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Sumario Vol. 42 - Nº 2 Abril - Junio 2013

New diagnostic tools in heart failure: gated-spect phase analysis for left ventricular dyssynchrony assessment

Lucas Gutiérrez, Fernando A. Peñafort,
Italo B. Seretti, Raúl E. Ortego

Instituto de Diagnóstico y Resonancia de Mendoza.
Buenos Aires 446. (5500) Mendoza, Argentina.
Correo electrónico

The authors declare not having a conflict of interest.
 


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SUMMARY

Introduction: Resynchronization therapy has proven to be an effective intervention in heart failure. Left ventricular dyssynchrony assessed by Gated-SPECT is becoming a new tool in the exploration of patients liable to Cardiac Resynchronization Therapy.
Objective: To evaluate cardiac synchrony through gated-SPECT phase analysis. To determine clinical, electrocardiographic, myocardial perfusion and function variables related to cardiac dyssynchrony and their clinical outcomes.
Material and Methods: We prospectively evaluated 160 patients with gated SPECT referred to the Department of Nuclear Cardiology with a follow-up of 12±4 months with various indications. All patients had given their informed consent.
Results: Bandwidth, standard deviation and entropy were used to assess synchrony as phase analysis parameters. We obtained different degrees of synchrony related to the ECG, and LBBB dyssynchrony had the highest. Positive correlation between resting perfusion defects, defined as scar and synchrony parameters were found. Inverse correlation between degree of deterioration of left ventricular function and synchrony  variables also were found. We obtained a non-significant trend that patients with cardiovascular outcomes in their evolution had greater dyssynchrony.
Conclusions: This method of evaluation found greater dyssynchrony in patients with LBBB, worse ventricular function, degree of scar and a nonsignificant trend to increased cardiovascular events. Through the phase analysis gated-SPECT without a higher cost, we could assess perfusion, cardiac function and myocardial synchrony simultaneously, in an automatic and reproducible fashion.

Key words: Left ventricular dyssynchrony. Cardiac resynchronization therapy. Gated SPECT.
Rev Fed Arg Cardiol. 2013; 42(2): 102-112

 

 

INTRODUCTION
Heart failure (HF) is one of the greatest challenges for current medicine due to its morbi-mortality and growing prevalence. The diagnostic and therapeutic procedures used in providing care for the patients with HF, some very expensive, require an increasing allocation of resources in sanitary systems [1,2,3,4].

Cardiac resynchronization therapy (CRT) is a well known therapeutic option in a subset of patients with advanced HF, characterized by left ventricular (LV) systolic function impairment, expressed by ejection fraction (LVEF) <35%, and who present in their electrocardiographic tracing (ECG), a QRS >120 ms [5,6].

CRT has shown consistent results in improving the quality of life of patients, increasing their capacity for exercise, and also a greater survival with a reduction in the rate of hospitalization. The mentioned improvement is linked to patients with CRT showing an increase in LVEF and decrease in left ventricular volumes (reverse remodeling), with reduction in mitral valve insufficiency also being observed, which these patients usually present before CRT [7,8,9].

CRT benefits responsive patients; approximately 70% of the patients who get this indication, with 30% of non-responsive patients [9,10].

The selection of patients with HF by systolic dysfunction in whom the benefits of CRT were attempted, started taking into account the width of QRS as an expression of slower ventricular electro-mechanic activation, the substrate of a phenomenon called electrical dyssynchrony.

Echocardiography, particularly with the application of tissue Doppler, has shown that as a consequence of mechanic dyssynchrony, resulting from the electrical homonym, the segments of the myocardium that contract late, and the overall performance of the heart is affected.

However, in spite of the promising facts, the prospective and multicenter PROSPECT study, which evaluated different echocardiographic variables, did not allow predicting the response of patients to CRT [11].

Nuclear cardiology through the gated SPECT (GS) perfusion test allows evaluating possible mechanical dyssynchronies, likewise determining global LVEF and myocardial perfusion in a simultaneous procedure.

Currently, there is a chance to program automation of gated SPECT to analyze different phases of ventricular contraction in a discriminate way, a procedure generically called Phase Analysis (PA). Automation makes the procedure independent from the operator, not the programmer of course, and allows to perform more reproducible studies, ergo comparable; moreover, previously made studies can be reanalyzed retrospectively.

PA is a procedure with a sustained development in nuclear cardiology, with the advantage of being an accessible method with the available technology [12,13].


OBJECTIVES
To perform an evaluation of cardiac synchronization applying PA in a population of patients with different indications of GS.

To determine the clinical, electrocardiographic, function and myocardial perfusion variables, related to cardiac dyssynchrony.

