Myocardial Sympathetic Innervation and Long-Term Left Ventricular Mechanical Unloading
Stavros G. Drakos, MD*,
Theodoros Athanasoulis, MD ,
Konstantinos G. Malliaras, MD*,
John V. Terrovitis, MD*,
Nikolaos Diakos, MD*,
Dimitrios Koudoumas, MD*,
Argirios S. Ntalianis, MD*,
Stergios P. Theodoropoulos, MD ,
Magdi H. Yacoub, MD, ,
John N. Nanas, MD, PhD*,*
* 3rd Cardiology Department and Department of Clinical Therapeutics, University of Athens, Athens, Greece
Division of Nuclear Medicine, Alexandra Hospital, Athens, Greece
Division of Cardiothoracic Surgery, IASO General Hospital, Athens, Greece
Harefield Heart Science Center and the Magdi Yacoub Institute, Harefield, United Kingdom
 |
Abstract
|
|---|
Objectives: The purpose of this study was to analyze the effects of left ventricular assist devices (LVADs) on myocardial sympathetic innervation of the failing heart.
Background: Ventricular unloading by LVADs seems to cause reverse remodeling of the failing heart, but little is known about the sympathetic nerve activity during long-term mechanical unloading.
Methods: We studied the effects of LVADs on myocardial sympathetic innervation, by iodine 123-meta-iodobenzylguanidine (123I-mIBG) scintigraphy performed before and 3 months after LVAD implantation in 12 end-stage heart failure patients. We calculated the: 1) heart-to-mediastinum (H/M) uptake ratio on early and delayed images, indicating myocardial accumulation of 123I-mIBG; and 2) rate of 123I-mIBG washout after initial accumulation. Similar 123I-mIBG imaging and functional and hemodynamic measurements were made 3 months apart in 6 other heart failure patients not treated with an LVAD.
Results: After 3 months of LVAD support, the mean left ventricular ejection fraction had increased from 19 ± 6% to 29 ± 9% (p = 0.006), peak oxygen consumption increased from 9 ± 4 ml/kg/min to 13 ± 3 ml/kg/min (p = 0.058), serum sodium increased from 135 ± 4 mEq/l to 140 ± 2 mEq/l (p = 0.014), whereas the left ventricular end-diastolic diameter decreased from 72 ± 7 mm to 56 ± 3 mm (p = 0.002), pulmonary capillary wedge pressure decreased from 30 ± 6 mm Hg to 5 ± 3 mm Hg (p = 0.012), serum creatinine decreased from 1.5 ± 0.6 mg/dl to 1.0 ± 0.4 mg/dl (p = 0.011), and B-type natriuretic peptide decreased from 2,279 ± 1,900 pg/ml to 102 ± 5 pg/ml (p = 0.003). After 3 months of LVAD, the H/M ratio increased on delayed images from 1.25 ± 0.18 to 1.43 ± 0.13 (p = 0.01) and on early images from 1.35 ± 0.19 to 1.44 ± 0.11 (p = 0.028), and the washout rate decreased from 51.0 ± 23.2% to 30.6 ± 8.7%, (p = 0.015). There was a significant correlation between the late H/M mIBG ratio and B-type natriuretic peptide (R = 0.77, p = 0.01) and systolic pulmonary pressure (R = 0.7, p = 0.05). No significant scintigraphic, functional or hemodynamic change was observed between the 2 evaluations in the 6 patients not treated with an LVAD.
Conclusions: Ventricular unloading caused clinical, functional, and hemodynamic improvements accompanied by improvements in sympathetic innervation in the failing heart.
Key Words: heart failure • 123I-metaiodobenzylguanidine • myocardial scintigraphy • myocardial sympathetic innervation • reverse cardiac remodeling
|
Abbreviations and Acronyms
| | HF = heart failure | | H/M = heart-to-mediastinum | | LV = left ventricular | | LVAD = left ventricular assist device | | mIBG = meta-iodobenzylguanidine |
|
Mechanical circulatory support with left ventricular assist devices (LVADs) has become a standard bridge to cardiac transplantation (1) and has also been approved as destination therapy for selected patients presenting with end-stage heart failure (HF) (2). Clinical applications of LVAD have shown that it might reverse the complex process of chronic left ventricular (LV) remodeling to a degree where a subset of patients can be weaned from the device after the return of essential cardiac function (3–6). Specifically, LVAD profoundly unloads LV volumes and pressures, reversing the compensatory and stress responses of the overloaded myocardium and causing its structural and functional reverse remodeling. The mechanisms that facilitate the process of reverse remodeling have recently become the object of intensive research.
