JNEPHROL 2009; 22: 367-372
ORIGINAL ARTICLE
www.sin-italy.org/jnonline – www.jnephrol.com
Cardiac magnetic resonance imaging in hemodialysis patients Rita L. McGill1, Robert W.W. Biederman2, Roger T. Getts1, Shawn M. Hazlett1, Sandeep B. Sharma1, Jonathan Duran1, Dana E. Brandys1, Joshua C. Sysak1, Kalathil K. Sureshkumar1, Stephen E. Sandroni1, Richard J. Marcus1
Abstract Background: The anatomy of left ventricular hypertrophy (LVH) in dialysis patients was studied with magnetic resonance imaging (MRI). Potential benefits of spironolactone were examined in a subset of patients. Methods: This was a prospective case series of 30 hemodialysis patients in whom cardiac MRI was performed. Repeat MRI was done in a subset of 13 patients after 9 months of daily oral spironolactone 25 mg. Results: Subjects exhibited a characteristic cardiac morphology, distinct from both concentric LVH (cLVH) and eccentric LVH (eLVH). Compared with normal controls, LV mass index was increased, end-diastolic volume index was increased, and ejection fraction was reduced, but sphericity indices did not differ. No significant changes were seen after spironolactone. Conclusions: LVH in dialysis patients has a unique MRI appearance which is distinct from either cLVH or eLVH, with profound LV thickening and moderate dilation of the ventricular cavity. A 9-month course of spironolactone therapy did not affect morphology. Key words: Cardiac MRI, ESRD, Left ventricular hyper-
trophy, Spironolactone
Introduction Left ventricular hypertrophy (LVH) is common in end-stage renal disease (ESRD), manifests before overt cardiovascular events and predicts increased risk of death (1, 2). The eccentric pattern of LVH (eLVH) presents a dilated left ventricle (LV) in patients with ischemic heart disease, due to chronic volume overload. The LV cavity is enlarged, and
Division of Nephrology and Hypertension, Allegheny General Hospital, West Penn Allegheny Health System, Pittsburgh, Pennsylvania - USA 2 Division of Cardiology, Allegheny General Hospital, West Penn Allegheny Health System, Pittsburgh, Pennsylvania - USA 1
wall thickness is increased; LV ejection fraction (EF) is usually decreased (3). Concentric hypertrophy (cLVH) presents a thickened hypertensive ventricle, due to chronic pressure overload. LV cavity size is near-normal; EF is usually preserved or increased (1, 3). Elevated aldosterone predicts mortality in eLVH and heart failure (4). Aldosterone causes cardiac fibroblasts to proliferate and increases myocardial collagen (5). Rats with elevated aldosterone had cardiac fibrosis and LV remodeling which improved with spironolactone, a competitive inhibitor of aldosterone (6, 7). Low-dose oral spironolactone decreased hospitalization, mortality and cardiac mortality in heart failure patients by 30%-35% (8, 9). Spironolactone plus angiotensin-converting enzyme (ACE) inhibition reduced LV mass (LVM) in animals and humans with cLVH (9-11). Echocardiography (ECHO) is abnormal in >75% of ESRD patients, with thickened LV walls, increased LVM and normal LV cavity size (1, 2). ECHO relies upon geometric assumptions derived from normal hearts, to calculate LVM and cavity size, which may not generalize to ESRD patients (12). Intravascular volume, body habitus and operator skill all influence results. Direct measurements of LV size and geometry with cardiac magnetic resonance (CMR) are detailed, precise and reproducible. Simultaneous ECHO and CMR have shown that ECHO systematically overestimates LVM by up to 50% in dialysis patients (13). CMR done before and after hemodialysis showed that LVM is independent of volume status (14). Serum aldosterone levels are elevated in ESRD patients (15), who often have ventricular remodeling on ECHO (16). The safety of spironolactone 25 mg daily in selected hemodialysis patients has been evaluated (15), and some authors have begun to call for widespread treatment of ESRD patients (17). This study uses CMR to compare ESRD patients with normal historical controls, and evaluates the effects of spironolactone in ESRD. 367
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Cardiac MRI
Methods This pilot trial involved hemodialysis patients >18 years old from October 2003 to February 2006. This trial was conducted in adherence to the Declaration of Helsinki. The study protocol and consent form were approved by the institutional review board. Informed consent was obtained from all subjects. Inclusion criteria were ≥4 months of dialysis; adequate dialysis, defined as a urea reduction ratio ([predialysis BUN – postdialysis BUN] / postdialysis BUN x 100) ≥65% (where BUN is blood urea nitrogen); and expected survival of >9 months. Exclusion criteria were noncompliance, hypersensitivity to spironolactone, inability to achieve effective contraception or a history of hyperkalemia (defined as any potassium value >6.5 mEq/L over the preceding 4 months, or a 4-month average potassium value >6 mEq/L). After demographic and laboratory data were collected, subjects underwent baseline CMR and began 270 days of oral spironolactone 25 mg per day. Repeat CMR was performed at treatment completion. Baseline cardiac MRI results were compared with 108 healthy, nondialyzing historical controls (18), and to the CMR results after spironolactone.
