production. Cardiac free carnitine balance changed from uptake (255 +/- 107 pmol.min-1, mean +/- SEM) to release, (-150 +/- 66 pmol.min-1) at 30 min after pacing in the group with lactate production. Arterial and coronary venous differences in free carnitine were significantly correlated with myocardial lactate extraction immediately after pacing. The change in coronary venous free carnitine was significantly correlated with the change in left ventricular ejection fraction at 10 min after pacing. Thus, in patients with coronary artery disease, short-term mild myocardial ischaemia results in significant cardiac free carnitine loss.

Long-term vasodilator treatment with flosequinan does not lead to hemodynamic tolerance or neurohormonal activation in severe heart failure.

Flosequinan is a balanced-type vasodilator with a prolonged mode of action due to an approximate 38-hour half-life of its active first metabolite, BTS 53554. As this may lead to tolerance and neurohormonal activation, the acute and long-term pharmacokinetic, hemodynamic, and neurohormonal profile of flosequinan was evaluated. On three consecutive days, 23 patients with heart failure (New York Heart Association classes II-IV), despite digitalis and diuretics, underwent invasive hemodynamic studies after receiving 100 mg oral flosequinan (day 1), placebo (day 2), and 100 mg flosequinan (day 3), followed by repeat invasive evaluation after long-term flosequinan (100 mg daily) for 17 +/- 2 weeks. On each study day, plasma flosequinan levels increased to 1.9 +/- 0.2 mg/L after 1 hour, but returned to baseline levels at 24 hours. In contrast, BTS 53554 increased progressively, reaching relatively high plateau levels (6 mg/L) during chronic therapy. First-dose flosequinan decreased the pulmonary wedge, right atrial pressure, and systemic resistance by 50, 60, and 22%, respectively, whereas the cardiac index was increased by 40%; these effects lasted for 48 hours. During long-term treatment, baseline values of the pulmonary wedge and right atrial pressure were comparable to prestudy values, whereas systemic resistance had decreased by 22%, and the cardiac index and heart rate had increased by 22 and 14%, respectively. Readministration of flosequinan did not further affect hemodynamics, apart from a moderate reduction in the pulmonary wedge and right atrial pressure. Neurohumoral activation did not occur during acute or long-term therapy. Thus, although changes in left and right heart filling pressures are attenuated during long-term treatment, flosequinan induces sustained arterial dilatation and improves cardiac pump function without activation of circulating neurohormones.

Renal hemodynamic effects in patients with moderate to severe heart failure during chronic treatment with trandolapril.

Treatment of patients with severe heart failure by ACE inhibition is often limited by worsening of renal function. To evaluate whether trandolapril, a potent lipophilic ACE inhibitor, affects renal function in severe heart failure, we studied 12 patients with severe heart failure treated with only diuretics and digoxin. Patients received increasing oral dosages of trandolapril (0, 1, and 2 mg) on 3 consecutive days (A). Patients were then discharged on 2 mg trandolapril bid and re-evaluated 8 weeks later (B). Mean arterial and pulmonary wedge pressures decreased by maximal 14% and 43%, and stroke volume and work indexes increased by 24% and 20% at A and similarly at B (11, 45, and 25 ns and 33%, respectively). In contrast, heart rate, systemic resistance, pulmonary artery pressure, and cardiac index decreased by 6%, 23%, 29%, and 17%, respectively, at only A. Renal blood flow improved by approximately 40% both at A and B. In contrast, the glomerular filtration rate decreased by 25% at only B, whereas serum creatinine, creatinine clearance, and urine osmolality were unaffected during the study. Norepinephrine, angiotensin II, and aldosterone levels decreased by approximately 30%, 60%, and 65%, respectively, at both A and B. Renin levels increased by 136% at A and remained elevated at B. Thus, whereas the initial systemic vasodilating and inotropic effects did not persist, long-term trandolapril results in sustained neurohormonal modulation, reduced preload, and improved organ perfusion, indicated by a persistent increase in renal blood flow and preservation of renal function in severe heart failure.

Anti-ischaemic efficacy of L-propionylcarnitine--a promising novel metabolic approach to ischaemia?