Sympathetic innervation has been inversely correlated with cardiac function with patients with chronic HF (7,8). A reduced myocardial accumulation of iodine 123-meta-iodobenzylguanidine (123I-mIBG) has been correlated with myocardial norepinephrine concentrations (9), myocardial cell injury (10), and adverse prognosis of patients with HF (7). However, little is known about sympathetic innervation during long-term unloading with an LVAD (11).
This study examined the effects of LVAD-induced unloading on cardiac function, structure, and hemodynamics and myocardial sympathetic innervation evaluated by 123I-mIBG myocardial scintigraphy in patients with end-stage HF.
|
Methods
|
|---|
Patient population.
Consecutive HF patients who required LVAD implantation due to progressive deterioration because of their syndrome were included in the study. These patients were followed long term in our HF program, and the investigators were highly familiar with the natural history of their HF syndrome. Important baseline demographic, clinical, hemodynamic, and laboratory characteristics of each patient are shown in Table 1. All patients were in New York Heart Association HF functional class IV and refractory to optimal medical therapy. Four patients had diabetes (2 insulin dependent and 2 insulin nondependent). After LVAD implantation, all patients were treated with standard doses of a beta-adrenergic blocker, renin-angiotensin axis inhibitors, spironolactone, and digoxin. The LVADs used were HeartMate XVE in 2 patients, and HeartMate II (Thoratec Corporation, Pleasanton, California) in 10 patients. The HeartMate XVE was set to auto mode for optimal ventricular unloading, and the HeartMate II was fixed between 9,000 and 11,000 rpm, to reach a pulsatility index (estimated by the device's software) between 3 and 4.
At the time of enrollment in the study, the patients underwent echocardiography, Naughton protocol treadmill cardiopulmonary exercise stress testing to measure peak oxygen consumption, and right heart catheterization. These tests were repeated at 3 months after LVAD implantation when the patients had completely recovered from the surgical procedure and were fully active.
Patients with advanced chronic HF, LV systolic dysfunction, and an ejection fraction <30%, untreated with LVAD were also included in our study if they fulfilled the criterion of being optimally treated medically for  6 months. These patients were randomly chosen from the population followed in a long-term HF program. They underwent the same general evaluation (myocardial scintigraphy and functional and hemodynamic evaluations), were followed for a similar period of observations, and were treated with the same HF medications as the LVAD patients (standard doses of beta-adrenergic blockers, renin-angiotensin system inhibitors, spironolactone, and digoxin).
123I-mIBG imaging.
Baseline 123I-mIBG imaging was performed in the fasting state, after withholding all medications on the morning of examination. Planar anterior images of the chest were obtained 1 h (early images) and 4 h (late images) after the intravenous injection of 111 to 148 MBq of 123I-mIBG. All scans were acquired with a single-headed, tomographic Sophycamera DS7 digital gamma camera (Sopha Medical Vision International, Buc, France), with a 256 x 256 matrix on a dedicated Sophy NXT computer system (Sopha Medical Vision International) equipped with a low-energy, all-purpose, parallel-hole collimator using a 20% window centered on the 159-keV peak. Myocardial 123I-mIBG activity was measured in a manually outlined region of interest surrounding the heart, excluding the ventricular blood pool, to standardize the cardiac uptake. A 20 x 15-pixel region of interest was also drawn over the upper mediastinum. The regions of interest were analyzed by a nuclear medicine expert unaware of the patients' clinical information. The heart/mediastinum (H/M) uptake ratio in early (H/M early) and late (H/M late) images was calculated, without background subtraction, as mean counts/pixel in the cardiac region of interest, divided by mean counts/pixel in the upper mediastinal region of interest.
