Conditions: Heart Failure Nonischemic Dilated Cardiomyopathy
Keywords: heart failure positron emission tomography magnetic resonance imaging myocardial energetics myocardial perfusion
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
We plan to study the concept of "energy starvation" in heart failure by evaluation of patients with nonischemic dilated cardiomyopathy (NIDCM) (heart failure with reduced heart pump function due to causes other than heart attack). We will use a combination of positron emission tomography and magnetic resonance imaging to study metabolism, anatomy, function, blood flow and efficiency, before and after 6 months' treatment with the drug spironolactone which blocks the deleterious effects of the hormone aldosterone on the myocardium (heart muscle).

Detailed description:
Preliminary results showed reduced subendocardial myocardial perfusion reserve in NIDCM compared to normal subjects, and that the degree of impaired perfusion reserve was related to the oxidative metabolic rate as measured by positron emission tomography.

Arms:
arm 1: patients with heart failure due to nonischemic dilated cardiomyopathy will be studied by 11C acetate positron emission tomography and magnetic resonance imaging using vasodilator and gadolinium to judge myocardial blood flow, before and after 6 months' treatment with spironolactone.

Interventions: intervention 1: spironolactone
Intervention descriptions: intervention 1: spironolactone 50 mg daily for 6 months

Protocol document:
Prot_SAP_000.pdf: 
Effect of Aldosterone on Myocardial Energy Starvation
NCT00574119
February 22, 2011


2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effect of Aldosterone on Myocardial Energy Starvation 
 
 
Marvin W. Kronenberg, M.D. 
 
 
 
 
 
 
Version 6 
Revised February 22, 2011 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
 
PROPOSED RESEARCH PLAN 
This proposal is intended to obtain sufficient data to allow an application to the NHLBI to further our 
understanding of the pathophysiology of heart failure (HF) and to evaluate the “energy starvation hypothesis” 
of HF in patients.  We can now use metabolic imaging with positron emission tomography (PET) and anatomic-
functional imaging with cardiac magnetic resonance (CMR) to study energy starvation in HF. 
 
1. SPECIFIC AIMS: 
a. To employ PET and CMR to evaluate several determinants of myocardial 
“energy starvation” in patients with HF due to nonischemic dilated cardiomyopathies (NIDCM): 
 
1) Left ventricular (LV) volume, ejection fraction (LVEF) and wall stress (CMR). 
 
2) LV hypertrophy (LVH) and fibrosis (CMR). 
 
3) LV subendocardial hypoxia, using blood oxygen level derived (BOLD) imaging  and 
adenosine/regadenoson-induced hyperemia imaging (CMR).        
 
4) The rate of myocardial oxidative metabolism using [11C]acetate (PET). 
b. To study LV energy supply-demand relations and efficiency in patients with NIDCM using the 
[11C]acetate decay rate, kmono, an index of energy supply, compared to indices of demand (LV wall 
stress and the rate-pressure product) plus an index of efficiency,  the work-metabolic index (LV minute 
work/kmono).  
c. To evaluate LV mass, volume and LVEF before and after aldosterone blockade, compared to 
changes in myocardial fibrosis, reactive hyperemia, BOLD estimates of hypoxia and myocardial 
oxidative metabolism.   
d. To evaluate the relations between clinical improvement, energy starvation and LV volume, for 
judging the hypothesis that drugs that reduce LV fibrosis and volumes are beneficial in HF.  
e. To evaluate the reproducibility of CMR measurements of myocardial perfusion. 
 
2. BACKGROUND AND SIGNIFICANCE:  (References are sometimes listed, rather than discussed in detail, 
due to page limits.).  Energy starvation. Heart failure (HF) may be caused by myocyte death, myocyte 
dysfunction and LV remodeling, leading to ischemia and neurohormonal abnormalities, with inadequate energy 
production, termed “energy starvation”, with HF progression (1), key elements in the HF syndrome.(2,3). There 
are long term maladaptive anatomical responses related to energy starvation, especially hypertrophy, 
reduced capillary density and abnormal mitochondrial architecture.  Energy-sparing compensation.  -
adrenergic downregulation is important, but is maladaptive by reducing LV performance, increasing -myosin 
heavy chains and decreasing sarcoplasmic reticulum calcium pumping sites (1,3). 
Remodeling (4,5,6,7,8,9,10,11,12).  Remodeling includes LV dilation, LVH and reduced function.  There is re-
expression of fetal gene programs (9,10). Myocyte loss (via necrosis and apoptosis) leads to subendocardial cell 
death with replacement fibrosis and a loss of vasodilator reserve (12) (all related to poorer prognosis). 
 