Cardiac MRI was performed on a General Electric (Milwaukee, WI, USA) 1.5T Horizon CV/i cardiac MRI scanner, with a slew rate of 150 mT/m per second and a gradient strength of 40 mT. A FIESTA sequence was used (using steady-state-free precession [SSFP]), with 12-14 views per segment, and a 224x224 imaging matrix. Temporal resolution varied from 33 to 38 ms. End-diastolic endocardium and epicardium (defined as the largest volume of the electrocardiogram-triggered sequence) were digitized at each contiguous short axis slice plane from the cine images using Medis Mass software (The Leiden, The Netherlands). LVM was calculated using a modified Simpson’s rule, corrected for myocardial specific gravity (1.055). Papillary muscles were excluded unless merged with the myocardium. An 8-mm slice thickness with 0-mm gap was used for contiguous base-apex images. A single cardiologist performed all manual cardiac measurements. Most patients had CMR performed on the dialysis day, prior to treatment. Patients with morning dialysis could delay the dialysis, or have CMR the preceding afternoon.
TABLE I DEMOGRAPHIC DATA AT BASELINE AND AFTER SPIRONOLACTONE Characteristic
Patients undergoing baseline cardiac MRI (n=30)
Patients completing spironolactone course (n=13)
Mean age, years (range)
59.1 (33-81)
66 (35-78)
Mean postdialysis weight, kg (range)
76.3 (50-121)
76 (54-110)
Mean body surface area, m2 (range) Female/male, number Etiology of ESRD Diabetes mellitus, number Hypertension, number Glomerulonephritis, number
1.9 (1.5-2.4) 10/20
1.9 (1.6-2.3) 4/9
7 11 8
4 4 3
Other, number Comorbid conditions Coronary disease, number Diabetes mellitus, number Hypertension, number Time on HD, years (range) Angiotensin receptor blocker, number ACE inhibitor, number
4
2
13 11 29 5 (1-21) 4 15
4 6 12 6 (1-20) 0 7
Data are means (range) or number, as indicated. ACE = angiotensin-converting enzyme; ESRD = end-stage renal disease; HD = hemodialysis. 368
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Data analysis
Results
LVM index (LVMi) was calculated as LVM / body surface area (BSA). LV cavity size was assessed with enddiastolic volume index (EDVi), defined as EDV/BSA. Relative wall thickness (RWT) was calculated as septal and lateral wall thickness divided by the LV diameter. Sphericity index (SI), used to evaluate ventricular shape, was calculated as ventricular length / diameter during diastole. Results were expressed as means with standard deviation in ESRD patients and compared with the mean values of controls using Student’s t-test. CMR parameters before and after spironolactone were compared with a Wilcoxon signed-ranks test. A p value 6.0 mEq/L were observed.