Statistical analysis.
The data are expressed as mean ± SD. The nonparametric Wilcoxon signed-rank test was used to assess the statistical significance of differences observed at consecutive time points. Correlations among the various variables were evaluated using Pearson's correlation coefficient. The nonparametric Spearman's correlation coefficient was used to assess associations of B-type natriuretic peptide changes with other parameters. The threshold of significance was set at p = 0.05. Statistical analysis was performed using the SPSS version 15.0 software (SPSS, Chicago, Illinois).
The study protocol was approved by our institutional review board, and after they had granted their informed consent, the patients were followed prospectively.
|
Results
|
|---|
123I-mIBG observations.
After 3 months of LVAD support, H/M early increased from 1.35 ± 0.19 to 1.44 ± 0.11 (p = 0.028) and H/M late from 1.25 ± 0.18 to 1.43 ± 0.13 (p = 0.01) (Fig. 1). Furthermore, the washout rate significantly decreased from 51.0 ± 23.2% to 30.6 ± 8.7% (p = 0.015) (Fig. 2). In Figure 3, we show the observed improvement in H/M late in 1 of our patients (Patient #5 in Table 1). The abnormalities in baseline H/M early and washout rates in 6 patients with ischemic heart disease versus 6 patients with nonischemic heart disease were similar. However, after 3 months of LVAD support, the increase in H/M late among patients with nonischemic heart disease (0.23 ± 0.15) was more than twice that observed among patients with ischemic heart disease (0.10 ± 0.14), a difference that did not reach statistical significance, probably because of the small study sample.
View larger version (7K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Effect of an LVAD on H/M Late Image
Changes in mean ± SD and individual heart-to-mediastinum (H/M) ratios in late images between baseline (Pre Op) and 3 months of left ventricular assist device (LVAD) support.
|
|
Functional, structural, hemodynamic, and biochemical changes at 3 months.
At 3 months of follow-up, echocardiographic, hemodynamic, functional, and biochemical changes were observed that were consistent with a significant improvement in clinical status (Table 2). A moderately strong correlation was found between the changes in H/M late and B-type natriuretic peptide (R = 0.77, p = 0.01) and systolic pulmonary artery pressure (R = 0.7, p = 0.05). Furthermore, a moderately strong correlation was found between changes in systolic pulmonary artery pressure and H/M early and washout rate (R = 0.7, p = 0.04 for both correlations).
View this table:
[in this window]
[in a new window]
|
Table 2 Baseline and 3-Month Clinical, Functional, Hemodynamic, and Biochemical Characteristics of the Study Sample
|
|
Observations in patients not treated with LVAD.
In the 6 patients with HF who were not treated with an LVAD, a significant difference between baseline and 3 months was observed in neither the mIBG scintigraphic uptake nor their functional or hemodynamic status. However, the filling pressures tended to decrease between baseline and 3 months (Table 3).
View this table:
[in this window]
[in a new window]
|
Table 3 Baseline and 3-Month Clinical, Functional, Hemodynamic, and 123I-mIBG Scintigraphic Observations in 6 Patients Not Treated With LVAD
|
|
|
Discussion
|
|---|
In this study, LV unloading by an LVAD improved the sympathetic innervation of the failing heart assessed by 123I-mIBG myocardial scintigraphy. Specifically, after 3 months of LVAD support, the H/M ratio on delayed images and the washout rate, the most important indicators of sympathetic innervation revealed by 123I-mIBG imaging, were both significantly improved.
LVAD profoundly unloads the LV volumes and pressures, which reverses the compensatory and stress responses of the overloaded myocardium and might cause enough structural and functional reverse remodeling of the heart to allow a subset of patients to be weaned from the device after restoration of cardiac function (3–6). The mechanisms by which this reverse remodeling and eventually recovery occur are an area of active research, with the aim of identifying the factors associated with a sustained functional myocardial recovery (12). In several studies, mechanical unloading of the heart with an LVAD caused significant changes in a wide variety of biomarkers (13). Specifically, with regard to myocardial adrenergic innervation, long-term mechanical unloading restored the density of beta-adrenergic receptors in cardiomyocytes (14), normalized the distribution of the myocardial beta-adrenergic receptors (15), and enhanced the response to beta-adrenergic stimulation (16). A significant increase in the mRNA expression of the beta2-adrenergic receptor has also been observed in the unloaded failing rat heart (17).
