Jane McCrohon

Differentiation of Heart Failure Related to Dilated Cardiomyopathy and Coronary Artery Disease Using Gadolinium-Enhanced Cardiovascular Magnetic Resonance

Background Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) from left ventricular (LV) dysfunction caused by coronary artery disease (CAD). Methods and Results Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%). Conclusions Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM. (Circulation. 2003;108:54‐59.)

Toward clinical risk assessment inhypertrophic cardiomyopathy withgadolinium cardiovascular magnetic resonance

OBJECTIVES We sought to assess whether hyperenhancement by gadolinium cardiovascular magnetic resonance (CMR) occurs in hypertrophic cardiomyopathy (HCM) and correlates with the risk of heart failure and sudden death. BACKGROUND The myocardial interstitium is abnormal in HCM at post-mortem. Focally increased interstitial myocardial space appears as hyperenhancement with gadolinium CMR. METHODS In a blinded, prospective study, HCM patients were selected for the presence (n = 23) or absence (n = 30) of an increased clinical risk of sudden death and/or progressive adverse left ventricular (LV) remodeling. Gadolinium-enhanced CMR was performed. RESULTS Myocardial hyperenhancement was found in 42 patients (79%), affecting 10.9% (range 0% to 48%) of the LV mass. There was a greater extent of hyperenhancement in patients with progressive disease (28.5% vs. 8.7%, p < 0.001) and in patients with two or more risk factors for sudden death (15.7% vs. 8.6%, p = 0.02). Improved discrimination was seen in patients >40 years old (29.6% vs. 6.7%, p < 0.001) for progressive disease and for patients <40 years old for risk factors for sudden death (15.7% vs. 2.1%, p = 0.002). Patients with diffuse rather than confluent enhancement had two or more risk factors for sudden death (87% vs. 33%, p = 0.01). CONCLUSIONS Gadolinium CMR reveals myocardial hyperenhancement in HCM. The extent of hyperenhancement is associated with progressive ventricular dilation and markers of sudden death.

Androgen Exposure Increases Human Monocyte Adhesion to Vascular Endothelium and Endothelial Cell Expression of Vascular Cell Adhesion Molecule-1

BACKGROUND Male sex is an independent risk factor for coronary artery disease. Owing to the importance of monocyte adhesion to endothelial cells in the development of atherosclerosis, we hypothesized that androgens might promote this process. We therefore studied the effects of the nonaromatizable androgen dihydrotestosterone (DHT) on human monocyte adhesion to human endothelial cells and on endothelial cell-surface expression of adhesion molecules. METHODS AND RESULTS Human umbilical vein endothelial cells (HUVECs) were grown to confluence in media supplemented with postmenopausal female serum, then exposed for 48 hours to either DHT (40 and 400 nmol/L), with or without the androgen receptor blocker hydroxyflutamide (HF) (4 micromol/L); HF alone; or vehicle control (ethanol 0.1%). Human monocytes obtained by elutriation were incubated for 1 hour with the HUVECs at 37 degrees C, and adhesion was measured by light microscopy. Compared with vehicle control, monocyte adhesion was increased in the androgen-treated HUVECs in a dose-dependent manner (116+/-6% and 128+/-3% for DHT 40 and 400 nmol/L respectively; P<0.001). HF blocked this increase (P>/=0.3 compared with control). Surface expression of endothelial cell adhesion molecules was measured by ELISA and revealed an increased expression of vascular cell adhesion molecule-1 (VCAM-1) in the DHT-treated HUVECs (125+/-5% versus 100+/-4% in controls; P=0.002), an effect also antagonized by HF (P>/=0.3 compared with controls). Furthermore, the DHT-related increase in adhesion was completely blocked by coincubation with anti-VCAM-1 antibody. Comparable results were obtained in arterial endothelial cells and in endothelium stimulated with the cytokine tumor necrosis factor-alpha. CONCLUSIONS Androgen exposure is associated with increased human monocyte adhesion to endothelial cells, a proatherogenic effect mediated at least in part by an increased endothelial cell-surface expression of VCAM-1.

Parenteral administration of recombinant human neuregulin‐1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses

Neuregulin‐1 (NRG‐1) plays a critical role in the adaptation of the heart to injury, inhibiting apoptosis and inducing cardiomyocyte proliferation. We have shown previously that rhNRG‐1 improves cardiac function and survival in animal models of cardiomyopathy. Here we report the first human study aimed at exploring the acute and chronic haemodynamic responses to recombinant human NRG‐1 (beta2a isoform; rhNRG‐1) in patients with stable chronic heart failure (CHF).

