Polysomnography underestimates altered cardiac autonomic control in patients with obstructive sleep apnea.

BACKGROUND: Repetitive nocturnal sympathetic activation during episodes of apnea and postapneic hyperventilation increases cardiovascular risk. The effects of hypopnea and non-apneic, non-hypopneic intervals before and after hypopnea/apnea on sympathico-vagal balance have not been assessed yet. HYPOTHESIS: Hypopnea and non-apneic, non-hypopneic intervals before and after hypopnea/apnea cause increased sympathetic activity when compared to normal respiration in nonREM stages 2­4. METHODS: A total of 34 patients were studied using in-laboratory polysomnography including continuous ECG recording. Absolute spectral power of heart rate variability in the very low (VLF), low (LF), and high frequency (HF) bands and low frequency to high frequency power ratio (LF/HF ratio) were analyzed during apnea, hypopnea, and during the pre- and post-phases of such respiratory episodes and compared to spectral powers during normal respiration in nonREM sleep 2­4. RESULTS: Patients with hypopnea and/or obstructive apnea showed higher power of VLF and the LF/HF ratio in intervals of hypopnea/apnea and in non-apneic, non-hypopneic intervals before and after hypopnea/apnea compared to normal respiration in nonREM stages 2­4. CONCLUSION: The effect of sleep-disordered breathing on alteration of autonomic tone in patients with hypopnea and obstructive apnea is more severe than estimated by conventional polysomnographic assessment of apnea and hypopnea. Patients with sleep apnea show a sympathetic overdrive not only during phases of hypopnea and obstructive apnea but also in non-apnea, non-hypopnea intervals before and after hypopnea, and obstructive apnea.

Safety of the novel atrial-selective K+-channel blocker AVE0118 in experimental heart failure.

Congestive heart failure (CHF) is often associated with atrial fibrillation. The safety of many antiarrhythmic drugs in CHF is limited by proarrhythmic effects. We aimed to assess the safety of a novel atrial-selective K(+)-channel blocker AVE0118 in CHF compared to a selective (dofetilide) and a non-selective IKr blocker (terfenadine). For the induction of CHF, rabbits (n = 12) underwent rapid right ventricular pacing (330-380 bpm for 30 days). AVE0118 (1 mg/kg) dofetilide (0.02 mg/kg) and terfenadine (2 mg/kg) were administered in baseline (BL) and CHF. A six-lead ECG was continuously recorded digitally for 30 min after each drug administration. At BL, dofetilide and terfenadine significantly prolonged QTc interval (218 +/- 30 ms vs 155 +/- 8 ms, p = 0.001 and 178 +/- 23 ms vs. 153 +/- 12 ms, p = 0.01, respectively) while QTc intervals were constant after administration of AVE0118 (p = n.s.). In CHF, dofetilide and terfenadine caused torsades de pointes and symptomatic bradycardia, respectively, and prolonged QTc interval (178 +/- 30 ms vs. 153 +/- 14 ms, p = 0.02 and 157 +/- 7 ms vs. 147 +/- 10 ms, p = 0.02, respectively) even at reduced dosages, whereas no QTc-prolongation or arrhythmia was observed after full-dose administration of AVE0118. In conclusion, atrial-selective K(+)-channel blockade by AVE0118 appears safe in experimental CHF.

Increased aldosterone levels in a model of type 2 diabetes mellitus.

BACKGROUND: Aldosterone is an important mediator of cardiovascular and renal remodeling. Type II diabetes mellitus leads to renal and cardiac end organ damage. We investigated the renin-angiotensin-aldosterone system in a model of type 2 diabetes mellitus with known diabetic nephropathy and cardiac remodeling, the Zucker Diabetic Fatty rat with and without ACE-inhibition (ZDF and ZDF+ACE-I) and its control, the Zucker Lean (ZDL) rat. METHODS: Male animals were studied from an age of 7-24 weeks. At ages 7, 14, 17, 20, and 23 weeks, urinary excretion of aldosterone-glucuronide and potassium was assessed. ACE-inhibition with ramipril was started orally at week 13 (1 mg/kg/d). At the end of the study rats were sacrificed and plasma aldosterone concentration and plasma renin activity were measured. Aldosterone synthase (CYP11B2) mRNA expression in the adrenals, kidney, heart and adipose tissue was assessed by real-time PCR. Urinary albumin excretion as marker for diabetic nephropathy was measured in metabolic cages and correlated to aldosterone. RESULTS: Plasma aldosterone concentration and aldosterone-glucuronide was significantly elevated in ZDF rats, and significantly reduced by ACE-inhibiton. In contrast, plasma renin activity was significantly reduced in ZDF rats and normalized by ACE-inhibition. The urinary aldosterone correlated significantly to albuminuria. Adrenal CYP11B2 expression was not significantly higher in ZDF rats. CYP11B2 mRNA was not detected in the kidney, heart and adipose tissue. CONCLUSION: In ZDF rats, urinary and plasma aldosterone levels were elevated despite reduced plasma renin activity. The reversible effect of ACE-inhibition shows that the up-regulation of aldosterone must be dependent of the renin-angiotensin-system in this type II diabetes model. The correlation between aldosterone and diabetic nephropathy suggests a clinical relevance of this observation.