Aldosterone and myocardial fibrosis.  Aldosterone’s (ALDO) role in LV pathology and HF became clearer 
following publications showing neurohormonal profiles in HF (13,14) and research showing the renin-
angiotensin-aldosterone system was related to LVH and fibrosis (15,16,17,18). Two HF trials showed reduced 
mortality in patients with HF randomized to treatment with the ALDO antagonist, spironolactone (19), or 
eplerenone  (20) following myocardial infarction.  A substudy of RALES showed decreased B-type natriuretic 
peptide (BNP) in patients randomized to spironolactone (21).  Tsutamoto found in patients a decrease by 
spironolactone of the myocardial extraction of ALDO (22).  In a randomized study of patients with NIDCM and 
H, 4 months’ treatment of 20 patients with spironolactone was associated with significantly reduced LV mass 
and volume, increased LVEF, and neurohormonal improvements, with a decrease in BNP, plus a decrease in 
plasma procollagen type III aminoterminal peptide (PIIINP) (23), an index of myocardial fibrosis.  Decreased LV 
mass on echocardiography was correlated with decreased PIIINP.  Others confirmed a slight increase in LVEF 
with spironolactone in HF patients (24,25).  In animals with myocardial infarctions, eplerenone increased the 
speed of isovolumic relaxation, increased endothelial nitric oxide synthase, and also reduced type I collagen 
gene expression and LVH (26).  Similarly, eplerenone reduced LV hydroxyprolene, improved LV filling and 


4 
 
coronary blood flow dynamics in the spontaneously hypertensive rat (27).  Noncardiac mechanisms involve 
blockade of brain mineralocorticoid receptors leading to reduced sympathetic outflow and improved cardiac 
function in the rat following MI (28).  Thus, there is substantial clinical evidence of cardiac benefit from ALDO 
blockade, confirmed in rat models, but relatively little evidence in patients for an actual reduction in fibrosis, or 
other mechanisms of benefit.  We speculate that ALDO blockade in patients with HF will reduce fibrosis 
and LV mass, which will likely reduce LV diastolic pressure and likely improve subendocardial 
perfusion, leading to less subendocardial ischemia in HF. This would improve the anatomic and 
physiologic substrate of “energy starvation”.   
 
Oxidative metabolism and cardiac efficiency in HF. Several studies have examined oxidative metabolism 
and LV efficiency in patients with HF, both using catheterization techniques (29) and noninvasive methods that 
employ PET and echocardiography (30,31,32). Oxidative metabolism can be estimated from the rate of clearance 
of [11C]acetate from myocardium (kmono), which correlates closely with myocardial oxygen consumption 
(MVO2) in animal models (33,34,35).  Importantly, in NIDCM patients there is a similar, quantitative linear relation 
between [11C]acetate decay and LV oxygen consumption (30).  Efficiency may be judged by the work-metabolic 
index (WMI) = LV minute work/kmono.   WMI has improved following metoprolol (36), but this has not yet 
been related to the anatomical substrate of energy starvation or to changes in that substrate.  
  
Cardiac magnetic resonance imaging (CMR).  CMR has become a “gold standard” method for cardiac 
imaging.  There is a quantitative relation of CMR to LV mass, volume and performance (37,38) and it is highly 
reproducible (39).  CMR is likely to be superior to echocardiography in judging the work-metabolic index.  
Imaging LV vasodilator reserve and hypoxia with CMR. Panting et al recently used gadolinium with 
adenosine/ regadenoson to image marked, inadequate subendocardial perfusion (40).  Deoxyhemoglobin is 
paramagnetic (41) and can be seen on BOLD images. Several studies have employed this property to study 
hypoxia and ischemia (41,,42,43,44,45,46,47,48).  There is a blunted dipyridamole-induced change in the BOLD 
transverse relaxation rate with LVH (p=0.0003), although in this study, none had HF (47).   
It is important to note the distinction between hypoxia and ischemia.  BOLD shows deoxyhemoglobin, but 
by itself cannot differentiate hypoxia from ischemia induced by hypoxia.  Inducible LV dysfunction associated 
with a large BOLD signal would be confirmatory evidence, but is not likely to be proven in this study, as 
opposed to study of patients with coronary artery disease. 
 
Critical evaluation of existing knowledge, gaps which this project is intended to fill, importance and 
relevance of the proposed research.   We hope to demonstrate in patients several anatomic and physiologic 
abnormalities that produce myocardial “energy starvation” in HF, and that energy starvation is reduced by 
therapy with the ALDO antagonist, spironolactone.  Gaps in our knowledge include:  1)  Most basic 
information regarding ALDO has been obtained in animal models, whereas clinical reports have mostly shown 
cruder information such as reduced LVH and improved LVEF (cited above).   2)  No clinical studies have 
addressed specifically the substrate of energy starvation in HF.   3)  To our knowledge, there is no information 
about whether ALDO antagonism can reverse subendocardial hypoxia, and possibly ischemia, and only 
partial information in patients about fibrosis from serum markers, such as PIIINP  4)  There is little 
mechanistic information to add physiologic support for the volume-remodeling hypothesis of how drugs 
improve outcomes in HF.  5).  There are no reproducibility data regarding resting or adenosine-stimulated 
myocardial blood flow using CMR. 
This study is likely to reduce these gaps in our knowledge of HF.   By CMR and PET, we expect to show 
“energy starvation” in NIDCM by demonstrating LVH and fibrosis, inadequate vasodilator reserve, hypoxia and 
reduced metabolism vs. demand.   Treatment with spironolactone will allow study of the effects of this proven 
therapy on the anatomy and physiology of energy starvation.  This will demonstrate the physiologic basis of the 
volume-remodeling hypothesis about how drugs improve outcomes in patients with HF.  BOLD and 
[11C]acetate imaging may identify patients with the worst physiologic consequences of HF. Drug therapy, and 
even selection for cardiac transplantation, might be improved by this work.   By doing repeated studies in a 
subset of patients, we expect to document close reproducibility of CMR estimates of myocardial perfusion.  
This will allow us to judge with greater confidence the serial changes we expect following spironolactone 
treatment.  