123I-mIBG imaging is useful to grade the severity of HF and estimate its prognosis. Specifically, an accelerated washout rate and a decreased H/M ratio on delayed 123I-mIBG images have both been correlated with LV dysfunction in patients presenting with HF, regardless of the underlying disease (7,8,18). Furthermore, the H/M ratio on delayed images and the washout rate have been widely recognized as reliable predictors of adverse cardiac events in patients with HF due to ischemic or nonischemic heart disease (7,19–24). Finally and importantly, comparative 123I-mIBG scintigraphic studies obtained before and during treatment with renin-angiotensin axis inhibitors, beta-adrenergic blockers, or spironolactone showed an improvement in the washout rate and the H/M ratio on delayed images, associated with an improvement in cardiac function, indicating the contribution of this technique in the evaluation of therapeutic effects (8,25–28). This observation might have important implications, particularly for LVAD recipients whose native cardiac function is difficult to evaluate. Improvements in the 123I-mIBG images could be used to identify responders to LVAD-induced unloading who might become candidates for explantation of the device after the development of a potentially sustained myocardial functional recovery.
To our knowledge this is the first study reporting improvement of myocardial sympathetic nervous activity during chronic mechanical unloading. Miyagawa et al. (11) observed no improvement in sympathetic nerve function, evaluated by 123I-mIBG scintigraphy, after 2 months of LV support. However, the investigators noted that none of the 10 patients included in their study had evidence of cardiac functional or histological recovery during LVAD support, which they attributed to an incomplete mechanical unloading by left atrial drainage-type assist devices in the majority of patients. In contrast, in our study, the marked improvement in various functional, morphological, and biochemical characteristics observed after effective chronic mechanical unloading with the HeartMate XVE and II devices was accompanied by significant improvements in sympathetic innervation. The results of these 2 studies suggest that responders to LVAD-induced unloading can be identified by evaluating the functional recovery of the native heart with 123I-mIBG imaging. The recovery of myocardial sympathetic innervation may be an important factor in the functional recovery of the myocardium during LVAD support, and 123I-mIBG imaging might be used to evaluate the reverse remodeling that occurs during long-term mechanical unloading of the native heart. The correlation that we observed between scintigraphic improvements and changes in blood concentrations of B-type natriuretic peptide or changes in pulmonary artery pressures supports this hypothesis. The lowering of B-type natriuretic peptide blood concentrations is consistent with the suppression of adverse neurohormonal activation. Furthermore, increased filling pressures have been associated with adverse progression of remodeling (29–31).
Study limitations.
The limitations of this study include the small number of patients studied and the fact that the follow-up period was relatively short. Furthermore, the hemodynamic and echocardiographic data provided were obtained during full LVAD support and may not represent the native's heart functional performance during increased pressure and volume-loading conditions. Another limitation is the fact that the patients were not on exactly the same medical regimen before and after LVAD implantation. However, the included patients were on the same classes of antiremodeling medications (beta-blockers and renin-angiotensin-aldosterone axis inhibitors) before and after LVAD therapy with the exception of 4 patients who were not administered beta-blockers and 2 patients who were not administered spironolactone in the pre-LVAD implantation period but received these agents post-implantation. In addition, in 1 of the included patients, no beta-blocker was administered, either before or after LVAD implantation, due to bradyarrhythmia. Noteworthy, however, in these particular patients, our 123I-mIBG and functional findings were not different compared with the rest of the study patients.
|
Conclusions
|
|---|
LVAD-induced ventricular unloading caused clinical and hemodynamic improvements that were associated with improvements in the sympathetic innervation of failing hearts. Most importantly, the improvement in sympathetic innervation needs to be prospectively explored, with a view to identifying potential predictors of sustained functional myocardial recovery during or even before LVAD therapy.
|
Footnotes
|
|---|
Dr. Drakos is currently working at the Division of Cardiology and the Molecular Medicine Program, University of Utah, Salt Lake City, Utah.