Fates of genetically engineered haematopoietic and mesenchymal stem cell grafts in normal and injured rat hearts.

There is an ongoing debate on the potential of adult stem cells as adjuvant therapy for patients with heart disease. The aim of our study was to evaluate the use of bone marrow (BM)-derived stem cells for cardiac cell and gene therapy in normal and ischaemia-injured rat hearts. Haematopoietic (HSCs) and mesenchymal stem cells (MSCs) were purified from the BM of adult rats and labelled by: (a) genetic transduction of the green fluorescent protein (GFP) using an oncoretroviral vector; (b) incorporation of the fluorescent dye PKH26 into the cell membrane; and (c) incorporation of bromodeoxyuridine into the chromosomal nucleic acid. Cells were directly injected into the beating heart (normal and shortly after coronary ligation). Retention of HSCs was--irrespective of the ischaemic injury--about 5% on day 3, and < 1% on days 10 and 28. Survival of MSCs was approximately 10-15% on day 3, but also < 5% at the later time points. Vector-mediated GFP expression was rapidly silenced after day 3. There was considerable tissue damage around the injection site. Transplanted cells did not migrate from the injection site. We did not observe phenotypical changes of the transplanted stem cells into cardiac or vascular cells.

Differential expression of cardiac ANP and BNP in a rabbit model of progressive left ventricular dysfunction.

OBJECTIVE: Activation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) is considered a hallmark of myocardial remodeling. To determine magnitude and relative proportion of activation during the progression to heart failure, we assessed ANP and BNP gene expression in atrial and left ventricular (LV) tissue in a newly developed model of progressive rapid ventricular pacing-induced heart failure in rabbits. METHODS: Six animals underwent progressive pacing with incremental rates (330 beats per min (bpm) to 380 bpm over 30 days), resulting in congestive heart failure (CHF). Five animals underwent pacing at 330 bpm for 10 days only (early LV dysfunction, ELVD) and five additional animals served as control group (CTRL). RESULTS: ELVD was characterized by decreased mean arterial pressure (P=0.05 vs. CTRL) as well as significantly impaired LV function (LV fractional shortening (FS) P<0.01 vs. CTRL) and dilatation (P<0.01 vs. CTRL). CHF was characterized by further decreased mean arterial pressure (P<0.01 vs. ELVD), further impaired LV function (FS P<0.03 vs. ELVD) and dilatation (P<0.01 vs. CTRL). In control animals, significant ANP expression was observed only in atrial tissue (P<0.02 vs. BNP) while BNP expression was ubiquitous but marginal (LV P<0.05 vs. ANP). In ELVD, activation of ANP (atria and LV P<0.05 vs. CTRL) and BNP (atria P<0.05 vs. CTRL, LV n.s.) was observed. In CHF, LV-BNP increased further markedly (P<0.01 vs. CTRL, P<0.05 vs. ELVD) while atrial ANP and BNP expression as well as LV ANP expression remained unchanged (all P=n.s. vs. ELVD). CONCLUSION: The current studies demonstrate differential activation of atrial and LV ANP and BNP under normal conditions and during the progression to heart failure and provide a molecular basis for the superiority of BNP as marker of LV dysfunction and CHF.

Central inhibition of AT1receptors by eprosartan--in vitro autoradiography in the brain.

