Analysis of ventricular synchrony: A complex puzzle
Analysis of ventricular synchrony: A complex puzzle
Guillermo Romero-Farina 0
FASNC 0 1 2
Santiago Aguade´-Bruix 0
0 Reprint requests: Guillermo Romero-Farina MD , PhD, FESC, FASNC , Cardiology Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Auto`noma de Barcelona , Paseo Vall d'Hebron 119-129, 08035, Barcelona , Spain; guir-
1 Department of Nuclear Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Auto`noma de Barcelona , Barcelona , Spain
2 Cardiology Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Auto`noma de Barcelona , Barcelona , Spain
The following editorial was focused on the most
relevant points of the article by Malik et al.:1 firstly,
normal cut-off values of phase analysis parameters and
different variables that influence in the ventricular
synchrony analysis; secondly, the impact of the duration of
type II diabetes mellitus on left ventricular mechanical
synchrony analysis; thirdly, the repercussions on the
cardiac function of the diseases associated with diabetes
mellitus (DM), and its complications; and fourthly, a
normal gated SPECT definition.
In the last 13 years, we have a new tool in the area
of nuclear cardiology called analysis of left ventricle
synchrony. Since 2005, several articles2–20 have been
published in relation to the normal cut-off values
(Table 1), and diagnosis and prognosis (Table 2). From
a physiological point of view, the study of the
mechanical synchronization of the ventricles is very
complex. Among the different publications, there is a
general agreement between the average values and the
cut-off values normality obtained; however, in spite of
that they are not exactly concordant. This is due to the
fact that these cut-off values depend on multiple
variables, which are difficult to control in the statistical
analysis (Figure 1). Until now, all the information
provided by different groups of researchers have taught us
that these influential variables can be grouped into four
main categories (Figure 1): type of software, type of
statistical methodology to find the appropriate cut-off
values, the moment that images are acquired, and
clinical patient data. But probably, as experimental studies
show21, the most complex thing to control is the effect
of the intrinsic myocardial properties on ventricular
synchrony, which are specific to each patient.
Through different mechanisms, patients with DM
have high cardiovascular morbidity and mortality. The
left ventricular diastolic dysfunction,22,23 systolic
dysfunction,24 and left ventricular mechanical
dyssynchrony (LVMD)1 are frequent.
In this issue of Journal of Nuclear Cardiology,
Malik et al. evaluated retrospectively 146 consecutive
patients with normal gated SPECT-MPI.1 LVMD was
determined by the cut-off values (mean ? 2 SD)
observed for phase standard deviation (SD) and phase
bandwidth (BW) from the control subjects. LVMD was
detected in 24 (28%) DM patients with the pre-defined
cut-off values for SD ([ 10.8) and BW ([ 35.6) derived
from the controls. Hyperlipidemia, overweight/obesity,
duration of DM, and its long-term complications were
independently associated with LVMD, with long-term
complications being the highest risk factor (OR 28.00;
p \ 0.001). The authors concluded that the evolution
time of the patients with type II DM affects the left
ventricular mechanical synchrony.
In this study, long-term type II diabetes
complications (nephropathy, neuropathy, neuropathy, and/or
retinopathy) were present in 27.9% (24/86) of patients,
and 18 of them (18/24, 75%) had LVMD. Therefore, the
cause and the degree of LVMD is not only due to the
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myocardial changes caused by diabetes directly, but also
by the myocardial repercussion caused by the effects of
DM on other organs (nephropathy, neuropathy, etc).
Previously, From et al.22 evaluated the diastolic function
in 486 patients with DM free of heart failure using tissue
Doppler echocardiography, and concluded that a
duration of DM of C 4 years is correlated with significant
LV diastolic dysfunction. On the other hand, most of the
asymptomatic diabetes patients with a 5- to 10-year
duration of DM have ECG changes; 70% of patients
with ECG changes have poor glycaemic control;24 and
the most common abnormality observed is ST-T
changes, left atrial enlargement, left ventricular hypertrophy,
left bundle branch block, and right bundle branch
block.24 In other study,23 1760 diabetic patients with a
tissue Doppler echocardiographic assessment of
diastolic function were identified; 411 patients (23%) had
diastolic dysfunction. The cumulative probability of the
development of heart failure at 5 years for diabetic
patients with diastolic dysfunction was 36.9% compared
to 16.8% for patients without diastolic dysfunction
(p \ 0.001), and who had a significantly higher
mortality compared to those without diastolic dysfunction.
Also, these patients have an elevated risk for heart
failure. The possible pathophysiological mechanisms
between diabetes and heart failure may include a higher
risk of atherosclerosis, microvascular dysfunction, and
deposition of interstitial myocardial fibrosis, and specific
neurohumoral deregulations.25 Ho¨ ke et al.25 studied 710
patients with diabetes with heart failure and cardiac
resynchronization therapy. At the 6-month follow-up,
they found a significant (p \ 0.001) improvement in
diastolic and systolic function after cardiac
resynchronization therapy. Therefore, the evolution time of the
diabetes is very important, because the longer the
exposure to diabetes, the higher the prevalences of
Furthermore, another interesting aspect of Malik
et al’s.1 work, is the association between diabetes,
arterial hypertension, and ventricular hypertrophy. The
left ventricular hypertrophy and remodeling is frequent
in patients with type II DM; cardiac steatosis and
impaired myocardial energetics can contribute to these
changes.26 Interstitial fibrosis is implied in the
pathogenesis of ventricular hypertrophy, and was identified in
advanced stages of diabetic cardiomyopathy.26–28 DM
per se is linked to significant cardiac steatosis, and there
exists a correlation between myocardial triglyceride and
the concentric ventricular remodeling. Also, the
myocardial steatosis is a predictor of concentric LV
remodeling and subclinical contractile dysfunction in
patients with type II DM.26
All this explains how complex it is to study the
ventricular dyssynchrony in DM patients. In future
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studies, to avoid these confounders (nephropathy,
neuropathy, arterial hypertension, ventricular hypertrophy,
etc.) in DM patients, it is very important to exclude
patients with diabetic complications, but this requires a
greater number of patients to be evaluated.
Noteworthy, in the current issue of the journal,1 this
study is titled ‘‘left ventricular mechanical
dyssynchrony assessment in long-standing type II diabetes
mellitus patients with normal gated SPECT-MPI.’’ All
patients have a normal gated SPECT. To consider a
normal gated SPECT, it is important to have a normal
synchrony. Actually in our Nuclear Cardiology
Department, we define a normal myocardial perfusion gated
SPECT stress-rest as normal perfusion, motility and
thickening (score 0), normal volumes, normal ejection
fraction, normal transient ischemic dilation ratio, normal
chape index, normal stress lung-heart ratio, normal
synchrony, normal coronary flow, normal coronary
reserve flow, normal ST, without angina, C 5 METs,
normal heart rate recovery, normal % heart rate
([ 80%), normal reserve pulse pressure, and normal
Duke treadmill score.
According to these considerations, perhaps in future,
research studies should use the same methodology and
the same adjustment variables to obtain the normal
cutoff values of phase parameters. Finally, we recognize the
effort and enthusiasm of Dr. Malik and the rest of the
authors in the preparation of this research work.
The authors report no potential conflict of interest
relevant to this editorial.
1. Malik D , Mittal B , Sood A , Parmar M , Kaur G , Bahl A . Left ventricular mechanical dyssynchrony assessment in long-standing type II diabetes mellitus patients with normal gated SPECT-MPI . J Nucl Cardiol . 2018 . https://doi.org/10.1007/s12350-018-1208-9.
2. Nakajima K , Okuda K , Matsuo S , Kiso K , Kinuya S , Garcia EV . Comparison of phase dyssynchrony analysis using gated myocardial perfusion imaging with four software programs: Based on the Japanese Society of Nuclear Medicine working group normal database . J Nucl Cardiol . 2017 ; 24 : 611 - 21 .
3. Romero-Farina G , Aguade´-Bruix S , Candell-Riera J , Pizzi MN , Garc´ıa-Dorado D. Cut-off values of myocardial perfusion gatedSPECT phase analysis parameters of normal subjects, and conduction and mechanical cardiac diseases . J Nucl Cardiol . 2015 ; 22 : 1247 - 58 .
4. Chen J , Kalogeropoulos AP , Verdes L , Butler J , Garcia EV . Leftventricular systolic and diastolic dyssynchrony as assessed by multi-harmonic phase analysis of gated SPECT myocardial perfusion imaging in patients with end-stage renal disease and normal LVEF . J Nucl Cardiol . 2011 ; 18 : 299 - 308 .
5. Atchley AE , Trimble MA , Samad Z , Shaw LK , Pagnanelli R , Chen J , et al. Use of phase analysis of gated SPECT perfusion imaging to quantify dyssynchrony in patients with mild-to-moderate left ventricular dysfunction . J Nucl Cardiol . 2009 ; 16 : 888 - 94 .
6. Trimble MA , Velazquez EJ , Adams GL , Honeycutt EF , Pagnanelli RA , Barnhart HX , Chen J , et al. Repeatability and reproducibility of phase analysis of gated single-photon emission computed tomography myocardial perfusion imaging used to quantify cardiac dyssynchrony . Nucl Med Commun . 2008 ; 29 : 374 - 81 .
7. Trimble MA , Borges-Neto S , Smallheiser S , Chen J , Honeycutt EF , Shaw LK , et al. Evaluation of left ventricular mechanical dyssynchrony as determined by phase analysis of ECG-gated SPECT myocardial perfusion imaging in patients with left ventricular dysfunction and conduction disturbances . J Nucl Cardiol . 2007 ; 14 : 298 - 307 .
8. Chen J , Garcia EV , Folks RD , Cooke CD , Faber TL , Tauxe EL , et al. Onset of left ventricular mechanical contraction as determined by phase analysis of ECG-gated myocardial perfusion SPECT imaging: Development of a diagnostic tool for assessment of cardiac mechanical dyssynchrony . J Nucl Cardiol . 2005 ; 12 : 687 - 95 .
9. Doi T , Nakata T , Yuda S , Hashimoto A . Synergistic prognostic implications of left ventricular mechanical dyssynchrony and impaired cardiac sympathetic nerve activity in heart failure patients with reduced left ventricular ejection fraction . Eur Heart J Cardiovasc Imaging . 2018 ; 19 : 74 - 83 .
10. Mori H , Isobe S , Suzuki S , Unno K , Morimoto R , Kano N , et al. Prognostic value of left ventricular dyssynchrony evaluated by gated myocardial perfusion imaging in patients with chronic kidney disease and normal perfusion defect scores . J Nucl Cardiol . 2017 . https://doi.org/10.1007/s12350-017-0889-9.
11. Malhotra S , Pasupula DK , Sharma RK , Saba S , Soman P . Relationship between left ventricular dyssynchrony and scar burden in the genesis of ventricular tachyarrhythmia . J Nucl Cardiol . 2017 . https://doi.org/10.1007/s12350-017-1095-5.
12. Zafrir N , Bental T , Strasberg B , Solodky A , Mats I , Gutstein A , et al. Yield of left ventricular dyssynchrony by gated SPECT MPI in patients with heart failure prior to implantable cardioverterdefibrillator or cardiac resynchronization therapy with a defibrillator: Characteristics and prediction of cardiac outcome . J Nucl Cardiol . 2017 ; 24 : 122 - 9 .
13. Hess PL , Shaw LK , Fudim M , Iskandrian AE , Borges-Neto S. The prognostic value of mechanical left ventricular dyssynchrony defined by phase analysis from gated single-photon emission computed tomography myocardial perfusion imaging among patients with coronary heart disease . J Nucl Cardiol . 2017 ; 24 : 482 - 90 .
