Cardiac steatosis and left ventricular hypertrophy in patients with generalized lipodystrophy as determined by magnetic resonance spectroscopy and imaging

Abstract

Generalized lipodystrophy is a rare disorder characterized by marked loss of adipose tissue with reduced triglyceride storage capacity, leading to a severe form of metabolic syndrome including hypertriglyceridemia, insulin resistance, type 2 diabetes mellitus, and hepatic steatosis. Recent echocardiographic studies suggest that concentric left ventricular (LV) hypertrophy is another characteristic feature of this syndrome, but the mechanism remains unknown. It has recently been hypothesized that the LV hypertrophy could be an extreme clinical example of "lipotoxic cardiomyopathy": excessive myocyte accumulation of triglyceride leading to adverse hypertrophic signaling. To test this hypothesis, the first cardiac magnetic resonance study of patients with generalized lipodystrophy was performed, using magnetic resonance imaging and localized proton spectroscopy to detect excessive triglyceride content in the hypertrophied myocytes. Six patients with generalized lipodystrophy and 6 healthy controls matched for age, gender, and body mass index were studied. As hypothesized, myocardial triglyceride content was threefold higher in patients than controls: 0.6 ± 0.2% versus 0.2 ± 0.1% (p = 0.004). The presence of pericardial fat was also found, representing a previously undescribed adipose depot in generalized lipodystrophy. Patients with generalized lipodystrophy, compared with controls, also had a striking degree of concentric LV hypertrophy, independent of blood pressure: LV mass index 101.0 ± 18.3 versus 69.0 ± 17.7 g/m(2), respectively (p = 0.02), and LV concentricity 1.3 ± 0.3 versus 0.99 ± 0.1 g/ml, respectively (p = 0.04). In conclusion, these findings advance the lipotoxicity hypothesis as a putative underlying mechanism for the dramatic concentric LV hypertrophy found in generalized lipodystrophy.

Figure 1

(A) Measurement of myocardial triglyceride content by localized¹H-MRS in a representative lipodystrophy patient. Top s: cine four-chamber and short axis cardiac image. The volume of interest (voxel) is placed within the interventricular septum (green rectangle). Below, spectrum from myocardial tissue collected simultaneously at end-expiration and end-systole with respiratory gating and ECG triggering, respectively. (B) Individual cross-sectional comparison of intramyocellular triglyceride content in six patients with generalized lipodystrophy compared to six age, gender and BMI match controls [●, patient 1, pair 1; ■, patient 2, pair 2; ○, patient 3, pair 3; □, patient 4, pair 4; ▼, patient 5, pair 5; Δ, patient 6; pair 6] . (C) Group average cross-sectional comparison of myocardial triglyceride content, demonstrating a three-fold difference in myocardial triglyceride content in patients versus controls. Data reported as mean ± SEM. P < 0.05.

Figure 2

High resolution magnetic resonance images. Top, cine four-chamber cardiac MR images. Note the presence of pericardial fat in both the patient and control. The control also has chest wall fat, whereas the patient does not. Middle, Axial T1-weighted MR image of calf. Increased typical intensity indicates fat, demonstrating a general lack of adipose tissue in the patient, whereas the control has normal levels of adipose tissue surrounding skeletal muscle. Bottom, axial abdominal MR images at the level of liver. Liver appears bright due to hepatic steatosis in patient with lipodystrophy. Note the general lack of subcutaneous and visceral adipose tissue in the patient with Generalized Lipodystrophy.

Figure 3

Left ventricular (LV) concentricity and LV mass are independent of arterial blood pressure. Note that with the 2 patients with the highest blood pressure removed, systolic blood pressure (A) decreases below that of the controls, yet LV mass indexed to body surface area (BSA) (B) and LV concentricity (C) remain elevated above controls. Subject specific data presented [●, patient 1, pair 1; ■, patient 2, pair 2; ○, patient 3, pair 3; □, patient 4, pair 4; ▼, patient 5, pair 5; Δ, patient 6; pair 6] , along with the mean and standard error (open bars). * indicates P < 0.05.