* Reprint requests and correspondence: Dr. John N. Nanas, 3rd Cardiology Department, University of Athens School of Medicine, 24 Makedonias, 10433 Athens, Greece (Email: jnanas{at}ath.forthnet.gr).
Manuscript received June 21, 2009;
revised manuscript received October 13, 2009,
accepted October 28, 2009.
|
REFERENCES
|
|---|
- Frazier OH, Rose EA, Oz MC, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation J Thorac Cardiovasc Surg 2001;122:1186-1195.[Abstract/Free Full Text]
- Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure N Engl J Med 2001;345:1435-1443.[CrossRef][Web of Science][Medline]
- Dandel M, Weng Y, Siniawski H, et al. Prediction of cardiac stability after weaning from left ventricular assist devices in patients with idiopathic dilated cardiomyopathy Circulation 2008;118:S94-S105.[Abstract/Free Full Text]
- Birks EJ, Tansley P, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure N Engl J Med 2006;355:1873-1884.[CrossRef][Medline]
- Maybaum S, Mancini D, Xydas S, et al. Cardiac improvement during mechanical circulatory support: a prospective multicenter study of the LVAD Working Group Circulation 2007;115:2497-2505.[Abstract/Free Full Text]
- Drakos SG, Charitos SE, Nanas SN, Nanas JN. Ventricular assist devices for the treatment of chronic heart failure Exp Rev Cardiovasc Ther 2007;5:571-584.[CrossRef]
- Merlet P, Valette H, Dubois-Rande JL, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure J Nucl Med 1992;334717–7.
- Lotze U, Kaepplinger S, Kober A, Richartz BM, Gottschild D, Figulla HR. Recovery of the cardiac adrenergic nervous system after long-term beta-blocker therapy in idiopathic dilated cardiomyopathy: assessment by increase in 123 I-metaiodobenzylguanidine uptake J Nucl Med 2001;42:49-54.[Abstract/Free Full Text]
- Schofer J, Spielmann R, Schuchert A, Weber K, Schlüter M. Iodine-123 meta-iodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy J Am Coll Cardiol 1988;12:1252-1258.[Abstract]
- Wakasugi S, Wada A, Hasegawa Y, Nakano S, Shibata N. Detection of abnormal cardiac adrenergic neuron activity in adriamycin-induced cardiomyopathy with iodine-125-metaiodobenzyl-guanidine J Nucl Med 1992;33:208-214.[Abstract/Free Full Text]
- Miyagawa S, Sawa Y, Fukushima N, et al. Analysis of sympathetic nerve activity in end-stage cardiomyopathy patients receiving left ventricular support J Heart Lung Transplant 2001;20:1181-1187.[CrossRef][Web of Science][Medline]
- Yacoub MH. A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery Eur Heart J 2001;22:534-540.[Free Full Text]
- Drakos SG, Terrovitis JV, Anastasiou-Nana MI, Nanas JN. Reverse remodeling during long-term mechanical unloading of the left ventricle J Mol Cell Cardiol 2007;43:231-242.[CrossRef][Web of Science][Medline]
- Ogletree-Hughes ML, Stull LB, Sweet WE, Smedira NG, McCarthy PM, Moravec CS. Mechanical unloading restores beta-adrenergic responsiveness and reverses receptor downregulation in the failing human heart Circulation 2001;104:881-886.[Abstract/Free Full Text]
- Bick RJ, Grigore AM, Poindexter BJ, et al. Left ventricular unloading with an assist device results in receptor relocalization as well as increased beta-adrenergic receptor numbers: are these changes indications for outcome? J Card Surg 2005;20:332-336.[CrossRef][Web of Science][Medline]
- Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure Circulation 1998;97:2316-2322.[Abstract/Free Full Text]
- Tsuneyoshi H, Oriyanhan W, Kanemitsu H, et al. Heterotopic transplantation of the failing rat heart as a model of left ventricular mechanical unloading toward recovery ASAIO J 2005;51:116-120.[CrossRef][Web of Science][Medline]