14. Cho SG , Jabin Z , Park KS , Kim J , Kang SR , Kwon SY , et al. Clinical values of left ventricular mechanical dyssynchrony assessment by gated myocardial perfusion SPECT in patients with acute myocardial infarction and multivessel disease . Eur J Nucl Med Mol Imaging . 2017 ; 44 : 259 - 66 .
15. Chiang KF , Hung GU , Tsai SC , Cheng CM , Chang YC , Lin WY , et al. Impact of cardiac reverse remodeling after cardiac resynchronization therapy assessed by myocardial perfusion imaging on ventricular arrhythmia . J Nucl Cardiol . 2017 ; 24 : 1282 - 8 .
16. Tsai SC , Chang YC , Chiang KF , Lin WY , Huang JL , et al. LV dyssynchrony is helpful in predicting ventricular arrhythmia in ischemic cardiomyopathy after cardiac resynchronization therapy: A preliminary study . Medicine . 2016 ; 95 : e2840 .
17. Hess PL , Shaw LK , Vemulapalli S , Pagnanelli R , O'Connor CM , Borges-Neto S . An alternative method to examine the predictive value of mechanical dyssynchrony . J Nucl Cardiol . 2015 ; 22 : 686 - 9 .
18. Zafrir N , Nevzorov R , Bental T , Strasberg B , Gutstein A , Mats I , et al. Prognostic value of left ventricular dyssynchrony by myocardial perfusion-gated SPECT in patients with normal and abnormal left ventricular functions . J Nucl Cardiol . 2014 ; 21 : 532 - 40 .
19. Hage FG , Aggarwal H , Patel K , Chen J , Jacobson AF , Heo J , et al. The relationship of left ventricular mechanical dyssynchrony and cardiac sympathetic denervation to potential sudden cardiac death events in systolic heart failure . J Nucl Cardiol . 2014 ; 21 : 78 - 85 .
20. Boogers MM , Van Kriekinge SD , Henneman MM , Ypenburg C , Van Bommel RJ , Boersma E , et al. Quantitative gated SPECTderived phase analysis on gated myocardial perfusion SPECT detects left ventricular dyssynchrony and predicts response to cardiac resynchronization therapy . J Nucl Med . 2009 ; 50 : 718 - 25 .
21. Dedkov EI , Bogatyryov Y , Pavliak K , Santos AT , Chen YF , Zhang Y , et al. Sex-related differences in intrinsic myocardial properties influence cardiac function in middle-aged rats during infarctioninduced left ventricular remodeling . Physiol Rep . 2016 . https://doi. org/10.14814/phy2. 12822 .
22. From AM , Scott CG , Chen HH . Changes in diastolic dysfunction in diabetes mellitus over time . Am J Cardiol . 2009 ; 103 : 1463 - 6 .
23. From AM , Scott CG , Chen HH . The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study . J Am Coll Cardiol . 2010 ; 55 : 300 - 5 .
24. Gupta S , Gupta RK , Kulshrestha M , Chaudhary RR . Evaluation of ECG abnormalities in patients with asymptomatic type 2 diabetes mellitus . J Clin Diagn Res . 2017 ; 11 : 39 - 41 .
25. Ho¨ke U , Thijssen J , van Bommel RJ , van Erven L, van der Velde ET , Holman ER , et al. Influence of diabetes on left ventricular systolic and diastolic function and on long-term outcome after cardiac resynchronization therapy . Diabetes Care . 2013 ; 36 : 985 - 91 .
26. Levelt E , Mahmod M , Piechnik SK , Ariga R , Francis JM , Rodgers CT , et al. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes . Diabetes . 2016 ; 65 : 44 - 52 .
27. Weber KT , Brilla CG . Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system . Circulation . 1991 ; 83 : 1849 - 65 .
28. Rubler S , Dlugash J , Yuceoglu YZ , Kumral T , Branwood AW , Grishman A . New type of cardiomyopathy associated with diabetic glomerulosclerosis . Am J Cardiol . 1972 ; 30 : 595 - 602 .