All components of the renin-angiotensin system have been demonstrated in the brain and AT1 receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT1 receptor antagonists, which are increasingly used in the treatment of arterial hypertension and chronic heart failure, have the potential to mediate action via the central renin-angiotensin system. Therefore, we tested the in vivo access of the non-peptide AT1 receptor antagonist, eprosartan (30 and 60 mg per kg of body weight (BW) for 4 weeks, i.p. administered by osmotic minipumps), to angiotensin II receptors in the rat brain by in vitro autoradiography with 125I- (Sar1- Ile8) angiotensin II as a ligand. Eprosartan significantly increased plasma renin activity by four-fold and six-fold at doses of 30 and 60 mg x kg(-1), respectively (P< 0.05 vs CTRL). In the brain, eprosartan produced a dose-dependent inhibition of AT receptor binding in the median cerebral artery ( 850 +/- 249 and 650 +/- 106 vs 1072 +/- 116 dpm x mm(-2) of CTRL; P< 0.05). Furthermore, eprosartan inhibited angiotensin II receptor binding in discrete brain areas, which express exclusively, or predominantly, AT1 receptors both outside and within the blood-brain barrier, such as the paraventricular nucleus ( 180 +/- 47 and 130 +/- 18 vs 545 +/- 99 dpm x mm(-2)of CTRL; P< 0.05), the subfornical organ ( 106 +/- 26 and 112 +/- 17 vs 619 +/- 256 dpm x mm(-2)of CTRL; P< 0.05), and the organum vasculosum laminae terminalis ( 461 +/- 110 and 763 +/- 136 vs 1033 +/- 123 dpmx mm(-2)of CTRL; P< 0.05). These results emphasize that eprosartan readily crosses the blood-brain barrier in vivo and selectively inhibits binding to AT1 receptors in specific brain nuclei. The modulation of central regulatory mechanisms might contribute to AT1 receptor antagonists overall therapeutic efficacy in cardiovascular disease.

[Heparin-induced type II thrombocytopenia as the etiology of severe recurrent pulmonary embolism]. / Heparininduzierte Thrombozytopenie Typ II als Ursache eines schweren Rezidivs einer Lungenembolie.

Heparin-induced thrombocytopenia (HIT) is a rare complication of anticoagulative heparin therapy. The more severe HIT type II is defined by peripheral thrombocytopenia combined with thrombotic and thromboembolic events. We report the case of a 24 year old male patient who was admitted to our ICU with thromboembolic obstruction of the right central pulmonary artery, and deep venous thrombosis (DVT) of the right superficial femoral vein. Systemic thrombolytic therapy with urokinase for seven days resulted in nearly complete resolution of the thromboembolic material in the pulmonary arteries. Antithrombotic therapy with intravenous heparin and overlapping oral phenoprocoumon was continued on the regular ward. Six days later, the patient had to be readmitted to the ICU with evidence of hemodynamic compromise due to massive bilateral pulmonary thromboembolism that could be confirmed by CT scan--DVT had extended to the right iliacal vein. Additionally, peripheral thrombocyte counts had markedly declined from 112.000 to 35.000/microliter within 3 days, indicating the presence of a Hit type II. This was verified by positive ELISA testing for antibodies against platelet factor 4 (PF4)-heparin-complex. A filter device was temporarily implanted into the inferior vena cava. The patients condition stabilized upon reinitiated systemic thrombolysis and replacement of heparin therapy against recombinant hirudin. Pulmonary artery pressures normalized. Peripheral thrombocytopenia diminished within three days. HIT type II is a severe complication of anticoagulative therapy with heparin. Here we report a case, and discuss diagnostic procedures as well as differential diagnosis to HIT type I.

Alterations in myocardial creatinine kinase (CK) and lactate dehydrogenase (LDH) isoenzyme-distribution in a model of left ventricular dysfunction.