L-propionylcarnitine, a naturally occurring derivative of L-carnitine, essential for mitochondrial fatty acid transport and high-energy phosphate exchange, acutely reduces myocardial ischaemia and improves ischaemia-induced cardiac dysfunction following intravenous administration. This randomized, crossover study was designed to compare the long-term anti-ischaemic effects of oral L-propionylcarnitine with diltiazem in patients with stable, exercise-induced angina. After a 2-week washout phase of anti-anginal medication and a 2-week single-blind placebo period, 46 patients were included in the study, 23 of whom received 1500 mg L-propionylcarnitine daily for 6 weeks, and 23 diltiazem (180 mg daily for 3 weeks, followed by 360 mg daily for 3 weeks), crossing over to the other treatment after a 1-week washout period. Three patients on L-propionylcarnitine and two on diltiazem discontinued. Both treatments resulted in comparable exercise duration (582 +/- 35 s and 588 +/- 33 s, mean +/- SEM), time to 0.1 mV ST depression (436 +/- 38 s and 465 +/- 36 s), and increase in time to 0.1 mV ST depression from baseline (20% and 28%), L-propionylcarnitine and diltiazem, respectively. Diltiazem decreased the rate-pressure product at rest and exercise, L-propionylcarnitine did not. Both compounds significantly reduced ST depression at maximal exercise [23% (L-propionylcarnitine) vs 35% (diltiazem), P < 0.05 diltiazem vs L-propionylcarnitine]. Diltiazem increased the time to onset of angina by 22%. In contrast, no significant changes occurred with L-propionylcarnitine. During the study, anginal attacks were reduced by 70% and 57%, and nitroglycerin consumption decreased by 57% and 70%, L-propionylcarnitine and diltiazem, respectively. Thus, both L-propionylcarnitine and (high-dose) diltiazem result in anti-ischaemic effects and decrease anginal attacks in daily life. Although the effect of diltiazem on exercise-induced ischaemia appears more pronounced than that of L-propionylcarnitine, this novel metabolic approach to ischaemia warrants further development.

Additional antiischemic effects of long-term L-propionylcarnitine in anginal patients treated with conventional antianginal therapy.

Cardiac L-carnitine content, essential for mitochondrial fatty acid transport and ATP-ADP exchange, decreases during ischemia. In animal models, administration of the natural derivative, L-propionylcarnitine, may reduce ischemia and improve cardiac function. To evaluate possible antiischemic effects of L-propionylcarnitine was compared with placebo in a randomized, double-blind, parallel design, in addition to preexisting therapy. Patients with > or = 2 anginal attacks per week and objective signs of ischemia with angina during bicycle exercise testing were included. After an initial 2-week, single-blind placebo phase, 37 patients received 500 mg L-propionylcarnitine tid, and 37 patients received placebo for 6 weeks. Both groups were comparable at baseline. Three patients discontinued the study while on placebo (two because of noncompliance, one because of palpitations) and one while on L-propionylcarnitine (noncompliance). Although heart rate, blood pressure at rest, and maximal exercise were not affected, L-propionylcarnitine increased the time to 0.1 mV ST-segment depression [44 +/- 3 vs. 8 +/- 2 seconds (mean +/- SEM) in the placebo group; p = 0.05], and exercise duration improved by 5% compared with placebo. Anginal attacks and the consumption of nitroglycerin were not affected in either group. Thus, following a 6 week treatment period, L-propionylcarnitine induced additional, albeit marginal, antiischemic effects in anginal patients who were still symptomatic despite maximal conventional antianginal therapy. It is questionable whether in these patients this form of metabolic treatment will achieve great benefit, although in some improvement can be expected.

Acute hemodynamic and neurohumoral profile of dilevalol in hypertensive patients with ischemic heart disease.