5 
 
 
3. PRELIMINARY STUDIES BY APPLICANT:  The PI has studied HF in several formats (49,50,51,52,53) and 
recently completed a study of LV oxidative metabolism using PET, RPP and echocardiography in patients with 
NIDCM (figs 1-4) (54).  Data for calculating kmono in NIDCM are shown in fig. 1.  Compared to normal subjects, 
the LV supply/demand relation (kmono/RPP) was depressed in patients with NIDCM (fig 2).  Normal subjects 
had a linear, significant relation between kmono and RPP, but patients with NIDCM did not (fig 3). Three of 7 
patients had results similar to 7 normal subjects, but 4 did not. The literature demonstrates normally linear 
relations between LV wall stress and MVO2 (55,56).  But, in the present study, there was no significant 
relationship in NIDCM between kmono and LV wall stress, as another index of oxygen demand (fig.4).  
0
2
4
6
8
10
NIDCM                                    NL
kmono/RPP  (min-1/bpm-mmHg)  (x 10-6)
P = 0.003
 
Fig. 1.                                                                                                                        Fig. 2. 
Fig. 3. 
4
6
8
10
12
14
Rate-Pressure Product (bpm-mmHg) (x 10
3)
0.04
0.06
0.08
0.10
kmono (min-1)
NL 
r = 0.83
N = 7
p = 0.02
NIDCM 
r = 0.62
N = 7
p = NS
Fig. 4.
0
50
100
150
200
250
300
Peak Meridional Wall Stress (dynes/cm
2)
0.02
0.04
0.06
0.08
0.10
kmono (min
-1)
r = 0.02
N = 6
p = NS
 
Such lack of correlation supports the hypothesis of “energy starvation" in HF.  The PI has studied LV 
remodeling as part of the Radionuclide Substudy of SOLVD which was among the first to establish that the 
angiotensin converting-enzyme inhibitor, enalapril, reduced LV volume, while placebo-treated patients had 
progressive LV volume dilation (remodeling) (51). A meta-analysis showed that drugs that are clinically 
beneficial for HF reduce or have a neutral effect on LV volume (57). The PI has continued studies of the LV 
volume-remodeling hypothesis (58), used the 6 minute walk test (59) and has significant nuclear cardiology 
experience (please see biosketch). 
 
4. RESEARCH DESIGN AND METHODS: 
Patient inclusion criteria. We plan to study 10 patients with NIDCM in each of two years (n based on budget).  
Most patients will have hypertensive or idiopathic dilated cardiomyopathy.  The limited literature suggests that 
with 20 patients we will see a significant improvement in LV ejection fraction(23).   
The inclusion criteria are : 
1) 18-80 years old, of either sex and any race; 
2) diagnosis of NIDCM based on clinical criteria; 
3) New York Heart Association Functional Class (NYHA FC) II-IV; 
4) an ECG showing no prior myocardial infarction; 


6 
 
5) LV ejection fraction of 35% or less; 
6) able to lie supine for PET and MRI studies. 
7) standard medical therapy for heart failure, including an angiotensin converting enzyme inhibitor or an 
  angiotensin receptor blocking drug; beta-adrenergic blocking drugs, and possibly digitalis and potassium, if 
needed; a no added salt diet; fluid restriction if needed.  Patients will be stable on the above anit-failure therapy 
for 3 months. 
8) Serum potassium less than 5.0 and serum creatinine 2.5 or less. 
Exclusion criteria will include 1) need for an internal cardioverter-defibrillator (ICD) based on ventricular 
tachyarrhythmias (we cannot perform CMR in patients with ICD’s); 2) other severe, concomitant illness; 3) prior 
stroke or orthopedic problems that limit exercise capacity. 4) Abnormal renal function as defined above; 
Cautious exclusion:  For patients with chronic moderate obstructive pulmonary disease (COPD) of severity 
that requires chronic, daily inhaler therapy the physician may consider Regadenoson for the diagnostic 
portions of the MRI.   This will be based on the physicians medical opinion.  If the patient has severe COPD 
he/she will be excluded from the study.    
  
Recruitment Plan.  Patients with newly identified HF due to NIDCM will be recruited from Vanderbilt University 
Medical Center,  the Nashville VA Medical Center and Meharry Medical College.   After stabilization with the 
above treatments, we will request their participation in this study.  Informed consent will be obtained using 
forms approved by our IRB.   
   
CMR Timeline
MPI= myocardial perfusion imaging
CSF=coronary sinus flow
MDE=myocardial delayed enhancement
Scout
Function
TI Scout
BOLD
Adenosine
MPI
Gd
CSF
EKG
MDE
0        1                   10             13                  
17        27    28       30
Time line (minutes)
              
Minutes
0
5
MVO2
[11C]acetate
40
35
CT attenuation
PET Study
(MVO2 = myocardial 
oxygen consumption)
CT attenuation
                    
The above figures demonstrate the protocol for the CMR and PET studies.  For CMR, patients will be 
studied while fasting to reduce chances of nausea during adenosine/regadenoson  infusion. The HR and BP by 
sphygmomanometer will be recorded every minute during the adenosine/regadenoson infusion, and at least 5 


