Dynamic changes in N-terminal pro-brain natriuretic peptide in acute coronary syndromes treated with percutaneous coronary intervention: a marker of ischemic burden, reperfusion and outcome.

BACKGROUND: Whereas N-terminal pro-brain natriuretic peptide (NT-proBNP) is approved for risk stratification of patients with acute coronary syndromes (ACS), short-term temporal changes in NT-proBNP concentrations and the optimal time points for sampling are not clear. The purpose of this study was to better define the short-term changes in NT-proBNP in relation to clinical presentation, reperfusion and prognostic value in patients with ACS, as well as to identify the optimum time points for sampling. METHODS: We studied daily plasma concentrations of NT-proBNP in 133 unselected patients with myocardial infarction (n=65), stable coronary artery disease (CAD, n=46) and no CAD (n=22) who underwent coronary angiography. RESULTS: Patients with non-ST-elevation myocardial infarction (NSTEMI) presented with markedly higher NT-proBNP than patients with ST-elevation myocardial infarction (STEMI) [1305 (741-3208) ng/L vs. 170 (70-424) ng/L, p<0.001]. Also, time to presentation from onset of pain was much longer in NSTEMI as compared to STEMI (>48 h vs. <6 h, p<0.001). Patients with NSTEMI also presented with higher NT-proBNP as compared with CAD [224 (98-732) ng/L] and no CAD [47 (26-102) ng/L; p<0.001, NSTEMI vs. both]. Following successful percutaneous coronary intervention [thrombolysis in myocardial infarction (TIMI) 3-flow established], NT-proBNP increased markedly within 24 h in patients with STEMI [718 (379-1338) ng/L, p<0.01 vs. 0 h], whereas no change in NT-proBNP was noted in patients with NSTEMI [1190 (1010-2024) ng/L, p=0.88 vs. 0 h]. In both STEMI and NSTEMI, NT-proBNP decreased significantly 96 h after successful reperfusion [STEMI -52%, 372 (189-610) ng/L, p<0.05; NSTEMI -52%, 613 (365-724) ng/L, p<0.05]. Unsuccessful reperfusion (TIMI<3) was associated with unchanged or increased NT-proBNP. NT-proBNP at 96 h and peak NT-proBNP further displayed a strong correlation with cardiac troponin T (r=0.64 and r=0.54, p<0.001), a marker of infarct size, and NT-proBNP at 96 h was a strong predictor of long-term prognosis (hazard ratio 7.29, p=0.025). CONCLUSIONS: In patients with NSTEMI, NT-proBNP may be increased as high as concentrations usually associated with acute congestive heart failure despite the absence of clinical signs. In contrast, patients with STEMI and short time to presentation may present with completely normal NT-proBNP, but dramatic short-term increases following reperfusion. NT-proBNP reflects ischemic burden, reperfusion success and prognosis, and the current data support repetitive sampling in patients with ACS.

Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats.

Inhibition of the renin angiotensin aldosterone system (RAAS) produces protective effects on cardio-renal injury in type 2 diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool, acting by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type 2 diabetes as compared to angiotensin converting enzyme inhibition (ACE-I). Zucker diabetic fatty rats aged 13 weeks were treated with either VPI (AVE7688, ZDF-VPI, n = 8) or ACE-I (Ramipril, ZDF-ACE-I, n = 7) or placebo (ZDF, n = 8). Heterozygous rats served as non-diabetic controls (Ctr, n = 8). Both treatments led to a similar decrease in blood pressure. After 10 weeks of treatment, ZDF developed marked albuminuria. The latter was significantly attenuated in ZDF-VPI as compared to ZDF and ZDF-ACE-I. Renal histology revealed a significant expansion in the glomerular tuft area in all ZDF groups. However, expression of glomerular desmin, which has been recognized as a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to Ctr. Desmin was reduced in ZDF-VPI but not in animals treated with ACE-I. There was a correlation between albumin excretion and desmin-positive glomerular area. In experimental type 2 diabetes, albuminuria correlates to podocyte damage. These hallmarks of diabetic nephropathy are attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest that podocyte damage is an early critical step in the progression of diabetic nephropathy, and that VPI is a promising pharmacological tool in the treatment of diabetic renal disease.