Acute systemic and, possibly, coronary vasoconstriction may limit the usefulness of i.v. beta-blockade for the management of hypertension in ischemic patients. The acute hemodynamic and neurohumoral profile of i.v. dilevalol (50 mg/5 min), a nonselective beta-antagonist and selective partial beta 2-agonist, was evaluated for 1 h in nine patients with stable angina, significant (> 50%) coronary artery disease, and mild hypertension. Immediately after administration, arterial pressures fell significantly by 13% and remained lowered for the entire study period. Concomitantly, heart rate slowed from 76 +/- 2 (mean +/- SEM; control) to 67 +/- 2 beats/min (60 min postadministration, p < 0.05), and cardiac index and stroke work decreased significantly by 15 and 21%, respectively. Isovolumetric contractility indices (measured at fixed heart rates) fell progressively by 9-12%, whereas relaxation (Tau1 and Tau2) slowed by 10% (all p < 0.05 vs. control). Consequently, left ventricular end-diastolic and right atrial pressures increased significantly from 17 +/- 3 and 9 +/- 1.2 mm Hg at baseline to 21 +/- 2.5 and 12 +/- 2.1 mm Hg, respectively. Dilevalol did not affect systemic or coronary resistance. However, coronary flow decreased by 24% (p < 0.05 vs. control), accompanied by significant reductions in myocardial oxygen demand and consumption of 23 and 14%, respectively. Levels of circulating norepinephrine and dopamine increased by 35 and 71%, whereas those of renin and angiotensin II decreased by 26 and 33%, respectively (all p < 0.05 vs. control). Adverse side effects did not occur. None of the patients became ischemic. Thus, at the dose level used, dilevalol has predominant beta-blocking effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic, neurohumoral, and myocardial energetic effects of pimobendan, a novel calcium-sensitizing compound, in patients with mild to moderate heart failure.

In contrast to cyclic AMP-dependent positive inotropes, the calcium-sensitizer and partial phosphodiesterase (PDE) inhibitor pimobendan may induce beneficial effects in heart failure. However, its effect on relaxation, myocardial energetics and neurohormones are unknown. Twelve patients with heart failure, New York Heart Association (NYHA) classification II-III, due to ischemic cardiomyopathy, were studied for 1 h after they received 5 mg pimobendan intravenously (i.v.). Pimobendan progressively reduced systemic resistance and left ventricular end-diastolic pressure (LVEDP) (22 and 50%, respectively) and improved isovolumetric contractility and relaxation parameters by 30% (all p < 0.05 vs. control). LV end-diastolic and end-systolic volumes (LVEDV, LVESV) decreased significantly by 20 and 19%, respectively. Cardiac output (CO) increased by 17% due to a simultaneous increase in heart rate (HR) from 75 +/- 3 to 86 +/- 5 beats/min (mean +/- SEM, p < 0.05). Pimobendan did not change coronary hemodynamics, but myocardial O2 extraction and consumption were decreased significantly by 18 and 20%, respectively. Catecholamines, angiotensin II (AII), and aldosterone levels did not change significantly. In contrast, arterial and coronary venous renin increased significantly from 57 +/- 17 and 53 +/- 14.7 microM/h at control to 69 +/- 20 and 69 +/- 20 microM/h, respectively, 60 min after pimobendan administration. Simultaneously, cardiac renin uptake at baseline (0.449 +/- 0.185 mumol/min) changed to release (-0.071 +/- 0.145 mumol/min, p < 0.05). Serious side effects did not occur. Thus, pimobendan had progressive positive inotropic and lusitropic effects, diminished preload and afterload despite modest stimulation of plasma renin activity (PRA), and reduced systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute improvement of cardiac function with intravenous L-propionylcarnitine in humans.

