Caroline Weytjens

Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease

BACKGROUND Restrictive valvular heart disease has been reported in patients with Parkinsons disease treated with pergolide. However, few data are available on frequency, severity, dose dependency, and reversibility of pergolide-induced disease, nor on the pulmonary pressures of these patients. We aimed to clarify these characteristics in a large group of patients. METHODS 78 patients with Parkinsons disease treated with pergolide and 18 never treated with an ergot-derived dopamine agonist (controls) were evaluated by echocardiography. A valvular scoring system was used, ranging from 1 (proven ergot-like restrictive valvular heart disease) to 4 (no disease). For the mitral valve, tenting areas and tenting distances were measured. Systolic pulmonary artery pressures were derived from the tricuspid regurgitant jet. FINDINGS Restrictive valvular heart disease of any type was present in 26 (33%) patients in the pergolide group and none in controls (p=0.0025). Important disease (score 1 or 2) was present in 15 (19%) patients in the pergolide group and none in controls (p=0.066). Mean tenting distances and tenting areas of the mitral valve were 1.08 cm (range 0.55-2.66) and 2.39 cm2 (0.88-4.59) in the restrictive mitral valve group versus 0.63 cm (0.22-1.20) and 1.39 cm2 (0.39-3.23) in the non-restrictive group (p=0.003 and p<0.0001, respectively). Significant correlation was noted between cumulative doses of pergolide and tenting areas of the mitral valves (r=0.412, p=0.017). Mean systolic pulmonary artery pressures were 39.3 mm Hg (range 25-71) in the high-dose group versus 38.5 mm Hg (20-65) in the low-dose group (p=0.76) and 31 mm Hg (25-40) in controls (p=0.02 vs all patients given pergolide). In six patients, pergolide treatment was stopped because of restrictive valvular heart disease, in two of whom regression of disease was shown. INTERPRETATION Restrictive valvular heart disease is not a rare finding in patients treated with pergolide. Clinicians should consider changing to a non-ergot drug if this disease is diagnosed.

Effect of a telemonitoring‐facilitated collaboration between general practitioner and heart failure clinic on mortality and rehospitalization rates in severe heart failure: the TEMA‐HF 1 (TElemonitoring in the MAnagement of Heart Failure) study

Chronic heart failure (CHF) patients are frequently rehospitalized within 6 months after an episode of fluid retention. Rehospitalizations are preventable, but this requires an extensive organization of the healthcare system. In this study, we tested whether intensive follow‐up of patients through a telemonitoring‐facilitated collaboration between general practitioners (GPs) and a heart failure clinic could reduce mortality and rehospitalization rate.

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Serotonergic drugs, such as pergolide, have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (5-HT)(2B) receptor (5-HT(2B)R). Therefore, we sought to determine whether cyproheptadine, a 5-HT(2B)R antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, 50 male Wistar rats received daily intraperitoneal injections of pergolide (0.5 mg/kg, n = 14), pergolide (0.5 mg/kg) combined with cyproheptadine (10 mg/kg, n = 12), cyproheptadine (10 mg/kg, n = 12), or no injections (control, n = 12) for 20 wk. Echocardiography was performed blindly at baseline and at 10 and 20 wk followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 wk, aortic regurgitation was present in all pergolide-treated animals, whereas it was less frequently observed in the other groups (P < 0.0001). For the other valves, this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid, and exhibited more 5-HT(2B)R-positive cells in pergolide-treated animals compared with the other groups. Moreover, regurgitant aortic and mitral valves were thicker than nonregurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats, which was associated with a reduced number of 5-HT(2B)R-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.

Effect of streptozotocin-induced diabetes on myocardial blood flow reserve assessed by myocardial contrast echocardiography in rats

AbstractThe role of structural and functional abnormalities of small vessels in diabetes cardiomyopathy remains unclear. Myocardial contrast echocardiography allows the quantification of myocardial blood flow at rest and during dipyridamole infusion. The aim of the study was to determine the myocardial blood flow reserve in normal rats compared with Streptozotocin-induced diabetic rats using contrast echocardiography.MethodsWe prospectively studied 40 Wistar rats. Diabetes was induced by intravenous streptozotocin in 20 rats. All rats underwent baseline and stress (dipyridamole: 20 mg/kg) high power intermittent imaging in short axis view under anaesthesia baseline and after six months. Myocardial blood flow was determined and compared at rest and after dipyridamole in both populations. The myocardial blood flow reserve was calculated and compared in the 2 groups. Parameters of left ventricular function were determined from the M-mode tracings and histological examination was performed in all rats at the end of the study.ResultsAt six months, myocardial blood flow reserve was significantly lower in diabetic rats compared to controls (3.09 ± 0.98 vs. 1.28 ± 0.67 ml min-1 g-1; p < 0.05). There were also a significant decrease in left ventricular function and a decreased capillary surface area and diameter at histology in the diabetic group.ConclusionIn this animal study, diabetes induced a functional alteration of the coronary microcirculation, as demonstrated by contrast echocardiography, a decrease in capillary density and of the cardiac systolic function. These findings may offer new insights into the underlying mechanisms of diabetes cardiomyopathy.

Doppler myocardial imaging in the diagnosis of early systolic left ventricular dysfunction in diabetic rats.

AIM To find out if Doppler myocardial imaging (DMI) can detect early signs of left ventricular (LV) dysfunction in a rat model of diabetic cardiomyopathy. METHODS Eight control and 12 Streptozotocin (STZ)-induced diabetic rats underwent transthoracic echocardiography with high-resolution technology at baseline and 2, 4, 8, 12, and 16 weeks after STZ injection. Radial function was analysed using conventional M-mode, and velocity, strain and strain rate imaging. Longitudinal function was analysed using pulsed Doppler imaging of the mitral annulus. RESULTS In the diabetic rats, a significant increase in LV end diastolic and end systolic diameter was measured when compared with controls (P < 0.001). Fractional shortening and LV ejection fraction remained unchanged in both groups. Using DMI, diabetic rats demonstrated a decrease in radial systolic velocity (rate of change: +0.01 vs. -0.003 week(-1); P < 0.01) and radial systolic strain rate (+0.003 vs. -0.205 week(-1); P = 0.08) of the anteroseptal wall. Histologic examination revealed dilated cardiomyopathy with no signs of fibrosis. CONCLUSION Although LV ejection fraction remained preserved, velocity and strain rate imaging was able to detect radial systolic dysfunction in diabetic rats. The absence of histological signs of fibrosis suggests that other mechanisms play a role in the development of diabetic cardiomyopathy.

Effect of streptozotocin-induced diabetes on left ventricular function in adult rats: an in vivo Pinhole Gated SPECT study

BackgroundRecent studies have suggested that diabetes mellitus (DM) may cause left ventricular (LV) dysfunction directly resulting in increased susceptibility to heart failure. Using pinhole collimators and advances in data processing, gated SPECT was recently adapted to image the rat heart. The present study was aimed to assess this new imaging technique for quantifying LV function and remodeling from the Streptozotocin (STZ) rat model compared to controls.MethodsTwenty one rats were randomly assigned to control or diabetic group. Six months after the induction of diabetes by STZ, Pinhole 99 m Tc-sestamibi gated SPECT was performed for determining rat LV volumes and function. Post-mortem histopathologic analysis was performed to evaluate the determinant of LV remodeling in this model.ResultsAfter six months, the normalized to body weight LV End-systolic volume was significantly different in diabetic rats compared to controls (0.46 ± 0.02 vs 0.33 ± 0.03 μL/g; p = 0.01). The normalized LV End-diastolic volume was also different in both groups (1.51 ± 0.03 vs 0.88 ± 0.05 μL/g; p = 0.001) and the normalized stroke volume was significantly higher in STZ-rats (1.05 ± 0.02 vs 0.54 ± 0.06 μL/g; p = 0.001). The muscular fibers were thinner at histology in the diabetic rats (0.44 ± 0.07 vs 0.32 ± 0.06 AU; p = 0.01).ConclusionPinhole 99 m Tc-sestamibi gated SPECT can successfully be applied for the evaluation of cardiac function and remodeling in STZ-induced diabetic rats. In this model, LV volumes were significantly changed compared to a control population, leading to a LV dysfunction. These findings were consistent with the histopathological abnormalities. Finally, these data further suggest the presence of diabetes cardiomyopathy.

IMPACT OF ANESTHESIA ON VALVULAR FUNCTION IN NORMAL RATS DURING ECHOCARDIOGRAPHY

Anesthetic agents have different effects on hemodynamic and cardiac functional parameters. The influence of these changes on valvular function has not been studied in small animals. For this purpose, 48 male Wistar rats were divided into three equal groups. An echocardiogram was performed under inhaled isoflurane 2% gas (group I) or under intraperitoneal pentobarbital 50 mg/kg (group II) or ketamine/xylazine (group III) 40/8 mg/kg. Aortic regurgitation was only found in group III (80%, p < 0.0001 vs. groups I and II). Pulmonary and mitral regurgitation (PR, MR) were observed in all groups but were more frequent in group III (PR 67%, MR 100%) compared with group I (PR 13%, p = 0.003; MR 44%, p = 0.001 vs. group III) and group II (PR 19%, p = 0.011; MR 25%, p < 0.0001 vs. group III). Moreover, valvular regurgitations in group III (except tricuspid regurgitation) were more severe compared with groups I and II. The findings in group III were the result of increased blood pressure and afterload, left ventricular (LV) dilation and decreased function. Also in group III, the regurgitations diminished over time as the blood pressure decreased and LV function recovered. Isoflurane and pentobarbital had less pronounced effects on valvular function (5 and 10 min after induction, respectively) compared with ketamine/xylazine and, therefore, might be the anesthetics of choice for valvular evaluation in male Wistar rats. In conclusion, anesthesia causes hemodynamic changes that may result in functional valvular regurgitations in normal rats.