To analyze the prospective clinical evolution of dyssynchronic patients and to gather data that would allow analyzing the feasibility of a prospective study in specific groups of patients with HF, that would allow improving the indication and the prognosis of the CRT results.


MATERIAL AND METHODS
There were 160 patients from the Nuclear Medicine Service of the Instituto de Diagnóstico y Resonancia from Mendoza, included and evaluated prospectively. They corresponded to the 2011-2012 term. Gated SPECT in rest and stress were performed in them. All the patients gave their informed consent.

Acquisition and processing
The radiotracer Sestamibi-Tc99m was used, applying an average dose of 25 mCi in a protocol of 2 days [14].

The acquisition was made with a Picker Prism 2000 XP Gamma camera, in 180º elliptical orbit. There were 60 projections acquired in a matrix of 64 x 64, with a projection time of 25 seconds. A 20% window of symmetric energy was applied on photopeak of 140 Kev. Both protocols were acquired in synchrony (gated) with the R wave of the ECG at 16 frames.

Analysis of images
The data were processed with the QPS and QGS software (Cedar’s Sinai-Suite2012).

Perfusion was evaluated applying an analysis of semi-quantitative interpretation that splits the LV into 20 segments [15], comparing the uptake in rest and in the peak of stress.

The amount of radiotracer present in each segment was expressed with a Score of 5 points [15]; 0 = normal uptake; 1 = mild uptake deficit; 2 = moderate deficit of uptake; 3 = severe uptake deficit; 4 = absence of uptake.

The result of comprehensive segmental uptake was reported preparing SSS (Summed Stress Score), SRS (Summed Rest Score), and SDS (Summed Difference Score) [15].

The evaluation of overall left ventricular function was made considering End Diastolic Volume (EDV), End Systolic Volume (ESV) and LVEF.

Evaluation by phase analysis
PA required only using the acquisition of GS images in rest, applying the “Phase” tool of the Cedar’s Sinai Quantitative Gated SPECT (QGS), The program establishes a mean LV surface, calculates the endocardial and epicardial surfaces by a profile of sums, a name used sometimes to express equivalents of energy emission of 99mTc, in systole and diastole, thus recording the time of parietal thickening, as a whole and with a segmental discrimination.

PA consists on relating the onset of QRS with the onset of overall mechanical contraction according to the segmental time discrimination.

The time dispersion of segmental contractility in regard to the whole expresses the degree of dyssynchrony.

Contractility is considered homogeneous if most of the segments contract at the same time, and therefore, the greater the time dispersion, the greater the dyssynchrony.

GS allows fractioning (sections) the LV in the captures at different heights on its short axis, recording the distribution of accounts in 3-D for each of this sections, and in turn discriminating them in segments.

A mathematical function applied to the variation of the sums during the phase of cardiac contraction, the derivative of the Fourier First Harmonic, is used as a representationof the time onset of parietal contraction.

With this methodology, a “phase” drive is constructed that represents the onset of regional mechanical contraction (MC) of the LV in 3-D.

Segmental time dispersions of contractility may be expressed in time units, milliseconds, but there are other options. The mean segmental time dispersion of the onset of mechanical contraction may be expressed in relation to the onset of the cardiac cycle, using a scale in degrees, where 0º corresponds to an R wave of ECG and the R-R interval of two continuing cycles define 360º.

The mean time dispersion of the onset of segmental contraction can also be expressed as percentage in regard to the duration of the cardiac cycle (0%-100% range) (Figure 1).

 

Figure 1. Representative outline about the way information from the Gated SPECT is acquired, analyzed and presented for Dny evaluation by PA.
A-Outline of distribution of phases in PM and BW within normal limits.
B- Outline of distribution of phases in PM and BW with Dny pattern.

Dny: Dyssynchrony; PA: Phase analysis; BW: Band width; PM: Polar map.

 

The different moments in which mechanical contraction starts in each segment of the short axis, the program is expressed by a histogram.

The evaluation of dyssynchrony through the phase analysis uses different variables to quantify the heterogeneity of the time of mechanical contraction. One of the variables is the Histogram Band Width (BW) that includes 95% of this distribution measured in degrees (º). Another way to measure contraction dispersion is estimating the Standard Deviation (SD) of the average and Entropy (Ep).

Ep is considered by some authors as a more appropriate dispersion measure than SD for this goals, and that is expressed from 0% to 100%.

In this modality of interpretation, the perfect synchrony would correspond to 0% of entropy, being significant from 60% and corresponding to 100%, the theoretical maximum possible of dyssynchrony. The degree of dyssynchrony will manifest then in increasing values [16].

Once segmental PA has been completed, the method allows analyzing global and regional synchrony.