Vascular Reactivity Is Impaired in Genetic Females Taking High-Dose Androgens

OBJECTIVE To assess the vascular effects of high-dose androgen treatment in genetic females. BACKGROUND Male gender is an independent risk factor for coronary artery disease, suggesting either a protective effect of estrogens and/or a deleterious effect of androgens. We have recently demonstrated that androgen deprivation is associated with enhanced vascular reactivity in adult men, however, the effects of androgen excess on vascular function in humans has not been reported previously. METHODS We studied vascular reactivity in two groups of genetic females: 12 female-to-male transsexuals receiving long-term high-dose androgens, and 12 healthy female control subjects, matched for age and smoking history. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (leading to flow-mediated dilatation [FMD], which depends on normal endothelial function) and after sublingual nitroglycerin (NTG), an endothelium-independent dilator. RESULTS Testosterone levels were higher (15.2+/-8.7 vs. 1.9+/-1.3 mmol/L, p < 0.001) and high-density lipoprotein cholesterol levels were lower (1.2+/-0.2 vs. 1.6+/-0.4 mmol/L, p=0.02) in the transsexuals compared with the control subjects. In each group, nine of 12 subjects were current or ex-smokers, leading to impaired FMD in both groups (5.1+/-3.7% in the transsexuals vs. 6.9+/-4.1% in controls, p=0.28). The NTG response was significantly decreased in the transsexuals (15.9+/-4.9% vs. 22+/-5.8% in controls, p=0.01), independent of the effects of age, cholesterol or vessel size. CONCLUSIONS Long-term treatment with high-dose androgens is associated with impaired vascular reactivity in genetic females, consistent with a deleterious effect of androgen excess on arterial physiology.

Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women

OBJECTIVE Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post‐menopausal women. As older age is associated with progressive arterial endothelial damage, a key event in atherosclerosis, we assessed whether hormone replacement therapy (HRT) with oestrogen alone, or oestrogen and progesterone combined, is associated with improved endothelial function in healthy women after the menopause.

Androgen Receptor Expression Is Greater in Macrophages From Male Than From Female Donors A Sex Difference With Implications for Atherogenesis

BACKGROUND Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. METHODS AND RESULTS Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64+/-0.06 versus 0.15+/-0.02 amol/microgram total RNA; P<0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (P=0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109+/-10%, 117+/-3%, and 120+/-4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, P=0.002; 95+/-8% for DHT with hydroxyflutamide, P=0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (P>0.2 versus controls). CONCLUSIONS Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.

Arterial Reactivity Is Enhanced in Genetic Males Taking High Dose Estrogens

OBJECTIVES We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. BACKGROUND Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. METHODS We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. RESULTS Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). CONCLUSIONS Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.

Estrogen and Progesterone Reduce Lipid Accumulation in Human Monocyte-Derived Macrophages A Sex-Specific Effect

BACKGROUND Males have an earlier onset and greater prevalence of clinical atherosclerosis than age-matched females, which is consistent with an atheroprotective effect of the female sex steroids, estrogen and progesterone. We therefore examined the effects of estrogen and progesterone on human foam cell formation, a key early event in atherogenesis. METHODS AND RESULTS Monocytes from healthy female and male donors were obtained from white cell concentrates and allowed to differentiate into macrophages over 10 days. These human monocyte-derived macrophages (MDMs) were exposed to either control (0.1% vol/vol ethanol) or estrogen or progesterone treatment on days 3 through 10. Lipid loading was achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the MDMs was then extracted for analysis of cholesteryl ester (CE) content. 17beta-Estradiol at both physiological (2 nmol/L) and supraphysiological (20 and 200 nmol/L) concentrations produced a significant reduction in macrophage CE content (88+/-3%, 88+/-2%, and 85+/-4%, respectively; P<0.02 compared with control). Physiological and supraphysiological levels of progesterone (2, 10, and 200 nmol/L) produced an even more dramatic reduction in CE content (74+/-9%, 56+/-10%, and 65+/-8%, respectively; P<0.002 compared with control). This effect could be abrogated by coincubation with the progesterone receptor antagonist RU486. Neither estrogen nor progesterone produced a reduction in lipid loading in male-donor-derived MDMs. Detailed lipid trafficking studies demonstrated that both estrogen and progesterone altered macrophage uptake and/or processing of modified LDL. CONCLUSIONS Physiological levels of estrogen and progesterone are associated with a female-sex-specific reduction in human macrophage lipid loading, which is consistent with an atheroprotective effect.

Isolated Noncompaction of the Myocardium A Rarity or Missed Diagnosis

. A physical examinationwas unremarkable except for a fourth heart sound. Baselineblood studies showed mildly elevated troponin and creatinekinase-MB levels and hypercholesterolemia. A cardiac ultra-sound showed the upper limit of normal wall thickness andnormal valvular flows, biventricular size, and function. Cardiaccatheterization revealed a mildly abnormal contraction of theanterobasal wall of the left ventricle and normal epicardialcoronary vessels. Cardiac magnetic resonance imaging wasperformed to help exclude myocardial/pericardial disease.Magnetic resonance documented intramyocardial recessesof the inferior and anterobasal left ventricular (LV) wall.These recesses were in communication with the LV lumen(Figure 2, A and B). In addition, prominent trabeculationextended into the LV cavity (Figure 3). Ventricular mass,size, and systolic function were normal. There was noevidence of myocardial hyperenhancement after gadoliniuminjection. Serology was normal.These appearances are consistent with myocardial non-compaction, a congenital disorder of endomyocardial embry-ogenesis. This example is less florid than cases detailed in thelimited number of echo and pathology series currently pub-lished and, in fact, would have been missed by ultrasoundcriteria. A diagnosis of noncompaction has important impli-cations because of the need for familial screening and thepossible association with other cardiac anomalies and/ormuscle disorders, progressive LV dysfunction, risk of sys-temic embolism, and life-threatening arrhythmias. Tech-niques such as magnetic resonance imaging may improvedetection rates and provide new insights into the prevalence,spectrum, and natural course of this potentially not-so-rarecondition.