As the myocardial carnitine content, a key control factor in myocardial oxidative metabolism and energy transfer, is reduced in heart failure, administration of L-propionylcarnitine (LPC), a potent analogue of L-carnitine, potentially may improve cardiac function, possibly through a positive inotropic effect. As its hemodynamic profile is unknown in humans, 32 fasting normotensive patients with coronary artery disease received either 15 mg/kg of LPC (n = 16) or vehicle (mannitol/acetate, n = 16) infused over 5 min. Hemodynamic, radionuclide [peak ejection and filling rates (PER and PFR, respectively)], and metabolic variables (myocardial O2, lactate, and carnitine uptake) were studied at baseline and 1, 3, 5, 10, 15, and 45 min postdrug. The baseline ejection fraction was depressed in LPC patients (40 +/- 3% vs. 48 +/- 4% in the vehicle group, p less than 0.05) as a result of a significant high incidence of previous infarctions. Immediately following LPC, the cardiac total carnitine uptake changed from 102 +/- 181 to 5,335 +/- 1,761 mumol/L (p less than 0.05). In both groups, left ventricular systolic and end-diastolic pressures increased significantly by 5 and 20%, respectively, during the first 5 min. In the vehicle group, contractility decreased by 5%, accompanied by a significant 11% fall in the stroke volume. In contrast, following LPC, isovolumetric contractility indices remained unaltered. Instead, both the PER and PFR improved by 16% at 45 min. Moreover, the cardiac output increased by 8%. LPC did not affect systemic or coronary hemodynamics. Lactate uptake increased by 42%, but myocardial O2 consumption did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute systemic and antiischemic effects of epanolol in patients with coronary artery disease.

Antiischemic effects of beta 1-blocking agents are based on intrinsic negative inotropic and chronotropic properties. Partial beta 1-agonistic activity, although useful in preserving cardiac function, may counteract such antiischemic properties by modulating the intrinsic negative cardiac effects of beta-blockade. To investigate the acute hemodynamic and antiischemic profile of epanolol, a cardioselective beta 1-antagonist and partial agonist, 20 patients with left coronary artery disease underwent two incremental atrial pacing tests, 45 minutes before (APST I) and 15 minutes after (APST II) 4 mg intravenous epanolol, administered over 5 minutes. Additional measurements were carried out at 1, 3, 5, 10, and 15 minutes after epanolol, at basal and fixed heart rates. Epanolol immediately reduced heart rate with a maximum of 10% at 15 minutes and decreased contractility (Vmax) by 7% (both p < .05), whereas cardiac output fell temporarily by 9% (p < .05). Other hemodynamic parameters did not change, except for a significant 11% reduction in myocardial oxygen demand. Despite comparable pacing conditions, both the double product and contractility decreased significantly less during APST II, resulting in a 17% lower myocardial oxygen consumption (p < .05). Myocardial ischemia was markedly reduced, indicated by normalization of lactate metabolism [lactate extraction 16 +/- 7% vs. -7 +/- 8% (APST I)], less ST depression (21%), and modulation of LV end-diastolic pressure postpacing (all p < .05 vs. APST I), whereas angina was absent or less in 14 patients. None of the patients reported an adverse effect. Thus, under resting conditions intravenous epanolol induces moderate, short-lasting negative chronotropic and inotropic effects, but does not alter cardiac pump function or vascular resistance, reflecting its additional beta 1-agonistic properties. Alternatively, during pacing it still reduces ischemia through negative inotropic effects and diminishes myocardial oxygen demand, reflecting its beta 1-antagonistic profile.

Early administration of ramipril in acute myocardial infarction: neurohormonal and hemodynamic effects and tolerability.

Although several large studies indicate a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction, the optimal timing of therapy in terms of safety and the effects on neurohormones during myocardial infarction are less well known. In order to investigate the effect of ramipril, administered within 24 h after myocardial infarction, on hemodynamics and neurohormones and its safety, 20 patients with a myocardial infarction were studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not. The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg during the next 4 days. Side effects did not occur. The mean arterial pressure decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate, cardiac and stroke indexes, and pulmonary artery and wedge pressures did not change. The ACE activity decreased within 1 h of ramipril administration with a maximum of 71% at 4 h after the second dose and remained at this level throughout the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5, whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of 71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril administration until the end of the study, with a maximum of 77% on day 3. Moreover, a late but significant decrease in norepinephrine occurred on day 5. Thus, oral ramipril results in early ACE inhibition, followed by progressive attenuation of the neuroendocrine activation and a reduction in afterload during the acute phase of myocardial infarction. It is well tolerated, also in combination with nitroglycerin and thrombolytic therapy.

Effects of epanolol, a selective beta1-blocker with intrinsic sympathomimetic activity, in patients with ischemic left ventricular dysfunction.