The cutoff values to define dyssynchrony in this study were [13,16]:

  • BW ≥ 38.7º for males and ≥ 30.6º for females.
  • SD ≥ 14º for males and ≥ 11.8º for females.
  • Ep ≥ 60% for both genders.

Follow-up
It was made by phone contact scheduled every 6 months since performing the study, gathering information about medical management after the GS.

The presence of mixed cardiovascular events (CVD) (death, heart failure and need of revascularization) was also analyzed.

Statistical analysis
The statistical analysis was made with the SPSS 20 program, the qualitative variables were expressed in percentages and the quantitative variables as averages, standard deviation and ranges.

The chi square or Fisher methods were used for the qualitative variables and t Test for symmetrical quantitative variables. The asymmetrical distributions were processed with the U test of Mann-Whitney and Kruskal-Wallis.

The correlation of the quantitative variables were made by the Pearson’s test. A p<0.05 value was considered statistically significant.


RESULTS
The population of the study was of 160 patients (p) with a mean age of 65 years (±10.37), with 81 of them corresponding to the male gender (50.6%).

The prevalence of hypertension was 124 pts (77.5%), diabetes mellitus 32 pts (20%), dyslipidemia 102 pts (63.7%), and smoking 18 pts (11.1%).

As cardiovascular history, 13 pts (8.1%) presented prior infarction, 7 pts (4.4%) necrotic dilated ischemic cardiomyopathy, 7 pts (4.4%) idiopathic dilated cardiomyopathy, 9 pts (11.9%) surgery of myocardial revascularization, and 18 pts (11.3%) prior angioplasty.

Electrocardiograms
There were 51 pts (31.9%) presenting normal ECG, 157 pts (98.1%) in sinus rhythm, 10 pts (6.3%) CLBBB, 10 pts (6.3%) CRBBB, 13 pts (8.1%) right bundle branch conduction disorder, 3 pts (1.8%) anterior fibrosis, 9 pts (5.6%) lateral fibrosis (Table 1).

Table 1

 

The synchrony values for phase analysis in the sample were globally BW 33.47º±24.13º, SD 9.8º±8.25º, and Ep 33.4%±14.8%.

The dyssynchrony in regard to the width of QRS was analyzed by splitting the sample into three categories: (Figure 2)

  • Narrow QRS, BW 3º, SD: 9º, Ep 31%
  • CRBBB, BW: 37º, SD: 11º, Ep: 31%.
  • CLBBB, BW: 49%, SD: 13º, Ep: 47%.

Figure 2. Differences in synchronies according to QRS width

 

The following were obtained: Ep= 31%, 30.7% and 46.7% p=0.003; BW=31.1º, 36.6º, 49.2º p=0.008, SD=8.6º, 10.9º, 12.8º p=0.032 respectively.

In comparison to the rest of the patients, the presence of CLBBB presented a greater dyssynchrony, we applied the test of Kruskal-Wallis of choice for analysis of asymmetrical data, and were able to represent better the data through an analysis of averaged ranges, obtaining: Ep (57% vs. 31% p=0.004), BW (122.75º vs. 77.68º p=0.003), SD (117.65º vs. 78.02º p=0.009).

There were no significant differences found in the synchrony between the patients with CRBBB and narrow QRS.

Myocardial perfusion
The analysis of myocardial perfusion through the semi-quantification scores showed an average of SSS=4.95±6.4, SRS=3.3±5 and SDS=1.71±2.76.

There were 61 pts (38.1%) that presented normal myocardial perfusion, 49 pts (30.7%) ischemia, from whom 39 (24.4%) were categorized in mild SDS, 6 (3.8%) in mild SDS, and 4 (2.5%) in severe SDS; 54 pts (34%) perfusion with necrosis, with 34 (21%) being categorized in mild SRS, 9 (5.7%) in moderate SRS, and 11 (6.9%) in severe SRS. The combination of ischemia and necrosis was found in 24 pts (15%) (Figure 3).

Figure 3. Patients with abnormal myocardial perfusion

 

A positive correlation was obtained between perfusion defects in rest, defined as necrosis (SRS>5) and the parameters of dyssynchrony.

SRS correlation with Ep=r: 0.497; p≤0.0001. BW= r: 0.453; p≤0.0001. SD= r: 0.324; p≤0.0001, respectively. (Figure 4)

Figure 4. Dyssynchrony parameters and correlation to necrosis severity

 

The relation between dyssynchrony and the extension of necrosis was analyzed, and for this the sample was divided into 4 groups according to the SRS score; 1) perfusion without necrosis (SRS<4); 2) mild necrosis (SRS 5-7); 3) moderate necrosis (SRS 8-12), severe necrosis (SRS>13). The following were obtained: Ep= 26.2%, 36%, 41.8%, 46% p=0.0001; BW=24.2º, 34.5º, 36.8º, 63.4º p=0.0001; SD= 7.6º, 8.6º, 936º, 16.1º p=0.0001 respectively.