Discussion In this report, a series of ESRD patients were examined with CMR using the SSFP technique; this modality may depict the ESRD heart more accurately than ECHO or gradient cine (GRE) CMR. ECHO overestimates LVM in ESRD, and is influenced by hydration (12, 14). CMR studies of ESRD hearts have been predominantly GRE, rather than SSFP. GRE CMR is heavily dependent upon blood flow and the contrast between the myocardium and the ventricular cavity during diastole. Image quality in SSFP depends on the difference in T2 and T1 signal intensity ratios of the blood and myocardium, so SSFP obtains sharper images of the LV in both systole and diastole (19). Study patients were compared with normal historical controls imaged with SSFP (18). While ESRD hearts were already known to differ from normal hearts, our images revealed a pattern of LVH distinct from that in patients with the common patterns of hypertrophy (Fig. 1). ESRD patients had profoundly increased LVM and LVMi. The modest enlargement of the LV cavity, even predialysis, was not proportional to wall thickening, in con-
trast to patients with ischemic cardiomyopathy (eLVH), in whom the ventricle dilates. The eLVH (heart failure) patient has equivalent increases in LV mass and cavity diameter, so the RWT does not increase. In ESRD, as in cLVH, LVM and RWT were both increased. However, LV cavity size is usually preserved in cLVH, whereas ESRD ventricles exhibited moderate enlargement (Fig. 1), though less than in eLVH. We were unable to detect any benefit after spironolactone. Our data are limited by the very small number of subjects who completed the entire study. The very limited number of hemodialysis patients (n=4) who underwent serial MRI after a course of placebo was insufficient to constitute a placebo group. These patients had very little percentage change in LVMi (+2.4%, +0.8%, -2.6% and -5.0%) but were far too few to constitute a significant control group. Without a placebo control group, we cannot prove that spironolactone was not preventing deterioration, although no evidence suggests that this was the case. We cannot rule out the possibility that a medication effect might have been seen if more patients had been studied, but the lack of any detectable effects did not suggest that it was desirable to commit further resources to expanding this pilot trial. Medication compliance issues could have contributed to the lack of spironolactone effects. Medications were not administered under direct observation, and spironolactone levels were not measured. We must consider the possibility that a beneficial effect was masked by nonadherence, but consider it unlikely that global noncompliance among our subjects was an adequate explanation for the complete lack of observable benefit. We also cannot rule out the possibility of benefit with higher-dose spironolactone or eplerenone, over a longer treatment period, such as the 24-month course of the Randomized Aldactone Evaluation Study (RALES). ESRD patients are a unique group with characteristic abnormalities which could have affected the efficacy of
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spironolactone. Despite selection of subjects with vigorously treated ESRD, the effects of chronic anemia, calcium-phosphate disorders and hyperparathyroidism on LVH were not assessed. In this study, spironolactone did not alter LVM, LVMi, RWT or EDVi. These findings contrast with decreases in eLVH seen after spironolactone in RALES (9), possibly because our patients did not have eLVH. Prior results of spironolactone in patients with cLVH have been modest (10, 11). ESRD LVH was distinct from typical eLVH or cLVH, which suggests that LVH in dialysis patients may differ from other forms of cardiac enlargement. The unique morphology of the ESRD heart might contain clues to the failure of spironolactone to alter cardiac geometry. The mechanism of ESRD LVH could be different at the intracellular level. Cardiac myocyte morphology differs between eLVH and cLVH. The changes in both eLVH and cLVH consist of changes in the quantity and number of sarcomeres. In eLVH, sarcomeres are added in series to existing sarcomeres. Wall thickness increases proportionally to the increase in chamber radius, because the additional sarcomeres increase the size of individual cardiac cells. In cLVH, wall thickening occurs as new sarcomeres are added in parallel; chamber radius does not change (20, 21). ESRD morphology resembled that in hypertrophic obstructive cardiomyopathy (HOCM) more than either of these patterns, which suggests that the changes at the intracellular level could be unique to ESRD. Although cardiac histology was beyond the scope of the present study, a resemblance to HOCM was also noted on endomyocardial biopsies performed on ESRD patients (16), and gadolinium-enhanced
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CMR has also suggested a specific, characteristic appearance of “uremic cardiomyopathy” that was distinct from other LVH (22). Further exploration of the ESRD heart with MRI may yield valuable insights and guide rational approaches to therapy.
Conclusions LVH in dialysis patients differed from both eLVH and cLVH, on CMR. No improvements could be detected in a small subset of patients treated with spironolactone for 9 months. Financial support: Internal funding only. Conflict of interest statement: None declared.
Meeting presentation: This manuscript has presented in part in abstract form, as a poster at the American Society of Nephrology meeting in San Diego, California, USA, in November 2006.
Address for correspondence: Rita L. McGill, MD Division of Nephrology and Hypertension Allegheny General Hospital 4th Floor, South Tower 320 East North Avenue Pittsburgh, PA 15212-4772, USA
[email protected]
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