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta1-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.04). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p < 0.05). A similar effect was observed for angiotensin II. Further, in the LV-dysfunction group, coronary sinus blood flow increased less, and coronary vascular resistance decreased less (both values, p < 0.05). Despite the fact that the increase in double product was decreased to a similar extent in both groups, ischemia was reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction, neurohumoral activation after epanolol may impair adequate coronary flow response, and this may limit its antiischemic properties. Because of the small size of the study, no definitive inference on the clinical benefit of epanolol in patients with ischemic LV function can be made from this study.

Differential anti-ischaemic effects of muscarinic receptor blockade in patients with obstructive coronary artery disease; impaired vs normal left ventricular function.

AIMS: In patients with coronary artery disease acetylcholine (a muscarinic agonist) causes vasoconstriction. The effect of atropine (a muscarinic antagonist) on coronary vasotone in patients with normal or impaired left ventricular function is unknown. METHODS AND RESULTS: Twenty-four patients who required atropine infusion (to supplement heart rate response) during atrial pacing (pacing was conducted to assess ischaemia as part of an experimental protocol) were studied; 17 patients had normal and seven impaired left ventricular function (ejection fraction < or =0.40). Two control groups were selected from a large database (from patients in whom atrial pacing was carried out but to whom atropine was not administered) to match the normal (n=20) and dysfunction (n=10) groups. In the normal left ventricular function group atropine increased rate pressure product by 12 +/- 4%, as compared to those without atropine (P < 0.05). Left ventricular end diastolic pressure increased less in the atropine group (+40 +/- 8% vs +78 +/- 6%;P < 0.05). Arterial norepinephrine increased similarly in both groups, but coronary flow (as assessed by using a thermodiluting method in the coronary sinus) increased 23 +/ -4% more in the atropine group (P < 0.05). Further, there were lower levels of myocardial lactate production and ST-segment depression in the atropine group [lactate extraction +13 +/- 6% (atropine) vs -19 +/- 4% (controls), ST-segment depression 1. 3 +/- 0.6 (atropine) vs 1.8 +/- 0.2 mm (control), both P < 0.05 between groups]. In contrast, in the dysfunction group the overall effect of atropine was less pronounced. CONCLUSION: In patients with normal left ventricular function atropine improves coronary flow and reduces myocardial lactate production and ST-segment depression during atrial pacing, suggesting a reduction in myocardial ischaemia.

Duration and reproducibility of initial hemodynamic effects of flosequinan in patients with congestive heart failure.

The duration and reproducibility of hemodynamic effects of flosequian, a direct-acting, balanced-type vasodilator, were studied in 19 heart failure patients (NYHA class 3.0 +/- 0.7) receiving 100 mg orally (day 1), placebo (day 2), and again 100 mg (day 3). Flosequinan immediately reduced systemic and pulmonary resistance (23% and 35%, respectively, at 60-90 minutes postdrug) and decreased pulmonary wedge, right atrial, mean pulmonary artery, and mean arterial pressure by 38%, 50%, 25%, and 7%, respectively. Concomitantly, cardiac output, and stroke volume and work increased by 26%, 20%, and 22%, respectively. Most hemodynamic effects persisted for 48 hours. In contrast, changes in pulmonary wedge and arterial pressures, stroke volume, and stroke work only lasted for 2-12 hours. Maximum absolute changes on day 3 were generally comparable with first-dose effects with, again, long-lasting effects on systemic resistance and cardiac output. However, changes in pulmonary artery, wedge, and resistance were significantly shorter than after first dose administration. These data indicate sustained and reproducible arterial dilating effects of flosequinan, but less pronounced and shorter lasting pulmonary arterial and venodilator properties.

Contrasting preload-dependent hemodynamic and neurohumoral effects of isomazole, a partial phosphodiesterase inhibitor and calcium sensitizer.