The purpose of the current study was to evaluate myocardial creatinine kinase (CK) and lactate dehydrogenase (LDH) systems in a model of epinephrine-induced cardiomyopathy in rabbits. Eight rabbits received four repetitive epinephrine infusions (300 mg/kg/60 min, i.v.) in 12-day intervals and eight untreated rabbits served as controls (CTRL). Echocardiography demonstrated a significant deterioration of LV function as well as increased LV-diameter and -mass index in catecholamine-induced cardiomyopathy. Histological examination revealed that repetitive catecholamine infusion resulted in LV fibrous areas with collagenous content and an increase in myocyte width (16.9+/-0.8 microm vs. CTRL 12.9+/-0.9; P<0.05). LV dysfunction was associated with a decreased total LV lactate dehydrogenase activity (LDH; 0.43+/-0.03 IU/mg protein vs. CTRL 0.52+/-0.04; P<0.05) whereas total creatinine kinase activity was unchanged (CK; 7.30+/-0.63 IU/mg protein vs. CTRL 9.20+/-0.49, n.s.). Furthermore, myocardial LDH isoenzymes were shifted with a decrease in LDH(1) and an increase in LDH2 and LDH3 (LDH(1): 84.90+/-2.60% vs. CTRL 94.50+/-0.40; LDH2: 7.30+/-1.20% vs. 1.50+/-0.13; LDH3: 5.40+/-0.90% vs. 3.20+/-0.25; all P<0.05). Foetal B-CK isoenzymes were significantly increased (CK-MB 5.30+/-0.66 vs. 2.20+/-0.35%; P<0.05). The current study demonstrates changes in cardiac energy metabolism including an impaired LDH activity with a shift towards anaerobic isoenzymes as well as a more efficient CK system in a model of catecholamine-induced LV dysfunction.

Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population.

OBJECTIVE: To evaluate brain natriuretic peptide (BNP) as marker of left ventricular (LV) dysfunction and hypertrophy in a population-based sample of 610 middle-aged subjects (50-67 years) who were further characterized with respect to hemodynamic and anthropometric parameters and by echocardiography. RESULTS: Left ventricular (LV) systolic function, LV mass-index, age, gender, heart rate, and medication with beta adrenergic receptor blockers were significant and independently correlated with BNP (multivariate analysis, P < 0.05 each). As compared to subjects with normal LV function and mass-index (control), subjects with LV dysfunction (LV fractional shortening < 28%) or hypertrophy (LV mass-index > 110 g/m2 in women and > 134 g/m2 in men) were characterized by increased BNP. The increase in BNP associated with LV hypertrophy (n = 69, +101% versus control, P < 0.0001) was similar in magnitude to that associated with LV dysfunction (n = 39, +98% versus control, P < 0.03). These increases were markedly exceeded in subjects with severe LV dysfunction (n = 11, LV fractional shortening < 22%, BNP +197% versus control, P < 0.01), particularly in the presence of concomitant hypertrophy (n = 7, +227%, P < 0.01). The predictive values of BNP varied considerably with the degree of LV dysfunction and the presence or absence of concomitant LV hypertrophy. With 0.81, the highest area under the receiver operator characteristic curve was obtained for the detection of severe LV dysfunction and concomitant hypertrophy and sensitivity, specificity, positive and negative predictive value for this condition were 71, 86, 7 and 99.5%, respectively, for a cut-off of 34 pg/ml. CONCLUSIONS: The current study provides new insight into regulation and diagnostic value of BNP in middle-aged subjects and demonstrates important independent effects of LV function and mass upon BNP plasma concentrations. Although measurement of BNP cannot be recommended for the detection of marginally impaired LV function in the population, it may be helpful to suggest or exclude severe LV dysfunction with concomitant hypertrophy.

Animal models of chronic heart failure.

Chronic heart failure is associated with multiple pathophysiological alterations and adaptations, such as marked anatomic and biochemical changes of the myocardium, left ventricular dysfunction and dilatation, increased systemic vascular resistance, and activation of neurohumoral and cytokine systems. The use of animal models has provided a new insight into the complex pathogenesis of this syndrome and supplemented clinical experience. However, all of the animal models used have advantages and limitations, and the transfer from experimental to human heart failure needs critical evaluation. The current review will focus upon new aspects of rat and rabbit models of heart failure.

Contribution of the endothelin system to the renal hypoperfusion associated with experimental congestive heart failure.