7 
 
times during the PET study. These results will be averaged.  For PET, after an attenuation CT scan, kmono 
will be assessed with serial imaging after bolus injection of  [11C]acetate. The CMR and PET studies will be 
performed on the same day to reduce variability in BP, HR and medications between studies.  Following PET, 
the patients will perform a 6-minute walk test 3 times for reproducibility within 10% of each other, with results 
on a standard form. 
Spironolactone therapy.  The initial dose will be 12.5 mg daily, and will be increased  to 50 mg daily based on 
serum potassium and side effects, which will be monitored on days 3,7, 30 and then monthly.  The BP, HR, 
body weight, cardiac physical examination, electrolytes and NYHA FC will be recorded at each visit on a 
standard form.  If there is symptomatic gynecomastia with spironolactone, eplerenone, 25 or 50 mg as 
tolerated,  will be used instead. (20).  Follow-up tests. After 6 months’ treatment, all the above tests will be 
repeated.  
 
 
 
 
 
 
The following chart shows the protocol in table format. 
Procedures for Aldosterone Study 
 
  
 
  
Screen and Consent 
  
Study 
1 
  
Study  2 
Study 2a 
WEEK 
1 
1.5 
2 
4 
5 
12 
24 
25 
History and Physical Exam 
X 
X 
  
X 
X 
X 
X 
 
Spironolactone Dose 
25 
25, CHK BMP, stop 
25 
50 
  
  
  
 
Review Meds 
X 
X 
X 
X 
X 
X 
X 
 
Basic Metabolic Panel (blood test) 
X 
X 
X 
X 
X 
X 
X 
 
Blood Sampling for Heart Failure 
  
  
X 
  
  
  
X 
 
6 Minute Walking Test 
  
  
X 
  
  
  
X 
 
Heart Failure Questionnaire 
  
  
X 
  
  
  
X 
 
PET 
  
  
X 
  
  
  
X 
 
CMR 
  
  
X 
  
  
  
X 
X 
  
 
STUDY 1 AND 2 = the tests shown in table by X on that day 
 
BMP= basic metabolic profile to check potassium and kidney function 
 
  
 
Spironolactone dose may be adjusted up or down as needed 
 
Eplerenone may substitute for spironolactone 
 
Weeks 1 and 5 may be done by drawing blood at other location 
 
Week 12 visit may be done by telephone follow up 
 
PET = positron emission tomography test of heart metabolism 
 
CMR = magnetic resonance imaging test of heart function, blood flow and scar tissue 
 
 
Data analysis.  All results will be stored securely.  PET and CMR data will be analyzed without reference to 
clinical data, and clinical results will be analyzed separately from CMR and PET data until finalized. 
 
Specific Aims a and b: Determinants of myocardial energy starvation,  LV energy supply-demand 
relations and efficiency.  With CMR we will accurately determine LVEDV, ESV, SV, LVEF and LV mass and 
calculate LV systolic wall stress with standard equations (60). Myocardial fibrosis will be graded using a visual, 
segmental method as outlined by McCrohon (61) in two representative short axis midventricular sections, with 


8 
 
results averaged.  Myocardial reactive hyperemia will be estimated using gadolinium during 
adenosine/regadenoson infusion, according to the method of Panting (40). We will calculate percent voxels with 
inadequate reactive hyperemia.  We will evaluate hypoxia using the BOLD imaging method suggested by 
Wacker (48)  and will estimate the extent of myocardial hypoxia, according to the equation: [BOLD + 
voxels/Total voxels] x 100% = % BOLD + voxels.  Lacking a predominantly subendocardial signal, we will 
employ a  parametric analysis (62).  Based on the findinds of Panting (40), we will compare myocardial 
perfusion in patients with NIDCM and normals.   
Specific comparisons.  We will evaluate the argument that subendocardial hypoxia by BOLD imaging is 
related to subendocardial ischemia, and that the volume of subendocardial hypoxia is related to LVEF. For this 
we will study the correlation between LVEF and the %BOLD + voxels. We recognize that other influences 
on each myocyte will also affect global LVEF, but we suspect that BOLD + regions may relate to LVEF.  
  
We will evaluate the argument that LVH is the substrate for subendocardial hypoxia by comparison of the 
%BOLD + voxels to LVH in gm. The relation of LVH, %BOLD + voxels and LVEF may be complex and may 
require a 3-dimensional display to express it satisfactorily.   
 
We will use CMR perfusion imaging with and without adenosine to compare myocardial perfusion in 
patients with NIDCM to patients with structurally normal hearts. Based on CMR procedural logs, we estimate 
there are up to 20 patients with structurally normal hearts studied with CMR during adenosine infusion. We will 
review the electronic medical records of these possible normal patients to determine if they have structurally 
normal hearts. We will then view and quantitatively analyze, using the method of Panting (40), these normal 
patients’ images. We will compare the myocardial perfusion indices and myocardial perfusion reserve indices 
of the normals to that of patients with NIDCM.   
We will compare LV mass to the percent fibrosis and will evaluate the relation between fibrosis and 
%BOLD + voxels using standard linear correlation.   We will quantify the monoexponential [11C]acetate decay 
rate using methodology we employed previously, averaging the [11C]acetate data in 4 midventricular slices. 
We will compare oxidative metabolic supply as estimated by kmono to 2 indices of myocardial 
demand, the RPP and LV systolic wall stress. We expect this will confirm our prior, more limited 
observations, shown in the Preliminary Studies and will support the hypothesis of energy starvation in HF.  We 
will calculate the WMI and compare this to results in the literature using the equation: WMI = (SBP x SVI x 
HR)/kmono, where SBP = systolic blood pressure, SVI = stroke volume index, HR = heart rate. 
 