- Imamura Y, Ando H, Mitsuoka W, et al. Iodine-123 metaiodobenzylguanidine images reflect intense myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause J Am Coll Cardiol 1995;26:1594-1599.[Abstract]
- Verberne HJ, Brewster LM, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review Eur Heart J 2008;29:1147-1159.[Abstract/Free Full Text]
- Agostini D, Verberne HJ, Burchert W, et al. I-123-mIBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: insights from a retrospective European multicenter study Eur J Nucl Med Mol Imaging 2008;35:535-546.[CrossRef][Web of Science][Medline]
- Kasama S, Toyama T, Sumino H, et al. Prognostic value of serial cardiac 123I-MIBG imaging in patients with stabilized chronic heart failure and reduced left ventricular ejection fraction J Nucl Med 2008;49:907-914.[Abstract/Free Full Text]
- Tamaki S, Yamada T, Okuyama Y, et al. Cardiac iodine-123 metaiodobenzylguanidine imaging predicts sudden cardiac death independently of left ventricular ejection fraction in patients with chronic heart failure and left ventricular systolic dysfunction: results from a comparative study with signal-averaged electrocardiogram, heart rate variability, and QT dispersion J Am Coll Cardiol 2009;53:426-435.[Abstract/Free Full Text]
- Henneman MM, Bengel FM, van der Wall EE, Knuuti J, Bax JJ. Cardiac neuronal imaging: application in the evaluation of cardiac disease J Nucl Cardiol 2008;15:442-455.[CrossRef][Web of Science][Medline]
- Anastasiou-Nana MI, Terrovitis JV, Athanasoulis T, et al. Prognostic value of iodine-123-metaiodobenzylguanidine myocardial uptake and heart rate variability in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy Am J Cardiol 2005;96:427-431.[CrossRef][Web of Science][Medline]
- Kasama S, Toyama T, Kumakura H, et al. Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction J Am Coll Cardiol 2005;45:661-667.[Abstract/Free Full Text]
- Agostini D, Verberne HJ, Hamon M, Jacobson AF, Manrique A. Cardiac 123I-MIBG scintigraphy in heart failure Q J Nucl Med Mol Imaging 2008;52:369-377.[Web of Science][Medline]
- Kasama S, Toyama T, Hatori T, et al. Evaluation of cardiac sympathetic nerve activity and left ventricular remodelling in patients with dilated cardiomyopathy on the treatment containing carvedilol Eur Heart J 2007;28:989-995.[Abstract/Free Full Text]
- Kasama S, Toyama T, Kumakura H, et al. Effect of spironolactone on cardiac sympathetic nerve activity and left ventricular remodelling in patients with dilated cardiomyopathy J Am Coll Cardiol 2003;41:574-581.[Abstract/Free Full Text]
- Stevenson LW, Tillisch JH, Hamilton M, et al. Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy Am J Cardiol 1990;66:1348-1354.[CrossRef][Web of Science][Medline]
- Komuro I, Katoh Y, Kaida T, et al. Mechanical loading stimulates cell hypertrophy and specific gene expression in cultured rat cardiac myocytes: possible role of protein kinase C activation J Biol Chem 1991;266:1265-1268.[Abstract/Free Full Text]
- Leri A, Claudio PP, Li Q, et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell J Clin Invest 1998;101:1326-1342.[Web of Science][Medline]
This article has been cited by other articles:
|
|
|
|
 
N. Haider, R. R. Baliga, Y. Chandrashekhar, and J. Narula
Adrenergic Excess, hNET1 Down-Regulation, and Compromised mIBG Uptake in Heart Failure: Poverty in the Presence of Plenty
J. Am. Coll. Cardiol. Img.,
January 1, 2010;
3(1):
71 - 75.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Dilsizian, Y. Chandrashekhar, and J. Narula
Introduction of New Tests: Low Are the Mountains, High the Expectations
J. Am. Coll. Cardiol. Img.,
January 1, 2010;
3(1):
117 - 119.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods
