Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study.

OBJECTIVE: Based upon epidemiological studies, male gender and younger age are risk factors for developing fatal myocarditis. The impact of age and gender on myocardial injury pattern in acute myocarditis, however, is not well understood. In patients with clinically acute myocarditis, this study sought to characterise the relation between patient age and gender and the extent of myocardial involvement using cardiovascular magnetic resonance (CMR) imaging. CMR markers for oedema, inflammation and fibrosis defined myocardial involvement. DESIGN, SETTING AND PATIENTS: 65 patients (42 years old (SD 15), 41 male) with clinically acute myocarditis were assessed. Using standard methods, T2-weighted and contrast-enhanced T1-weighted (early and late enhancement) CMR images were acquired. T2 images were visually and quantitatively assessed for oedema. Early enhancement images were quantified for inflammation, as was regional fibrosis in late enhancement images. Data were analysed for groups of age (>40, <40 years) and gender. RESULTS: 62% of all patients had evidence of regional oedema, which was more prevalent in patients below 40 years of age (80.7% vs 51.3%, p<0.05), as was myocardial fibrosis (76.9% vs 48.7%, p<0.05). However, early enhancement was more frequently found in patients above 40 years (84.2% vs 61.5%, p<0.05). Men were twice as likely as women to demonstrate myocardial fibrosis (73.2 vs 37.5%, p<0.01). CONCLUSION: In patients with clinically acute myocarditis, myocardial fibrosis was more frequent in men and in patients younger than 40 years. Injury sustained in younger patients appears to be more regional and more severe, as indicated by a higher incidence of irreversible injury.

Contrast-enhanced adenosine-stress magnetic resonance imaging--feasibility and practicability of a protocol for detection or exclusion of ischemic heart disease in an outpatient setting.

BACKGROUND: Evaluating myocardial function, assessing ischemic myocardial areas and detecting myocardial viability are necessary diagnostic information for guiding further therapy in patients with angina. The aim of this study was to show feasibility and safety of a compiled contrast- enhanced magnetic resonance imaging (ceMRI) protocol providing the above mentioned diagnostic possibilities and to demonstrate its applicability in daily routine. METHODS: Consecutive patients with angina were screened on a 1.5 Tesla system. Functional images in short and long axis orientation were acquired for each patient. First-pass kinetics of a gadolinium-based contrast agent (0.1 mmol/kg) were measured after three minutes of stress with adenosine infusion (140 microg/kg/min). 10 min after a second bolus injection of contrast agent "late enhancement" (MLE) sequences were acquired for the detection of myocardial necrosis. RESULTS: We enrolled 3174 patients referred for ceMRI for detection or exclusion of ischemic heart disease. One patient experienced a major complication due to hyperventilation followed by grand mal seizure. In 1121 (35.3%) patients minor complications, such as mild chest pain or dyspnea (30%), temporarily and asymptomatic AV block (3%) or nausea (2%) could be observed under adenosine infusion. Hypoperfusion in more than one myocardial segment and affecting more than 1/3 of the myocardial wall diameter could be detected in 1972 (62%) patients. Subendocardial hypoperfusion with limited duration could be shown in 897 (28%) patients. In 305 (10%) patients hypoperfusion could be excluded. MLE could be seen in 532 (17%) patients. CONCLUSION: This compiled ceMRI protocol is suitable for detection or exclusion of ischemic heart disease in an outpatient routine. We showed feasibility, applicability and safety of our protocol. CeMRI may serve as a useful surrogate for non-invasive diagnostics prior to invasive coronary angiography in many outpatients.

Magnetic resonance planimetry of the vena contracta as a new approach to assessment of stenotic heart valves: an in vitro study.

Exact determination of the orifice area in stenotic valve disease is essential to guide therapy. With the standard imaging methods, the orifice area has to be calculated by empirically-derived formulas, which may be susceptible to changes in hemodynamic status, leading to wrong therapeutic decisions. We tested the ability of magnetic resonance imaging (MRI) to quantify the orifice area by planimetry of the proximal vena contracta (PVC) in an idealized, constant-flow model in a 1.0-T tomograph (Siemens Magnetom Expert). There was a close correlation of the PVC area in MRI and the true orifice area (r2 = 0.985), and agreement of the methods as measured by the Bland-Altman test was significant with a low systematic error of -0.02 cm2. We conclude that MRI planimetry of the PVC in stenotic valves in a constant-flow model may be used to reliably measure the orifice area.

Measurement of left ventricular dimensions and function in patients with dilated cardiomyopathy.

Studies on medical therapy in heart failure are focused on changes of left ventricular (LV) dimensions and function. These changes may be small, requiring a large study group. We measured LV parameters (LV volumes, LV ejection fraction (LV-EF), and left ventricular mass (LVM)) with two-dimensional echocardiography (2D-echo) and magnetic resonance imaging (MRI) in 50 patients. Based on the difference between the measurements, we determined the variance of the results and calculated the sample sizes needed to detect changes of baseline values. For the calculated and measured parameters we found significant differences between the two techniques: LV-EF and LVM were higher in 2D-echo, and LV dimensions were comparable. The sample size to detect relevant changes from baseline with MRI was significantly (P < 0.01) smaller than in 2D-echo. We conclude that MRI is superior in clinical studies on left ventricular dimensional and functional changes, since measurements are more reproducible and the required sample size is substantially smaller, thereby reducing costs.

The somatotrophic system in patients with dilated cardiomyopathy: relation of insulin-like growth factor-1 and its alterations during growth hormone therapy to cardiac function.

OBJECTIVE: Treatment with human recombinant growth hormone has yielded conflicting results in patients with congestive heart failure. In addition, growth hormone resistance has been reported in severe heart failure. Therefore, the purpose of this study was to evaluate the somatotrophic axis and effects of growth hormone on haemodynamics in patients with heart failure due to dilated cardiomyopathy. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Fifty clinically-stable patients with moderate heart failure (mean left ventricular ejection fraction = 26 +/- 2%) due to dilated cardiomyopthy were examined. MEASUREMENTS: Patients were randomly assigned to treatment with placebo or 2 IU/d sc human recombinant growth hormone for a mean of 14 weeks. Cardiac size and function were evaluated by magnetic resonance imaging. Central haemodynamics were obtained by right heart catheterization. Measurements of plasma noradrenaline, serum insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were performed by standard assays at baseline and at the end of the treatment period. RESULTS: The severity of heart failure as determined by stroke volume, left ventricular end diastolic diameter and plasma noradrenaline concentrations correlated significantly to baseline serum insulin-like growth factor-1 levels (each P < 0.05). The growth hormone-induced increase of insulin-like growth factor-1 predicted the changes in ejection fraction (P < 0.05). A significant increase in ejection fraction of 7% was observed in patients whose insulin-like growth factor-1 increased by more than the median increase in comparison to the patients with an increase below the median (+ 4.0 +/- 2.3% vs. - 3.0 +/- 1.8%; P = 0.03). CONCLUSIONS: Serum levels of insulin-like growth factor-1, reflecting growth hormone secretion, are diminished in relation to the severity of heart failure in patients with dilated cardiomyopathy. Growth hormone induced increases of insulin-like growth factor-1 of more than 77 ng/l caused significant improvement of ejection fraction.

The severity of chronic heart failure due to coronary artery disease predicts the endocrine effects of short-term growth hormone administration.

Treatment with human recombinant GH has yielded conflicting results in patients with heart failure. As GH sensitivity may be important for treatment effects, the present study evaluated GH secretion and sensitivity in noncachectic patients with ischemic heart failure. Twenty clinically stable, male patients with moderate heart failure (mean New York Heart Association class, 2.0 +/- 0.8; mean ejection fraction, 30.0 +/- 8.4%) due to coronary artery disease were randomly assigned single blind to a low dose (group A; n = 10) and a high dose (group B; n = 10) group, receiving either 5 microg/kg x day recombinant human GH for 4 days followed by 10 microg/kg x day GH for another 4 days or 10 and 20 microg/kg x day GH, respectively. Cardiac function was assessed by echocardiography. Serum insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and 24-h urinary GH excretion as a measure of pituitary GH secretion were determined at baseline and on days 5 and 9. Baseline IGF-I and IGFBP-3 levels and GH excretion were significantly diminished compared to those in age-matched controls. There was a dose-dependent increase in IGF-I and IGFBP-3 during GH treatment. The increase in IGF-I induced by 10 microg/kg x day GH correlated positively to left ventricular ejection fraction (r = 0.59; P = 0.006) and inversely to left ventricular end-diastolic and end-systolic dimensions (r < -0.6 and P < 0.01 for both). In conclusion, GH secretion and serum levels of IGF-I and IGFBP-3 are diminished in patients with moderate ischemic heart failure. Left ventricular function determines the sensitivity of the GH/IGF-I system, measured as the IGF-I response to GH application. This finding suggests that individual dose adjustments may be an indispensable prerequisite for successful GH therapy in heart failure.

The value of magnetic resonance imaging of the left ventricular outflow tract in patients with hypertrophic obstructive cardiomyopathy after septal artery embolization.

BACKGROUND: We tested the value of magnetic resonance imaging (MRI) in the follow-up of patients with hypertrophic obstructive cardiomyopathy after septal artery embolization. MRI provides a noninvasive visualization of transplanar turbulent flow in order to quantify left ventricular outflow tract obstruction. METHODS AND RESULTS: We followed 10 patients who were treated with septal artery embolization for 12 months. We used gradient echo sequences to document continuous improvement of the outflow tract area and T1- and T2-weighted spin echo sequences to visualize myocardial infarction. A continuous, but not linear, improvement of the outflow tract area occurred after septal artery embolization during the 12-month follow-up period. The improvement of the outflow tract area correlated well with the amelioration of symptoms (r(2)=0.86). CONCLUSIONS: We conclude that MRI reliably detects the degree of obstruction in patients with hypertrophic obstructive cardiomyopathy. This modality may be especially useful for follow-up after septal artery embolization.

Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. METHODS: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. RESULTS: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P = 0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 mumol/mmol creatinine (P = 0.027) and 65 nmol/mmol creatinine (P = 0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. CONCLUSION: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

Visualization of cardiac involvement in patients with systemic sarcoidosis applying contrast-enhanced magnetic resonance imaging.

Contrast-enhanced MRI may serve as a sensitive noninvasive tool for the detection and follow-up of myocardial involvement in patients with systemic sarcoidosis.

Safety of implantable coronary stents during 1H-magnetic resonance imaging at 1.0 and 1.5 T.

The safety of most available implantable intracoronary stents during magnetic resonance imaging (MRI) has not been sufficiently tested. Minor, but possibly clinically significant, increases in temperature have not been excluded. We measured temperature changes of 14 different stents clinically in use or currently tested for release on the world market. Stents were examined in 1.0- and 1.5-T MR scanners with multiple sequences used in routine cardiac and thoracic MRI examinations ("clinical worst case") and after implantation of the stents into the coronary arteries of excised pig hearts (1.5-T scanner only). We used a highly sensitive infrared camera with a thermal resolution of 10 mK and did not see significant heating of any stent during the examinations. We conclude that MRI is safe in patients with the currently available intracoronary stents.

Growth hormone therapy in heart failure.

Clinical and experimental data in animals and patients with endstage heart failure due to dilated cardiomyopathy or ischemic heart disease suggest a beneficial role of growth factors like human recombinant growth hormone or insulin-like growth factor I. Their cardiac effects are an increase in myocardial mass and a decrease in systolic wall stress. Based on the results of animal studies and of preliminary studies in patients with dilated cardiomyopathy, double-blind and placebo-controlled studies have proven the increase in myocardial mass and a significant reduction of left ventricular wall stress, as demonstrated by magnetic resonance imaging.The risk of the additional therapy with human growth factors in this high-risk group of patients with a high mortality is justified, if this new approach becomes a possible alternative to cardiac transplantation or a bridge toward transplantation.If future randomized studies in larger patient groups with an individualized substitution therapy with growth hormone and/or IGF-I can demonstrate a beneficial effect on mortality and morbidity, this new therapeutic approach could become an attractive alternative in these high-risk patients.

Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy.