The objective of this study was to define further the local activation of endothelin-1 (ET-1) and the ETA receptor as well as the functional consequences of activated ET-1 for renal hypoperfusion associated with experimental congestive heart failure (CHF). We studied eight rabbits permanently instrumented with Doppler flow probes around the renal arteries before and after the induction of epinephrine-induced CHF. CHF was characterized by left-ventricular dysfunction (fractional shortening 34+/-2% vs. 46+/-3%; p < or = 0.05) and dilatation (LVEDd 13.6+/-0.3 vs. 11.5+/-0.4 mm; p < or = 0.05), decreased mean arterial pressure (59.4+/-2.9 vs. 74.6+/-3.7 mm Hg; p < or = 0.05), increased heart rate (236+/-11 vs. 216+/-8 beats/min; p < or = 0.05) and renal vasoconstriction (vascular resistance 49.65 +/-8.55 vs. 24.61+/-5.85 U; p < 0.05; blood flow velocity, 1.58+/-0.21 vs. 3.63+/-0.31 kHz; p < 0.05). ET-1 concentrations were significantly increased not only in plasma (7.67+/-0.47 vs. 4.56 +/-0.69 pg/ml; p < 0.05) but also in renal tissue (4.8+/-0.5 vs. 3.5 +/-0.64 pg/mg; p < 0.05). Northern analysis revealed an unchanged expression of ETA receptor messenger RNA (0.79+/-0.05 vs. 0.77+/-0.04 arbitrary units; NS) in renal tissue, whereas expression of prepro-ET-1 was below the range of detection. In CHF, selective ETA-receptor antagonism with BQ-123 (1 mg/ kg bolus, i.v.) significantly increased renal blood flow velocity (3.07+/-0.38 vs. 1.33+/-0.19 kHz; p < 0.05) and reduced renal vascular resistance (29.63+/-6.22 vs. 58.17+/-8.75 U; p < 0.05) without significant effects on mean arterial pressure or heart rate. These studies demonstrate activation of the renal ET system, unaltered gene expression, and functional integrity of the renal ETA receptor in CHF. They indicate a principal functional role for the ETA receptor in renal vasoconstriction and suggest blockade of the renal ETA receptor as an important strategy to attenuate renal hypoperfusion in CHF.

Modulation of renal blood flow by endogenous endothelin-1 in conscious rabbits with left ventricular dysfunction.

The current study addresses the functional status and role of the endothelin ET(A) receptor for renal vascular function in rabbits with and without heart failure (epinephrine-induced cardiomyopathy). Under baseline conditions, the ET(A) receptor antagonist BQ-123 did not change basal renal hemodynamics, but completely prevented endothelin-1 (ET-1)-induced renal vasoconstriction. In heart failure, in the presence of elevated plasma ET-1 concentrations (P < .05), renal vasoconstriction in response to exogenous ET-1 was intact. Unlike under baseline conditions, ET(A) receptor antagonism markedly increased renal blood flow (P <.05) and decreased renal vascular resistance (P < .05) in heart failure. The current study provides new insight into the pathophysiology of renal vasoconstriction associated with heart failure and the specific role of the renal ET(A) receptor in this pathophysiologic adaptation.

Hemodynamic changes and neurohumoral regulation during development of congestive heart failure in a model of epinephrine-induced cardiomyopathy in conscious rabbits.

BACKGROUND: The present study was designed to study the progression of heart failure in rabbits with catecholamine-induced cardiomyopathy. METHODS AND RESULTS: We investigated the effects of three repetitive applications (at 16-day intervals) of high-dose epinephrine (first infusion, 5 micrograms/kg/min for 60 minutes; second and third infusions, 4 micrograms/kg/min for 60 minutes) on hemodynamics, echocardiographic parameters, and plasma hormone levels in eight conscious rabbits chronically instrumented with a Doppler flow probe around the proximal abdominal aorta and a catheter in the right atrium. Mean arterial pressure and blood flow velocity, as well as the acceleration of blood flow velocity (df/dt) in the proximal abdominal aorta were progressively reduced, and right atrial pressure was significantly elevated. On echocardiography, progressive left ventricular (LV) dilatation with depressed LV systolic function and an increase in LV mass were observed. Plasma atrial natriuretic peptide level was enhanced approximately fourfold after each epinephrine infusion, with a tendency to return to baseline values. Plasma renin activity (PRA) was increased after the first epinephrine application (3.0 +/- 0.5 to 6.4 +/- 0.9 ng angiotensin I (AI)/mL/h; P < .05), followed by a return to control levels. After the second epinephrine infusion, a significant decrease to 1.0 +/- 0.3 ng AI/mL/h (P < .05) was observed. After the third catecholamine treatment, PRA levels insignificantly increased. Plasma vasopressin level significantly increased from 0.5 +/- 0.2 to 1.1 +/- 0.5 pg/mL (P < .05) after the second epinephrine infusion. CONCLUSION: Repetitive infusions of high doses of epinephrine induce a cardiomyopathy with progressive hemodynamic deterioration, LV dilatation and hypertrophy, depressed systolic function, and different stages of neurohumoral compensation. This model appears to be suitable to study the progression of chronic heart failure by serial measurements in a small animal preparation.

Central vasopressin is modulated by chronic blockade of the renin-angiotensin system in experimental left ventricular hypertrophy.

We studied the interaction of the central renin-angiotensin system (RAS) and vasopressin system in rats with left ventricular hypertrophy (LVH) due to aortic banding. In these animals plasma vasopressin is elevated and vasopressin content is increased in specific brain areas. Chronic blockade of the RAS by angiotensin-converting enzyme (ACE) inhibition (ramipril) and AT1 receptor antagonism (losartan) significantly attenuated circulating and central vasopressin in rats with LVH. Given the antidiuretic, vasoconstrictive, and growth-promoting effects, vasopressin may participate in the cardiovascular alterations in LVH. Blockade of the RAS strongly ameliorates central and peripheral-vasopressin. Therefore, central modulatory effects on vasopressin might contribute to the therapeutic efficacy of ACE inhibitors and AT1 antagonists.

Development of heart failure following isoproterenol administration in the rat: role of the renin-angiotensin system.

OBJECTIVE: High dosages of catecholamines induce cardiomyocyte necrosis and interstitial fibrosis in rats. We investigated whether this initial damage is followed by the development of heart failure and assessed the particular role of the renin-angiotensin system using ramipril. METHODS AND RESULTS: Following the administration of 0 mg or 150 mg isoproterenol/kg 6 groups of Wistar rats were followed for 2 or 16 weeks: Sham, isoproterenol, isoproterenol + ramipril. Isoproterenol induced significant increases of echocardiographically measured left ventricular end-diastolic posterior wall thickness and dimension, whereas ramipril treatment significantly attenuated these changes. Left ventricular end-diastolic pressure was markedly increased in isoproterenol-treated rats and normalized following ramipril. Isoproterenol rats were further characterized by hormonal activations including transient elevations of plasma renin activity, aldosterone and cardiac angiotensin converting enzyme activity. Histomorphological characterization of isoproterenol-treated hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Ramipril treatment only slightly reduced the amount of necrosis as well as the expression of extracellular matrix proteins. CONCLUSIONS: In rats, a toxic dosage of isoproterenol caused characteristic myocardial damage that subsequently resulted in mild heart failure. Ramipril administration following isoproterenol was highly effective to attenuate hemodynamic and hormonal alterations as well as the development of left ventricular hypertrophy, but had only little influence on the expression of extracellular matrix proteins. Since angiotensin converting enzyme inhibition had no impact on the initial myocardial injury, the development of heart failure in this model seems to require functional integrity of the renin-angiotensin system.

Neurohormonal activity and left ventricular geometry in patients with essential arterial hypertension.

The purpose of this study was to investigate whether the basal activity of the renin-angiotensin-aldosterone system or the basal levels of the atrial natriuretic peptide (ANP) are related to distinct patterns of left ventricular (LV) geometry in patients with essential hypertension. The left ventricle of patients with arterial hypertension may be exposed to a variety of growth-regulating mechanisms, including pressure overload and humoral activation. The interaction of such growth stimuli may be involved in the modulation of LV geometry. LV geometry was determined echocardiographically in 104 patients with mild to moderate essential hypertension. The same number of age- and sex-matched normotensive subjects served as controls. Plasma renin activity (PRA) and serum concentrations of aldosterone and ANP were measured by radioimmunoassay. Correlation analyses revealed that PRA was significantly associated with septal wall thickness and LV mass index (r = 0.25; p < 0.005 each). In addition, as compared with normal subjects (1.0 +/- 0.7 ng/ml/hr), PRA was significantly increased in patients with concentric LV hypertrophy (LVH) (3.4 +/- 6.6 ng/ml/hr, p < 0.01). Aldosterone displayed a close correlation with septal, posterior, and relative wall thickness (r > 0.27, p < 0.005 each). Compared with normal subjects (74 +/- 27 pg/ml), patients with hypertension and pathologic patterns of LV geometry were characterized by elevations of aldosterone (LV remodeling 203 +/- 93 pg/ml, concentric LVH 123 +/- 67 pg/ml; eccentric LVH 199 +/- 89 pg/ml; p < 0.05 each). ANP was significantly associated with septal wall thickness, left ventricular dimension, and LV mass index (r > 0.22, p < 0.005 each). Furthermore, compared with normal subjects (50 +/- 17 pg/ml), ANP values were significantly increased in patients with hypertension and concentric LVH (80 +/- 44 pg/ml, p < 0.005) and eccentric LVH (88 +/- 24 pg/ml, p < 0.001). Multivariate analysis adjusting for systolic blood pressure, body mass index, and age revealed that renin and ANP were independently associated with LV mass index (p < 0.05 each). Interestingly, adjusted PRA levels were not related to any specific pattern of LV geometry. In contrast, adjusted ANP levels were associated with concentric and eccentric LVH, whereas adjusted aldosterone levels were significantly elevated in subjects with LV remodeling and eccentric LVH (p < 0.005). Thus elevated levels of renin and ANP may be found in patients with hypertension and elevated LV mass index. In addition, ANP and aldosterone are related to specific geometric patterns of the left ventricle. The data may further stimulate the discussion on the mechanisms that account for alterations of LV geometry in hypertension.

Evaluation of plasma natriuretic peptides as markers for left ventricular dysfunction.

To test the hypothesis that elevated plasma levels of natriuretic peptides may serve to identify patients with left ventricular (LV) dysfunction, we assessed the predictive diagnostic value of natriuretic peptide levels, in addition to clinical and electro-cardiographic risk factors, as noninvasive indicators of cardiac dysfunction. Plasma levels of atrial natriuretic peptide (cANP) (99-126), N-terminal fragment of proANP (nANP) (26-55), nANP(80-96), brain natriuretic peptide (BNP-32), proBNP(22-46), and C-type natriuretic peptide (CNP-22) were measured in 211 subjects before cardiac catheterization. The strongest correlations with parameters of LV function were found for nANP(80-96) (up to r = -0.55, p < 0.0001), whereas there was no significant correlation with proBNP(22-46) or CNP-22. In patients with LV ejection fractions (LVEF) < or = 45% (n = 38) nANP(26-55), nANP(80-96), cANP(99-126), and BNP-32 were significantly increased (p < 0.001). Partition values for elevated versus normal natriuretic peptide levels were obtained from normal controls and used to separate subjects with and without LV dysfunction. Receiver operating characteristic analysis for LVEF < or = 45% indicated a significantly better diagnostic accuracy for high levels of nANP(80-96), nANP(22-56), cANP(99-126), and BNP-32 than for proBNP and CNP-22. Multivariate analysis by logistic regression identified Q waves and bundle branch block in the electrocardiogram as well as elevated plasma levels of cANP, nANP(80-96), and nANP(26-55) as the strongest independent predictors of low ejection fractions. The relative risk of LV dysfunction was raised up to tenfold in subjects with high natriuretic peptide levels (p < 0.001). The addition of nANP(80-96) and nANP(26-55) to the combination of clinical and electrocardiographic risk factors did not further improve the diagnostic sensitivity for the detection of LVEF < or = 45%, but it markedly increased the overall accuracy (59% to 81%, p < 0.001) and specificity (55% to 81%, p < 0.001). Among natriuretic peptides, elevated nANP(80-96) and nANP(26-55) levels have the strongest impact on the detection of LV dysfunction. They add to the diagnostic information contained in clinical and electrocardiographic factors. Plasma levels alone or in combination with clinical factors seem to be of value for a refined identification of abnormal LV function in the individual patient.

Chronic ACE inhibition by quinapril modulates central vasopressinergic system.