Evaluation of contractile function and inotropic reserve with tissue velocity, strain and strain rate imaging in streptozotocin-induced diabetes

AIMS The aim of the present study was to evaluate left ventricular (LV) function and contractile reserve (CR) with Doppler myocardial imaging (DMI) in a small animal model for type 1 diabetes. METHODS AND RESULTS Cardiac function was assessed in anaesthetized Wistar rats 6 and 8 weeks after injection of 60 mg/kg of streptozotocin. At 6 weeks of diabetes, colour DMI echocardiography was performed at rest and during incremental dosages of dobutamine (5, 10, 20 microg/kg/min). Left ventricular fractional shortening was decreased after 8 weeks of follow-up [36 +/- 5 (D) vs. 41 +/- 4% (C); P = 0.049]. After 6 weeks of diabetes, DMI measurements were reduced in the diabetic rats in the inferolateral wall at rest [systolic velocity: 2.5 +/- 0.4 (D) vs. 4.4 +/- 0.3 (C) cm/s; P < 0.001; systolic strain rate: 12.2 +/- 3.4 (D) vs. 17.4 +/- 3.2 (C) 1/s; P = 0.012] and during inotropic stimulation [delta velocity (cm/s): 0.2 +/- 0.1 (D) vs. 0.5 +/- 0.3 (C)/5 microg dobutamine; P = 0.002; delta strain rate (1/s): 1.4 +/- 0.9 (D) vs. 3.3 +/- 2.2 (C)/5 microg dobutamine; P = 0.049]. Furthermore, the intraventricular delay in time-to-peak systolic strain was larger in diabetes [20 +/- 18 (D) vs. 10 +/- 7 (C) ms; P= 0.01]. Systolic mitral annular velocity was also lower in the diabetic rats at rest [2.7 +/- 0.4 (D) vs. 3.5 +/- 0.4 (C) cm/s; P < 0.001] and in response to dobutamine [delta velocity (cm/s): 0.1 +/- 0.1 (D) vs. 0.3 +/- 0.2 (C)/5 microg dobutamine; P = 0.013]. CONCLUSION In experimental diabetes, a reduction in radial and longitudinal LV function and CR can be detected with DMI before the onset of a reduced global LV function.

Prevalence of potential cardiac resynchronization therapy candidates and actual use of cardiac resynchronization therapy in patients hospitalized for heart failure.

Cardiac resynchronization therapy (CRT) is increasingly used as an additional therapy for patients with chronic heart failure (CHF) in New York Heart Association (NYHA) class III or IV on optimal medical therapy who have a left ventricular ejection fraction (LVEF) ≤35% and an increased QRS duration (≥120 ms). A recent meta-analysis also indicates that patients with milder heart failure could potentially benefit from this therapy. Despite the evidence regarding the effects of CRT, recent surveys suggest that this therapy is probably underused, with a large variation between hospitals regarding implantation rates in patients hospitalized with CHF. Also, although implantation rates for implantable cardioverter defibrillator and CRT-D have increased significantly in Europe, there remain major (and unexplained) differences between countries. Finally, data on the prevalence of CRT candidates in hospitalized CHF patients are limited.

Influence of Heart Rate Reduction on Doppler Myocardial Imaging Parameters in a Small Animal Model

In small animals studies, sick animals often have a significant reduction in heart rate while under anesthesia. The influence of heart rate reduction on Doppler myocardial imaging (DMI) parameters is not known. The aim of the present study was to assess the effect of heart rate reduction on DMI parameters in a small animal model. Twenty-four rats underwent transthoracic echocardiography at baseline and during the administration of ivabradine IV. In all rats, left ventricular (LV) systolic velocity, strain and strain rate were measured in the anteroseptal and inferolateral wall segments from short axis views. In 12 rats (group A), M-mode analysis was also performed for assessment of global LV function. In the other 12 rats (groups B), contractility was quantified invasively using the end-systolic pressure-volume relation (ESPVR) and the preload recruitable stroke work (PRSW). During ivabradine, administration heart rate decreased by 18% in group A (p < 0.001) and 36% in group B (p < 0.001). There was a slight increase in LVEDD and LVESD, with no change in cardiac output or LV ejection fraction. During ivabradine administration, DMI parameters did not change significantly in any group. No significant correlation between DMI parameters and heart rate (r(2) = 0.05) or ejection time (r(2) = 0.14) could be found. The absence of changes in contractility was confirmed by the absence of change in PRSW and end-systolic elastance (Ees). In conclusion, moderate heart rate reduction did not influence DMI measurements in this specific rat model. Therefore, in the interpretation of DMI data when performing small animal studies, moderate heart rate reduction does not need to be taken into account.