Specific Aim c: To evaluate relations among LV mass, volume and LVEF before and after aldosterone 
blockade, compared to changes in myocardial fibrosis, reactive hyperemia, BOLD estimates of hypoxia 
and myocardial oxidative metabolism.  The improvements in clinical status, LV mass and LVEF have been 
shown in two studies, and we expect the same results.  The goal of this Specific Aim is to judge the 
parameters of energy starvation (LVH, fibrosis, reactive hyperemia, LV hypoxia and oxidative metabolism) 
before and during 4 months’ spironolactone treatment.  Thus, we will compare changes in LVH, % fibrosis, 
%BOLD+ voxels and the percent reactive hyperemia to LVEDV, LVESV, LVEF, SV, kmono/RPP and the 
WMI before and during spironolactone treatment.  
 
Specific Aim d:  To evaluate the relations between clinical improvement, the energy starvation theory 
and LV volume, for judging the hypothesis that drugs that reduce LV volumes are beneficial in HF.   
We expect a spectrum of responses to aldosterone-blocking therapy. It will be useful to compare the response 
clinically and by LV volume analysis to myocardial supply-demand relations, BOLD imaging and reactive 
hyperemia. We will compare changes in LVEDV, LVESV, SV and LVEF to NYHA FC, 6-minute walk test 
performance to kmono/RPP, WMI, %BOLD+ voxels and reactive hyperemia. We will use paired t-tests and 
linear correlation. We believe these results will add evidence to support the volume-remodeling hypothesis. 
 
Specific Aim e. To evaluate the reproducibility of CMR measurements of myocardial perfusion.  We 
expect close reproducibility of the CMR estimates of myocardial perfusion at rest and during adenosine 
infusion, but since we have been unable to document this in the literature, we propose to perform this study in 
a subset of 8 HF patients.  This is based on the advice of our biostatistical consultants.  We will then have 
greater confidence in judging the changes that we expect to detect following spironolactone therapy. 
 


9 
 
 
Statistical analysis.   Based on the only available actually randomized data (23) 20 subjects will provide 
statistically significant information for our goals.   Subsequent NHLBI applications will have more 
detailed goals.  The study of patients before and during spironolactone treatment will allow us to use each 
patient as his/her own control. The data analysis will employ standard techniques, including paired t-tests and 
linear regression analysis as appropriate. Statistical significance will be judged as p < 0.05. 
 
Potential difficulties and limitations.  Patient recruitment.  We are confident it will be possible to recruit 
sufficient patients with NIDCM at Vanderbilt and the adjacent Nashville VA Medical Center.  [11C]acetate 
decay in HF.  There is a strong, quantitative relation between myocardial oxygen consumption and [11C] 
acetate decay in HF (30). Thus, this measurement reflects oxidative metabolism in HF.  BOLD and reactive 
hyperemia in HF.  There is support in the literature (see Background) for making these measurements with 
our equipment (1.5 T magnet).  Selection of spironolactone.  The literature supports using this drug in HF(19) 
unless there are significant side effects of gynecomastia, whereupon we will change to eplerenone (20).  
Timing of repeat testing.  Based on the initial studies of spironolactone in NIDCM (23) we expect to see by 4 
months an improvement in LVEF and a decrease in LVEDV. Responders and nonresponders to 
spironolactone. We expect a spectrum of response to spironolactone. This should be a strength of the 
analysis of our data concerning the anatomic and physiologic mechanisms of energy starvation. A sample size 
of 20 patients (23) should be adequate to demonstrate striking responses in some patients and to produce 
sufficient encouraging data for an application for further support 
 
5. ETHICAL ASPECTS OF THE PROPOSED RESEARCH:  We believe there are no ethical problems in the 
proposed research.  Given the well-documented benefits of ALDO-blocking drugs, it is no longer ethical to 
conduct a placebo-controlled study of ALDO-blocking effects. Thus, we will use a before and after (during) 
approach. The problem of when to implant an ICD might be considered an issue. However, it is reasonable to 
institute aldo-blocking therapy, in addition to the other anti-failure therapy in newly diagnosed HF patients 
because this may improve LVEF such that an ICD may not be needed. Present guidelines (63) are moot on 
the duration of treatment before placing an ICD.  However, If we discover significant ventricular arrhythmias 
during this research that require an ICD, we will end the patient's participation in the study and promptly notify 
the patient's physician of these developments.  Human subjects:  Consent will be obtained using forms 
approved by the Vanderbilt IRB.  Women and minorities will be included.  The targeted enrollment will be 20 
subjects of both sexes for reasons noted above.  Inclusion and exclusion criteria were listed above. 
 
 
LITERATURE CITED: 
                                                 
1 Colucci WS and Braunwald EB. Pathophysiology of heart failure. In:Braunwald’s Heart Disease. A Textbook 
of Cardiovascular Medicine. Zipes DP, Libby P, Bonow RO, Braunwald E, eds. 7th ed. Elsevier Saunders, 
Philadelphia, 2005. pp 512-524. 
 
 
2 Ingwall JS, Weiss RG. Is the failing heart energy starved? On using chemical energy to support cardiac 
function. Circ Res. 2004;95:135-45.  
 
3 Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J 
Med. 1990;322:100-10. 
 
4 Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S.  Mitochondrial abnormalities in 
myocardium of dogs with chronic heart failure. J Mol Cell Cardiol. 1992;24:1333-47. 
 
55 Unverferth DV, Leier CV, Magorien RD, Croskery R, Svirbely JR, Kolibash AJ, et. al. Improvement of human 
myocardial mitochondria after dobutamine: a quantitative ultrastructural study. J Pharmacol Exp Ther. 
1980;215:527-32. 
 


10 
 
                                                                                                                                                                                     
6 Maytin M, Colucci WS. Molecular and cellular mechanisms of myocardial remodeling. J Nucl Cardiol. 
2002;9:319-27. 
 
7 Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS. Role of oxidative stress in myocardial 
hypertrophy and failure. J Mol Cell Cardiol. 2002;34:379-88. 
 
8 Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure.  N Engl J Med. 1999;341:1276-
83. 
 
9 Dorn GW 2nd, Mann DL. Signaling pathways involved in left ventricular remodeling: summation. J Card Fail. 
2002;8:S387-8. 
 
10 Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper 
from an international forum on cardiac remodeling. On Behalf of an International Forum on Cardiac 
Remodeling. J Am Coll Cardiol. 2000;35:569-82. 
 
11 Vatner SF. Reduced subendocardial myocardial perfusion as one mechanism for congestive heart failure. 
Am J Cardiol. 1988;62:94E-98E. 
 
12 Neglia D, Michelassi C, Trivieri MG, Sambuceti G, Giorgetti A, Pratali L, et. al. Prognostic role of myocardial 
blood flow impairment in idiopathic left ventricular dysfunction. Circulation. 2002;105:186-93. 
 
13 Benedict CR, Francis GS, Shelton B, Johnstone DE, Kubo SH, Kirlin P, Nicklas J, Liang CS, 
Konstam MA, Greenberg B, et al. Effect of long-term enalapril therapy on neurohormones in patients 
with left ventricular dysfunction. SOLVD Investigators.  Am J Cardiol. 1995;75:1151-7.   
 
14 Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, 
Yusuf S.  Comparison of neuroendocrine activation in patients with left ventricular dysfunction with 
and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction 
(SOLVD).  Circulation. 1990;82:1724-9. 
 
15 Brilla CG, Rupp H, Maisch B.  Effects of ACE inhibition versus non-ACE inhibitor antihypertensive 
treatment on myocardial fibrosis in patients with arterial hypertension. Retrospective analysis of 120 
patients with left ventricular endomyocardial biopsies.  Herz. 2003;28:744-53. 
 
16Wilke A, Funck R, Rupp H, Brilla CG.  Effect of the renin-angiotensin-aldosterone system on the 
cardiac interstitium in heart failure.  Basic Res Cardiol. 1996;91 Suppl 2:79-84. 
  
17 Brown NJ.  Aldosterone and end-organ damage.  Curr Opin Nephrol Hypertens. 2005;14:235-41. 
Weber KT.  Aldosterone in congestive heart failure.  N Engl J Med. 2001;345:1689-97. 
 
18 Weber KT.  Aldosterone in congestive heart failure.  N Engl J Med. 2001;345:1689-97. 
 
19 Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J.  The effect of 
spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone 
Evaluation Study Investigators.  N Engl J Med. 1999 ;341:709-17. 
 
20 Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, 
Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study 


11 
 
                                                                                                                                                                                     
Investigators.  Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction 
after myocardial infarction.  N Engl J Med. 2003;348:1309-21. 
 
21 Rousseau MF, Gurne O, Duprez D, Van Mieghem W, Robert A, Ahn S, Galanti L, Ketelslegers JM; 
Belgian RALES Investigators.  Beneficial neurohormonal profile of spironolactone in severe 
congestive heart failure: results from the RALES neurohormonal substudy.  J Am Coll Cardiol. 
2002;40:1596-601. 
 
22 Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, 
Matsumoto T, Horie H, Sugimoto Y, Kinoshita M.   Spironolactone inhibits the transcardiac extraction 
of aldosterone in patients with congestive heart failure.  J Am Coll Cardiol. 2000;36:838-44 
 
23 Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, 
Matsumoto T, Matsui T, Kinoshita M.   Effect of spironolactone on plasma brain natriuretic peptide 
and left ventricular remodeling in patients with congestive heart failure.  J Am Coll Cardiol. 
2001;37:1228-33. 
 
24 Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Brighetti G, Marino P, Zardini P.  Long-term, 
dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in 
patients with chronic heart failure.  J Am Coll Cardiol. 2002;40:304-10. 
 
25 Feola M, Menardi E, Ribichini F, Vado A, Deorsola A, Ferrero V, Visconti G, Milanese U, Uslenghi 
E.  Effects of the addition of a low dose of spironolactone on brain natriuretic peptide plasma level 
and cardiopulmonary function in patients with moderate congestive heart failure.  Med Sci Monit. 
2003;9:CR341-5. 
 
26 Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J.  Additive improvement of 
left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with 
eplerenone and ACE inhibition in rats with myocardial infarction.  J Am Coll Cardiol. 2003;42:1666-73. 
 
27 Susic D, Varagic J, Ahn J, Matavelli L, Frohlich ED.  Long-term mineralocorticoid receptor blockade 
reduces fibrosis and improves cardiac performance and coronary hemodynamics in elderly SHR.  Am 
J Physiol Heart Circ Physiol. 2007;292:H175-9. 
 
28 Huang BS, Leenen FH.  Blockade of brain mineralocorticoid receptors or Na+ channels prevents 
sympathetic hyperactivity and improves cardiac function in rats post-MI.  Am J Physiol Heart Circ 
Physiol. 2005;288:H2491-7. 
 
29 Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield BA, Marcoux LG, Malloy 
CR. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated 
cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1994;24:1310-20. 
 
30 Beanlands RS, Bach DS, Raylman R, Armstrong WF, Wilson V, Montieth M, et. al. Acute effects of 
dobutamine on myocardial oxygen consumption and cardiac efficiency measured using carbon-11 acetate 
kinetics in patients with dilated cardiomyopathy. J Am Coll Cardiol. 1993;22:1389-98. 
 
31 Beanlands RS, Armstrong WF, Hicks RJ, Nicklas J, Moore C, Hutchins GD, et. al. The effects of afterload 
reduction on myocardial carbon 11-labeled acetate kinetics and noninvasively estimated mechanical efficiency 
in patients with dilated cardiomyopathy. J Nucl Cardiol. 1994;1:3-16. 
 


12 
 
                                                                                                                                                                                     
32 Bengel FM, Permanetter B, Ungerer M, Nekolla S, Schwaiger M. Non-invasive estimation of myocardial 
efficiency using positron emission tomography and carbon-11 acetate--comparison between the normal and 
failing human heart. Eur J Nucl Med. 2000;27:319-26. 
 
33 Brown M, Marshall DR, Sobel BE, Bergmann SR. Delineation of myocardial oxygen utilization with carbon-
11-labeled acetate. Circulation. 1987;76:687-96. 
 
34 Brown MA, Myears DW, Bergmann SR. Validity of estimates of myocardial oxidative metabolism with 
carbon-11 acetate and positron emission tomography despite altered patterns of substrate utilization. J Nucl 
Med. 1989;30:187-93. 
 
35 Armbrecht JJ, Buxton DB, Schelbert HR. Validation of [1-11C]acetate as a tracer for noninvasive 
assessment of oxidative metabolism with positron emission tomography in normal, ischemic, postischemic, 
and hyperemic canine myocardium. Circulation. 1990;81:1594-605. 
 
36 Beanlands RS, Nahmias C, Gordon E, Coates G, deKemp R, Firnau G, et. al.  The effects of beta(1)-
blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular 
dysfunction: A double-blind, placebo-controlled, positron-emission tomography study. 
Circulation.2000;102:2070-5. 
 
37 Myerson SG, Bellenger NG, Pennell DJ. Assessment of left ventricular mass by cardiovascular magnetic 
resonance. Hypertension. 2002;39:750-5. 
 
38 Longmore DB, Klipstein RH, Underwood SR, Firmin DN, Hounsfield GN, Watanabe M, Bland C, Fox K, 
Poole-Wilson PA, Rees RS, et al. Dimensional accuracy of magnetic resonance in studies of the heart. Lancet. 
1985;1:1360-2.   
 
39 Grothues F, Smith GC, Moon JC, Bellenger NG, Collins P, Klein HU, Pennell DJ. Comparison of interstudy 
reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal 
subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol.2002;90:29-34. 
 
40 Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P, Pennell DJ. Abnormal 
subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N 
Engl J Med. 2002;346:1948-53. 
 
41 Pauling L, Coryell C. The magnetic properties and structure of hemoglobin. Proc Natl Acad Sci USA 
1936;22:210-216. 
 
42 Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of 
rodent brain at high magnetic fields. Magn Reson Med 1990;14:68-78. 
 
43 Ogawa S, Lee TM. Magnetic resonance imaging of blood vessels at high fields: in vivo and in vitro 
measurements and image simulation. Magn Reson Med 1990;16(1):9-18. 
 
44 Wendland MF, Saeed M, Lauerma K, de Crespigny A, Moseley ME, Higgins CB. Endogenous susceptibility 
contrast in myocardium during apnea measured using gradient recalled echo planar imaging. Magn Reson 
Med. 1993;29:273-276. 
 
45 Atalay MK, Reeder SB, Zerhouni EA, Forder JR. Blood oxygenation dependence of T1 and T2 in the iolated, 
perfused rabbit heart at 4.7T. Magn Reson Med. 1995;34:623-627. 
 


13 
 
                                                                                                                                                                                     
46 Li D, Dhawale P, Rubin PJ, Haacke EM, Gropler RJ. Myocardial signal response to dipyridamole and 
dobutamine: demonstration of the BOLD effect using a double-echo gradient-echo sequence. Magn Reson 
Med. 1996;36:16-20. 
 
47 Beache GM, Herzka DA, Boxermann JL, Post WS, Gupta SN, Faranesh AZ, Solaiyappan M, Bottomley PA, 
Weiss JL, Shapiro EP, Hill MN. Attenuated myocardial vasodilator response in patients with hypertensive 
hypertrophy revealed by oxygenation-dependent magnetic resonance imaging. Circulation. 2001;104:1214-
1217. 
 
48 Wacker CM, Hartlep AW, Pfleger S, Schad LR, Ertl G, Bauer WR. Susceptibility-sensitive magnetic 
resonance imaging detects human myocardium supplied by a stenotic coronary artery without a contrast agent. 
J Am Coll Cardiol 2003;41:834-840. 
 
49 Kronenberg MW, Konstam MA, Edens TR, Howe DM, Dolan N, Udelson JE, Benedict C, Stewart D, Yusuf S 
for the SOLVD Investigators: Factors influencing exercise performance in patients with left ventricular 
dysfunction. J Card Fail 1998; 4: 159-167. 
 
50 Konstam MA, Kronenberg MW, Udelson JE, Kinan D, Metherall J, Dolan N, Edens T, Howe D, Kilcoyne L, 
Benedict C, Youngblood M, Barrett J, Yusuf S: Effectiveness of preload reserve as a determinant of clinical 
status in patients with left ventricular systolic dysfunction. Am J Cardiol 1992; 69:1591-1595. 
 
51 Konstam MA, Rousseau MF, Kronenberg MW, Udelson JE, Melin J, Stewart D, Nolan N, Edens TR, Ahn S, 
Kinan D, Howe DM, Kilcoyne L, Metherall J, Yusuf S, Pouleur H for the SOLVD Investigators: Effects of the 
angiotensin converting enzyme inhibitor, enalapril, on the long-term progression of left ventricular 
dysfunction in patients with heart failure. Circulation 1992; 86:431-438. 
 
52 Konstam MA, Kronenberg MW, Rousseau MF, Udelson JE, Melin J, Stewart D, Dolan N, Edens TR, Ahn S, 
Kinan D, Howe DM, Kilcoyne L, Metherall J, Benedict C, Yusuf S, Pouleur H for the SOLVD Investigators: 
Effects of the angiotensin converting enzyme inhibitor, enalapril, on the long-term progression of left ventricular 
dilatation in patients with asymptomatic systolic dysfunction. Circulation 1993; 88:2277-2283. 
 
53 Patten RD, Kronenberg MW, Benedict CR, Udelson JE, Kinan D, Stewart D, Yusuf S, Smith JJ, Kilcoyne L, 
Dolan N, Edens TR, Metherall J, Konstam MA: Acute and long term effects of the angiotensin-converting 
enzyme inhibitor, enalapril, on adrenergic activity and sensitivity during exercise in patients with left 
ventricular systolic dysfunction. Am Heart J 1997; 134: 37-43. 
 
54 Kronenberg MW, Cohen GI, Leonen MF, Mladsi TA, Di Carli MF.  Myocardial oxidative metabolic 
supply-demand relationships in patients with nonischemic dilated cardiomyopathy.  J Nucl Cardiol. 
2006;13:544-53. 
 
55 Kissling G. Mechanical determinants of myocardial oxygen consumption with special reference to external 
work and efficiency. Cardiovasc Res. 1992;9:886-92. 
 
56 Graham TP Jr, Covell JW, Sonnenblick EH, Ross J Jr, Braunwald E. Control of myocardial oxygen 
consumption: relative influence of contractile state and tension development. J Clin Invest. 1968;47:375-85. 
 
57 Konstam MA, Udelson JE, Anand IS, Cohn JN. Ventricular remodeling in heart failure: a credible surrogate 
endpoint. J Card Fail. 2003;9:350-3. 
 
58 Udelson JE, McGrew FA, Flores E, Ibrahim H, Katz S, Koshkarian G, O’Brien T, Kronenberg MW, 
Zimmer C, Orlandi C, Konstam MA.  Multicenter randomized, double-blind, placebo-controlled study 


14 
 
                                                                                                                                                                                     
on the effect of oral tolvaptan on left ventricular dilatation and function in patients with heart failure 
and systolic dysfunction.  J Am Coll Cardiol 2007; in press. 
 
59 Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala SI, Kronenberg MW, Kostis JB, Kohn 
RM, Guillotte M, et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left 
ventricular dysfunction. SOLVD Investigators. JAMA.1993;270:1702-7. 
 
60 Reichek N, Wilson J, St John Sutton M, Plappert TA, Goldberg S, Hirshfeld JW.  Noninvasive determination 
of left ventricular end-systolic stress: validation of the method and initial application. Circulation. 1982;65:99-
108.  
 
61 McCrohon JA, Moon JC, Prasad SK, McKenna WJ, Lorenz CH, Coats AJ, Pennell DJ.Differentiation of heart 
failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced 
cardiovascular magnetic resonance. Circulation. 2003;108:54-9. 
 
62 Beache GM, Herzka DA, Boxerman JL, Post WS, Gupta SN, Faranesh AZ, Solaiyappan M, Bottomley PA, 
Weiss JL, Shapiro EP, Hill MN.Attenuated myocardial vasodilator response in patients with hypertensive 
hypertrophy revealed by oxygenation-dependent magnetic resonance imaging. Circulation.  2001;104:1214-7. 
 
63 Hunt SA; American College of Cardiology; American Heart Association Task Force on Practice 
Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of 
Heart Failure).  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart 
failure in the adult: a report of the American College of Cardiology/American Heart Association Task 
Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation 
and Management of Heart Failure).  J Am Coll Cardiol. 2005;46:e1-82.