Dietmar Elsner

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.

Effectiveness of endopeptidase inhibition (Candoxatril) in congestive heart failure

Candoxatril is a novel, orally active inhibitor of neutral endopeptidase EC 3.4.24.11, the enzyme that degrades atrial natriuretic peptide (ANP). The acute and chronic (10 days treatment) hemodynamic and hormonal effects of candoxatril (150 mg twice daily) in 12 patients with moderately severe congestive heart failure were investigated in a randomized, placebo-controlled, double-blind study. On study day 1, candoxatril acutely increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After 10 days of treatment, basal ANP was increased and basal aldosterone was decreased. Body weight was reduced, most likely reflecting chronic natriuretic or diuretic effects, or both, and there was a trend toward increased cardiac index and reduced preload values. On study day 10, the acute effects of candoxatril were similar to those on day 1 (i.e., ANP was further increased, aldosterone was suppressed, and right and left ventricular filling pressures were decreased). Thus, candoxatril may offer a new and effective therapeutic approach in the treatment of heart failure.

Efficacy of prolonged infusion of urodilatin (ANP-(95-126)) in patients with congestive heart failure

Urodilatin [ANP-95-126] is a new natriuretic peptide of renal origin not subjected to tolerance in experimental congestive heart failure (CHF). To evaluate its therapeutic potentials in CHF, we investigated the efficacy of a prolonged infusion of urodilatin (15 ng/kg/min for 10 hours) in 12 patients with CHF (New York Heart Association functional classes II and III) in a randomized, double-blind, placebo-controlled study. Urodilatin elevated plasma cyclic guanosine monophosphate (cGMP) concentrations and increased urinary cGMP excretion. Systolic blood pressure (121 +/- 9 mm Hg to 111 +/- 7 mm Hg) and central venous pressure (7.4 +/- 3.3 mm Hg to 5.2 +/- 3.4 mm Hg) decreased significantly, and diastolic blood pressure and heart rate remained unchanged. Urine flow (0.7 +/- 0.6 ml/min to 1.5 +/- .6 ml/min) and urinary sodium excretion (48 +/- 16 mumol/min to 180 +/- 97 mumol/min) were significantly increased. Plasma norepinephrine, renin, aldosterone, and vasopressin were unaltered. The substance was well tolerated. Thus prolonged infusion of urodilatin lowers preload and increases diuresis and natriuresis without neurohumoral activation or adverse side effects, demonstrating a profile of effects that may be beneficial in patients with CHF.

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.

Vascular remodeling and growth factor gene expression in the rat lung during hypoxia

Recent studies suggest that the vasoactive peptides endothelin-1 and -3 and the mitogens VEGF and PDGF-A and -B could be involved in the pathogenesis of hypoxic pulmonary hypertension. We were interested to investigate whether these peptides could also be involved in the vascular remodeling occurring during chronic hypoxia (10% oxygen; 1 and 3 weeks) in the rat. Hypoxia increased significantly systolic right ventricular pressure and typical morphological signs of vascular remodeling were found. This was accompanied by increased ET-1 and the ET-3 mRNA expression after acute (6 h; P < 0.05) and chronic hypoxia of 1 (P < 0.05) and 3 weeks (P < 0.05). In contrast, we found no effects of hypoxia on the gene expression of VEGF and PDGF-A and -B in the lung. Our findings indicate that ET-3 in addition to ET-1 could be involved in the process of hypoxia-induced vascular remodeling, whereas it appears less likely that the mitogens VEGF and PDGF-A and -B are essentially involved in the pathogenesis of hypoxic pulmonary hypertension.

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.

Transgastric Doppler Echocardiographic Assessment of the Severity of Aortic Stenosis Using Multiplane Transesophageal Echocardiography

We investigated whether multiplane transesophageal Doppler echocardiography using transgastral views allows determination of pressure gadients and valve areas in patients with aortic stenosis. This technique was feasible in 35 of 39 patients (90%), with highly significant correlations with results obtained from transthoracic Doppler echocardiography and cardiac catheterization, thus offering an alternative approach for quantification of aortic stenosis.

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.

Experimental heart failure produced by rapid ventricular pacing in the dog.

To study the complex pathophysiology of chronic heart failure and the efficacy of pharmacologic interventions, a number of experimental models have been developed. ~ Most animal models used previously were ones of surgically induced volume or pressure overload, myocardial ischemia, and toxic depression of cardiac function. Many of these models had major limitations, for example, requiring major surgery and/or thoracotomy deranging neurohormonal systems and cardiovascular reflexes, exhibiting only left ventricnlar (LV) hypertrophy or dysfunction that lacked essential features of congestive heart failure (such as elevated filling pressures, low cardiac output, activation of neurohumoral systems, and systemic vasoconstriction), producing only rightsided heart failure, or causing systemic damage by cardiotoxic agents. In many preparations, the degree of damage to the heart and the resulting state of heart failure are not predictable. In addition, models in very small animals are limited due to the restricted number of functional and humoral parameters to be assessed. In the last decade, because of its apparent advantages over many other preparations, the model of pacing-induced heart failure has become one of the most widely used and best-studied models of heart failure. This model was developed in dogs and has most often been used in that species. Recently, it was modified for other species, such as sheep, s,6 pigs, 7,8 rabbits, 9,~° and rats. H Because most of the literature on the pacing model is based on the canine model and because variations between species and differing techniques cannot be excluded, our review will focus mainly on experiments performed in dogs. A model of pacing-induced heart failure was briefly reported for the first time in 196272 Rapid atrial stimulation in dogs was performed using external pacemakers. Due to largely varying atrioventricular (AV) conduction,

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.