BACKGROUND: Currently evaluated positive inotropic agents that act predominantly through phosphodiesterase III-inhibiting properties, have been disappointing in the treatment of heart failure. Lack of efficacy as a result of diminished cellular cyclic adenosine monophosphate and vasodilating tolerance and side effects are prevalent. In contrast, calcium sensitization is preserved in heart failure and agents that combine phosphodiesterase-inhibiting and calcium-sensitizing properties may be more efficacious. Isomazole is such a novel agent with combined properties. This study investigated the acute hemodynamic and neurohormonal effects of intravenous isomazole (3 micrograms/kg/min for 30 minutes). METHODS AND RESULTS: The effects of preexisting preload were evaluated in 18 patients with heart failure, New York Heart Association class II/III, and elevated (> 15 mmHg, n = 11, group I) and normal; (n = 7, group II) pulmonary wedge pressure at baseline. In the overall group, isomazole increased myocardial contractility and relaxation and decreased systemic resistance by 20%. Left and right filling pressures fell by 35-45%, accompanied by a 69% reduction in cardiac atrial natriuretic peptide release. In contrast, levels of arterial norepinephrine and renin both increased by 27%. Cardiac output increased in group I (23%), but fell in group II (18%), accompanied by a 51% increase in arterial norepinephrine. Cardiac atrial natriuretic peptide decreased in group I, but not in group II. CONCLUSIONS: Isomazole induced positive inotropic and lusitropic effects and arterial vasodilation in all patients. Cardiac pump function improved only in group I, accompanied by a reduction in sympathetic activity and renin-angiotensin and aldosterone levels and a more pronounced decrease in cardiac atrial natriuretic peptide release. In contrast, in patients with normal to low preload, the further reduction in preload led to a deterioration of pump function and increased sympathetic tone.

L-propionylcarnitine does not affect myocardial metabolic or functional response to chronotropic and inotropic stimulation after repetitive ischemia in anesthetized pigs.

In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine and citric acid cycle intermediates and fatty acylCoA-induced inhibition of adenine nucleotide translocase. During postischemic stress, the impairment of the fatty acid oxidation may become more apparent. We therefore investigated in open-chest anesthetized pigs the effect of L-propionylcarnitine [100 mg/kg per day orally (p.o.) for 3 days and 50 mg/kg intravenously (i.v.) 2 h before the first occlusion; n = 13] on myocardial function and metabolism of postischemic (two cycles of 10-min occlusion each followed by 30-min reperfusion) myocardium under resting conditions and during chronotropic and inotropic stimulation with dobutamine. Myocardial levels of free carnitine were higher after pretreatment (5.7 +/- 1.4 vs. 4.0 +/- 1.3 mumol/g protein, p < 0.05). The ischemia-reperfusion-induced decreases in free carnitine were similar for both the untreated and treated animals, but in the latter free carnitine was not different from the baseline levels in the control animals. In untreated animals (n = 15), regional systolic segment shortening (SS) was 18.5 +/- 5.5% (means +/- SD) at baseline, but was reduced to 5.1 +/- 5.5% (p < 0.05) at the end of the second reperfusion period. Myocardial ATP levels had decreased by 30% (p < 0.05) in the presence of a maintained energy charge, while myocardial oxygen and lactate consumption had decreased to 61% and 9% of baseline, respectively. During subsequent i.v. infusion of dobutamine (2 micrograms/kg/min), SS and myocardial oxygen consumption per beat increased to 75 and 65% of baseline, respectively, whereas lactate consumption per beat increased to only 25% of baseline. Decreases in myocardial ATP and oxygen and lactate consumption were not different between treated and untreated animals. L-Propionylcarnitine-treated animals displayed slightly better postischemic recovery of systolic SS than did control animals; to 39 and 28% (p = 0.056) of baseline, respectively, probably owing to a reduction in arterial blood pressure (BP), because L-propionylcarnitine prevented the increase in systemic vascular resistance produced by ischemia-reperfusion. L-Propionylcarnitine did not affect myocardial metabolic and contractile functional responses to chronotropic and inotropic stimulation. In a model of repetitive myocardial ischemia, L-propionylcarnitine prevents systemic vasoconstriction in response to ischemia and reperfusion and, probably as a result of the lower afterload, slightly ameliorates postischemic hypofunction, but loss of carnitine apparently does not play a role in myocardial hypofunction after brief repetitive ischemia and reperfusion in pigs.