BACKGROUND: Some studies have suggested that treatment with recombinant human growth hormone (rhGH) increases left-ventricular mass and improves haemodynamic and functional status in patients with heart failure due to dilated cardiomyopathy. We did a double-blind, randomised, placebo-controlled study of rhGH in patients with chronic heart failure due to dilated cardiomyopathy. METHODS: 50 patients (43 men) were randomly allocated treatment with subcutaneous rhGH (2 IU daily) or placebo for a minimum of 12 weeks. The primary endpoints were the effects on left-ventricular mass and systolic wall stress. The secondary endpoints were the effects on left-ventricular size and function. Data were analysed by intention to treat. FINDINGS: Patients in the rhGH group had an increase in left-ventricular mass compared with those in the placebo group (27%, p=0.0001). There was no significant difference in left-ventricular systolic wall stress, mean blood pressure, or systemic vascular resistance between the two groups. New York Heart Association functional class, left-ventricular ejection fraction, and distance on the 6 min walking test were unchanged. The change in serum insulin-like growth factor (IGF)-I concentrations (rhGH 77 ng/mL; placebo -19 ng/mL, GH vs placebo p=0.0001) was significantly related to the change in left-ventricular mass (r=0.55, p=0.0001). One patient in the rhGH group was withdrawn at 6 weeks because of worsening heart failure. INTERPRETATION: There is a significant increase in left-ventricular mass in patients with dilated cardiomyopathy given rhGH but this is not accompanied by an improvement in clinical status. Changes in left-ventricular mass are related to changes in serum IGF-I concentrations. Whether a longer treatment period would provide clinical benefits and decrease mortality is unknown.

Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis.

BACKGROUND: The course of tissue changes in acute myocarditis in humans is not well understood. Diagnostic tools currently available are unsatisfactory. We tested the hypothesis that inflammation is reflected by signal changes in contrast-enhanced magnetic resonance imaging (MRI). METHODS AND RESULTS: We assessed 44 consecutive patients with symptoms of acute myocarditis. Nineteen patients met the inclusion criteria revealing ECG changes, reduced myocardial function, elevated creatine kinase, positive troponin T, serological evidence for acute viral infection, exclusion of coronary heart disease, and positive antimyosin scintigraphy. We studied these patients on days 2, 7, 14, 28, and 84 after the onset of symptoms. We obtained ECG-triggered, T1-weighted images before and after application of 0.1 mmol/kg gadolinium. We measured the global relative signal enhancement of the left ventricular myocardium related to skeletal muscle and compared it with measurements in 18 volunteers. The global relative enhancement was higher in patients on days 2 (4.8+/-0.3 [mean+/-SE] versus 2.5+/-0.2; P<.0001); 7 (4.7+/-0.5, P<.0001); 14 (4.6+/-0.5, P<.0002); and 28 (3.9+/-0.4, P=.009) but not on day 84 (3.1+/-0.3; P=NS). On day 2, the enhancement was focal, whereas at later time points, the enhancement was diffuse. In patients with evidence of ongoing disease, the values remained elevated. CONCLUSIONS: Acute myocarditis evolves from a focal to a disseminated process during the first 2 weeks after onset of symptoms. Contrast media-enhanced MRI visualizes the localization, activity, and extent of inflammation and may serve as a powerful noninvasive diagnostic tool in acute myocarditis.

[Therapy of dilated cardiomyopathy with recombinant human growth hormone]. / Therapie der dilatativen Kardiomyopathie mit rekombinantem humanem Wachstumshormon.

Dilated cardiomyopathy is a disease of the myocardium which is characterized by predominant enlargement of the left ventricle, decreased systolic function, and reduced myocardial wall thickness. The reduction in the number and function of myocardial fibers induces hypertrophy and leads to interstitial fibrosis. Ventricular dilatation and reduced wall thickness contributes to a further increase of the already elevated myocardial wall stress and triggers the continuous decrease of myocardial function. The initial myocyte injury by different and mostly unknown causes leads to progressive myocyte damage resulting in a similar uniform clinical picture independent from the initial myocellular derangement. One of the common pathways may be an inadequate response of the heart to human growth hormone (GH). Several studies support this hypothesis: GH deficiency results in a significant reduction of ventricular wall thickness and myocardial function, and GH-substitution is able to normalize the depressed left ventricular function. In addition, Sacca et al. reported in an uncontrolled study that GH-therapy reduced left ventricular wall stress by 40% in 7 patients with dilated cardiomyopathy. There was a parallel increase of the ejection fraction from 34% to 47%. This improvement was accompanied by a decrease of the functional classification of heart failure from NYHA 2.7 to 1.6. This therapeutic approach to alter the myocyte function directly by growth factors may open a new therapeutic concept in dilated cardiomyopathy. If double blind, randomized studies confirm the results of Sacca's study, a new era of therapeutic options may be available for the treatment of dilated cardiomyopathy.