OBJECTIVE: The role of the brain as a target for angiotensin converting enzyme (ACE) inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibitors may modulate other central neuropeptide systems such as the central vasopressin system, we studied the effects of chronic treatment with the ACE inhibitor, quinapril, on ACE activity and on central vasopressin content in specific brain areas in rats. METHODS: 22 rats were chronically treated with quinapril (6 mg.kg-1 BW per gavage daily for 6 weeks; untreated controls, n = 14). ACE density in various brain regions was assessed by in vitro autoradiography using the specific ACE inhibitor, 125I-351A. Vasopressin content was determined in 19 brain areas (micropunch technique) known to be involved in cardiovascular regulation. RESULTS: Following chronic quinapril treatment ACE was significantly decreased in the thalamus (-38%), hypothalamus (-37%), hypophysis (-35%), cerebellum (-36%) choroid plexus (-20%), and locus coeruleus (-35%). Additionally, a marked reduction in serum ACE activity (-97%) was observed. Plasma levels of vasopressin were significantly decreased after quinapril treatment (0.97[s.e.m. 0.11] vs. 1.63[0.24] pg.ml-1 in controls, P < 0.05). Vasopressin content was significantly reduced in 9 of 19 specific brain areas. Regarding the hypothalamic vasopressin-producing nuclei, vasopressin was decreased in the paraventricular (292[197] vs. 2379[585] pg.mg-1 crotein in controls; P < 0.001) and supraoptic nuclei (13618[1979] vs. 24525[3894] pg.mg-1 protein; P < 0.05), but not in the suprachiasmatic nucleus. Vasopressin content was significantly reduced in brain areas connected by vasopressinergic fibres originating in the hypothalamic paraventricular nucleus: namely central gray, subcommissural organ, organum vasculosum laminae terminalis, dorsal raphe nucleus, and locus coerules. Vasopressin content was also significantly reduced in the median eminence (5887[1834] vs. 28321[4969] pg.mg-1 protein, P < 0.001), where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. CONCLUSIONS: Autoradiographic studies in vitro indicate that orally administered quinapril suppresses central ACE activity after chronic treatment. ACE inhibition by quinapril strongly influences vasopressin content in important brain areas which are involved in central cardiovascular regulation. Therefore, central modulatory effects of ACE inhibitors may also contribute to overall therapeutic efficacy.

ANP gene expression in rat hearts during hypoxia.

It is unclear whether the increase in plasma atrial natriuretic peptide (ANP) concentration during hypoxia is due to direct, hypoxia-induced upregulation of ANP secretion in the heart, or to pressure overload of the right ventricle (RV) following hypoxia-induced pulmonary hypertension. To test the hypothesis that hypoxia leads to an early upregulation of the ANP gene, we examined the influence of acute and prolonged inspiratory hypoxia (6 h, 1 or 3 weeks) on the expression of ANP messenger ribonucleic acid (mRNA) in rat heart and compared the results with the expression of the ANP gene after acute pressure overload induced by experimental coarctation of the main pulmonary artery. As a molecular marker for hypertrophy we determined the ratio of alpha- and beta-myosin gene expression. Hypoxia increased systolic RV pressure from 20.0 +/- 1.6 mmHg to 27.8 +/- 1.6 mmHg (P < 0.01) and 41.6 +/- 2.1 mmHg (P < 0. 05) after 1 and 3 weeks hypoxia respectively. The ANP plasma concentration did not change significantly after 6 h or 1 week: 232 +/- 21 pg/ml (control), 246 +/- 25 pg/ml (6 h), 268 +/- 25 pg/ml (1 week), but increased significantly after 3 weeks hypoxia (446.8 +/- 99.56 pg/ml; P < 0.05). ANP mRNA levels in different regions of the heart did not change after 6 h or 1 week hypoxia. After 3 weeks hypoxia ANP mRNA had increased 2.7-fold in the RV (P < 0.05), 4. 2-fold in the left ventricle (LV, P < 0.05), 3.5-fold in the septum (S, P < 0.05) and about 1.4-fold in the right (n.s.) and left atrium (n.s.). Relative ventricular masses increased significantly only for the RV (190%, P < 0.05) during hypoxia. The beta/alpha-myosin mRNA ratio did not change after 6 h hypoxia but, contrary to ANP gene expression, increased after just 1 week (6.1-fold in RV, 7.8-fold in LV, 6-fold in S; P < 0.05) and was more pronounced in the RV after 3 weeks (9.4-fold in RV, 7.6-fold in LV, 9.1-fold in S; P < 0.05). The increase in the beta/alpha-myosin mRNA ratio in the LV contrasts with a lack of increase in relative ventricular mass. Acute pressure overload in the RV after pulmonary arterial banding significantly increased ANP-mRNA and the beta/alpha-myosin mRNA ratio after 1 day in the RV. In the LV ANP mRNA was unchanged. The delayed upregulation of the ANP gene suggests that hypoxia per se is not a significant stimulus for ANP gene expression in the heart and that hypoxia-induced ANP-gene expression in the heart is regulated predominantly by the increase in RV afterload due to hypoxia-induced increased pulmonary pressure. The upregulation of ANP and beta-myosin mRNA in the LV during chronic hypoxia has yet to be elucidated.