Efficacy of patient activated antitachycardia pacing therapy using the Medtronic AT500 pacemaker.

A 28-year-old female with corrected anomalous pulmonary venous drainage presented with multiple atrial arrhythmias many years later. Ablation techniques eliminated most of the arrhythmias except atrial tachycardia with 1:1 AV conduction. A dual-chamber pacemaker with antiatrial tachycardia features was implanted and was shown to be effective in arrhythmia control when the standard algorithm was overridden by an external patient activation device.

Clinical results of intracoronary brachytherapy (ICBT) for multiple in-stent restenosis.

BACKGROUND AND PURPOSE: Treatment of in-stent restenosis (ISR) with percutaneous coronary intervention (PCI) alone is often followed by early re-restenosis. The present study focused on the effect of intracoronary brachytherapy (ICBT) on multiple in-stent restenosis (MISR) after repeated PCI. PATIENTS AND METHODS: 40 patients (27 male, 13 female, age: 66 +/- 9 years) with MISR (two to six ISRs, median three ISRs) were retrospectively analyzed. All patients were treated by using the Novoste((R)) Beta-Cathtrade mark 3.5F System after PCI. The target vessel received 18.4-25.3 Gy of radiation at a depth of 2 mm from the center of the source. The restenosis-free survival and overall survival were calculated by Kaplan-Meier analysis (log-rank). The time interval between last PCI without ICBT and the consecutive recurrence was compared with the follow-up time after PCI with ICBT. RESULTS: The 3-year overall survival rate after ICBT was 93%. The 0.5-, 1-, 2-, and 3-year ISR-free survival rates after PCI + ICBT were 81%, 72%, 52%, and 38%, respectively. After PCI alone, the 0.5-, 1-, and 2-year ISR-free survival rates were 30%, 13%, and 0%, respectively. This difference was highly significant (p < 0.0001). Patients with more than three ISRs before ICBT had a better outcome (3-year ISR-free survival: 80%) than patients with only two or three ISRs before ICBT (3-year ISR-free survival: 25%; p < 0.05). CONCLUSION: ICBT is highly effective and safe in patients with ISR. The results of this study are in accordance with the WRIST and BETA-WRIST data. After 6 months both studies revealed an ISR-free survival rate of 86% (WRIST) and 66% (BETA-WRIST), respectively. The ISR rates in the own control group (70%) were comparable to the placebo groups in WRIST (68%) and BETA-WRIST (72%). Interestingly, patients with more than three ISRs before ICBT had the lowest ISR rate after ICBT.

Planimetry of aortic valve area in aortic stenosis by magnetic resonance imaging.

BACKGROUND: The aim of the study was to determine whether noninvasive planimetry of aortic valve area (AVA) by magnetic resonance imaging (MRI) is feasible and reliable in patients with valvular aortic stenosis in comparison to transesophageal echocardiography (TEE) and catheterization. METHODS AND RESULTS: Planimetry of AVA by MRI (MRI-AVA) was performed on a clinical magnetic resonance system (1.5-T Sonata, Siemens Medical Solutions) in 33 patients and compared with AVA calculated invasively by the Gorlin-formula at catheterization (CATH-AVA, n = 33) as well as to AVA planimetry by multiplane TEE (TEE-AVA, n = 27). Determination of MRI-AVA was possible with an adequate image quality in 82% (27/33), whereas image quality of TEE-AVA was adequate only in 56% (15/27) of patients because of calcification artifacts (P = 0.05). The correlation between MRI-AVA and CATH-AVA was 0.80 (P < 0.0001) and the correlation of MRI-AVA and TEE-AVA was 0.86 (P < 0.0001). MRI-AVA overestimated TEE-AVA by 15% (0.98 +/- 0.31 cm2 vs. 0.85 +/- 0.3 cm2, P < 0.001) and CATH-AVA by 27% (0.94 +/- 0.29 cm2 vs. 0.74 +/- 0.24 cm2, P < 0.0001). Nevertheless, a MRI-AVA below 1,3 cm2 indicated severe aortic stenosis (CATH-AVA < 1 cm2) with a sensitivity of 96% and a specificity of 100% (ROC area 0.98). CONCLUSIONS: Planimetry of aortic valve area by MRI can be performed with better image quality as compared with TEE. In the clinical management of patients with aortic stenosis, it has to be considered that MRI slightly overestimates aortic valve area as compared with catheterization despite an excellent correlation.

Myocardial IL-6 regulation by neurohormones--an in vitro superfusion study.

BACKGROUND: Interleukin-6 (IL-6) is expressed in the myocardium and has been implicated in cell proliferation, negative inotropic effects and myocardial hypertrophy. To determine whether myocardial IL-6 is modified by neurohumoral and immunoregulatory stimuli, we studied the effects of lipopolysaccharide (LPS), corticosterone (CS), isoproterenol and angiotensin II on myocardial IL-6 secretion in superfused myocardium. METHODS: Slices of rat left ventricular myocardium were superfused in 80 microl chambers for up to 5h. LPS (1, 50, and 100 microg/ml), CS (10(-7), 10(-6), and 10(-5)M, DSMO as vehicle), isoproterenol (10(-6), 10(-7), and 10(-8)M) and angiotensin II (10(-5), 10(-7), and 10(-9)M) were added to the culture medium at hour 2. IL-6 was measured in the perfusate by ELISA. RESULTS: Physiological corticosterone concentrations (10(-7)M) resulted in an increase in IL-6 concentration (142%) while high doses of steroid decreased IL-6 significantly (CS 10(-6)M: 88+/-14%,p<.05; CS 10(-5): 91+/-9%,p<.05) after 5h. Left ventricular IL-6 secretion was significantly stimulated by LPS 50 microg/ml (3262+/-1684% vs. CTRL: 116+/-34%, p<.01). Isoproterenol treatment increased in IL-6 secretion compared to controls with and without CS, while angiotensin II reduced IL-6 concentration only in combination with CS. CONCLUSION: Myocardial IL-6 secretion is modulated by physiological concentrations of corticosterone or angiotensin II and can be induced by LPS or isoproterenol, indicating a tight regulation of this cytokine. Suppression of cytokine expression within the heart might be a potential therapeutic goal in the treatment of various cardiovascular diseases.

Enhanced ventilatory response to exercise in patients with chronic heart failure and central sleep apnea.

BACKGROUND: In patients with chronic heart failure (CHF), central sleep apnea (CSA) and enhanced ventilatory response (VE/VCO2 slope) to exercise are common. Both breathing disorders alone indicate poor prognosis in CHF. Although augmented chemosensitivity to CO2 is thought to be one important underlying mechanism for both breathing disorders, it is unclear whether both breathing disorders are related closely in patients with CHF. METHODS AND RESULTS: We investigated 20 CHF patients with clinically important CSA (apnea-hypopnea-index (AHI), number of episodes per hour >or=15) and 10 CHF patients without CSA. Patients with and without CSA did not differ with respect to exercise capacity (peak VO2, 63.4+/-3.4% versus 60.8+/-4.4% of predicted value; P=0.746) and left ventricular ejection fraction (LVEF, 31+/-2% versus 31+/-3%; P=0.948). The AHI was not correlated with exercise capacity (peak VO2, percent of predicted value; P=0.260) and LVEF (percent, P=0.886). In contrast, the positive correlation of the VE/VCO2 slope, determined by cardiopulmonary exercise testing, with the AHI was highly significant (P<0.001). The VE/VCO2 slope was significantly increased in patients with CSA compared with those without CSA (29.7 versus 24.9; P<0.001). CONCLUSIONS: The ventilatory response to exercise is significantly augmented in CHF patients with CSA compared with those without. In contrast to peak VO2 and LVEF, the VE/VCO2 slope is strongly related to the severity of CSA in patients with CHF, which underscores an augmented chemosensitivity to CO2 as a common underlying pathophysiological mechanism.

The central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction.

In the course of cardiac diseases, various neuruhomonal systems in the plasma are activated. So far there have been only isolated results of investigations about the functional state of central neuropeptide systems in cardiac diseases and, in particular, in heart failure. We investigated, therefore, the central vasopressinergic system, an important neuropeptide system in cardiocirculatory regulation in a model of myocardial hypertrophy and left ventricular dysfunction, a model of supravalvular aortic stenosis. In addition to increased vasopressin concentrations in plasma, central vasopressin is also altered in this model. A differential stimulation of vasopressin in the hypothalamic areas and in the areas of the brain stem that are involved in central cardiocirculatory regulation was detected. Reduced vasopressin concentrations in the locus coeruleus, an important regulatory area of sympathetic nervous activity, suggest a central regulatory mechanism through which stimulation of the sympathetic nervous activity can be prevented. Our investigations showed that non-osmotic factors like the baroreceptor reflex and angiotensin II, are important stimuli of the vasopressinergic system. We were also able to show that the central vasopressinergic system in rats with experimental heart failure and myocardial hypertrophy is inhibited by treatment with an ACE inhibitor and AT1 receptor antagonist. As seen with autoradiography, this effect is mediated by a central effect of the drugs. Research into central regulatory mechanisms in cardiovascular diseases is, on the one hand, of crucial importance to our understanding of complex pathophysiological processes, and on the other hand, it serves the development of new therapeutic approaches with the goal of influencing these mechanisms directly pharmacologically and for the elucidation of central, currently unknown effects of cardiovascular drugs.

Systemic immunosuppression fails to suppress cardiac cytokine induction in pressure overload hypertrophy in rats.

BACKGROUND: Activation of cytokines such as interleukin-6 (IL-6) has been implicated in the pathogenesis of left ventricular dysfunction and hypertrophy since they have been shown to mediate cell proliferation, negative inotropic effects and myocardial hypertrophy. However, the effects of immunosuppressive therapy on cytokines in the treatment of heart failure and hypertrophy are unclear. AIMS: To test the hypothesis that systemic immunosuppresion may influence serum and myocardial IL-6 and, thereby, may affect progression of myocardial hypertrophy. We studied the effects of chronic treatment with methotrexate (MTx) and with the ACE inhibitor ramipril on IL-6 in rats with pressure overload left ventricular hypertrophy (LVH) due to aortic banding. METHODS: Animals were treated with either vehicle (n = 6) or methotrexate (MTx 1: 0.3 mg/kg BW/week; MTx 2: 0.9 mg/kg BW/week; i.p.; n = 6 each group) once a week during weeks 4-12 after aortic banding; sham-operated rats served as controls (CTRL; n = 8). During the development of LVH, serum IL-6 was determined by rat-specific ELISA and 12 weeks after aortic banding myocardial IL-6 was measured using a tissue superfusion technique or determining of protein concentration. RESULTS: Aortic banding significantly lowered blood pressure, increased left ventricular weight and resulted in elevated serum IL-6 levels (27.6 +/- 5.1 vs 19.1 +/- 2.3 pg/ml, p < 0.05) compared to CTRL. MTx treatment normalised the initially elevated serum IL-6 levels after 8 weeks of treatment. The significant increase in IL-6 concentration in the superfusate of all aortic banding groups compared to CTRL (< 30%, p < 0.05) was not altered by prior MTx therapy. Accordingly, both doses of MTx failed to prevent LVH progression (1.67 +/- 0.23 g vs. 2.32 +/- 0.31 g, p < 0.05). In contrast, chronic inhibition of the RAAS not only prevents LVH but also reduces myocardial IL-6 concentration (6898 +/- 355 vs. 3073 +/- 366 pg/mg protein, p < 0.05). CONCLUSION: Pressure overload LVH in rats is characterized by an increase in serum levels of IL-6 as well as myocardial IL-6. Chronic immunosuppressive therapy normalized systemic IL-6 levels, but failed to reduce cardiac IL-6 expression and the progression of LVH, while ACE inhibition is sufficient to modify LVH and thereby normalises myocardial IL-6 expression.