Myocardial function
The analysis of ventricular function of the global sample showed an LVEF of 60%±13%, EDV in rest of 94 ml±42 ml and ESV in rest of 41 ml±34 ml. There were 22 pts (13.8%) who presented deterioration of LVEF in rest. Patients with necrotic ischemic cardiomyopathy (NICM) and idiopathic cardiomyopathy (ICM) presented a greater dyssynchrony in relation to normal perfusions, (Ep= 47.5%, 47.1%, 26.9%, BW= 65.1º, 48.8º, 24.2º; SD= 16.6º, 12.4º, 7.6º p=0.0001 respectively) (Figure 5). We objectified an inverse correlation between the degree of LVEF deterioration and the indicators studied (Ep=r: -0.652, p≤0.0001, BW=r: -0.575, p≤0.0001. SD=r: -0.473; p≤0.0001 respectively) (Figure 6).

Figure 5. Dyssynchrony parameters according to pathology

 

Figure 6. Dyssynchrony parameters and their correlation with left ventricular function

 

Cardiovascular events
The follow-up was achieved for 12±4months of 137 pts (85.6%), of whom 2 pts (1.3%) were admitted by HF; 3 pts (1.9%) died by cardiovascular causes; 4 pts (2.5%) underwent myocardial revascularization surgery and 6 pts (3.8%) underwent PTCA.

We verified a non-significant tendency of patients with CVD in evolution presenting a greater dyssynchrony (BW 85.1º vs. 67.1º p=0.12; SD 85.6º vs. 67.2º p=0.11 and Ep=42% vs. 33% p=0.08).


DISCUSSION
The contraction at different times of the segments of the left ventricle, intraventricular dyssynchrony, mainly produced by the conduction disorder that causes CLBBB, has been of great interest in the last two decades, because of the optimization of mechanical ventricular synchrony by CRT.

Currently, there is a controversy on whether the analysis of mechanical dyssynchrony, prior to the implantation of a resynchronizer, may predict the response to it.

The line of investigation we developed was inspired in the first papers by Chen J, et al, from 2005, who by the evaluation of width (wall thickening) and phase of regional counts of the LV, made an analysis of synchrony by PA in Gated SPECT [13]. Our group of investigation could apply a similar tool of software for analysis obtaining measurements of regional and global counts to evaluate synchrony or dyssynchrony validated by Tissue Echo as established by Van Kriekinge et al [16,17].

Our study allows discriminating groups of patients that could benefit by CRT by the identification of dyssynchrony.

Our characterization of patients with CLBBB, QRS>120 ms and LVEF deterioration showed similar results to a work by Van Kriekinge et al, who applied a similar tool of analysis in 86 patients with low probability of intraventricular conduction disorder vs. 72 patients with CLBBB. By Gated SPECT they analyzed dyssynchrony parameters, verifying that Ep was the variable with greater sensibility and specificity to determine the presence of dyssynchrony in patients with CLBBB. In this paper, the most significant difference of dyssynchrony evaluated regionally (as the difference of the average between the septum with lateral side) than the global one of the left ventricle, achieving to establish what parameters of dyssynchrony, whether regional or global, analyzed by PA were useful when characterizing the different mechanical conduction disorders.

Another work by Van Kriekinge took a group of 40 patients who received CRT, including electrocardiographic criteria (CLBBB, QRS complex>120 ms) of impaired left ventricular function (LVEF<35%) and clinical criteria (NYHA FC III-IV). These patients had evaluation of dyssynchrony done by Tissue Doppler Echo (TDE) and PA by Gated SPECT with a follow-up at 6 months, evaluating the response to CRT by improvement in their Functional Class. Van Kriekinge objectified a significant correlation between the dyssynchrony measured by Tissue Doppler Echo and BW of Phase Analysis (PA) with Gated SPECT.

In regard to the prediction of CRT responders, these patients presented a greater BW (94º±23º vs. 68º±21º p<0.01) and SD (26º±6º vs. 18º±5º p<0.01) than those that did not respond. A relevant datum was the significant difference that responders presented with a low number of cardiac segments and defects in perfusion, in comparison to non-responders (5±2 vs. 8±2 p<0.001) [17,18]. Data from our study allow making theories and projecting similar groups of benefit to predict a response in patients candidates to CRT and its practical implementation.

Our work could differentiate between the different subgroups of normal conduction, CRBBB and CLBBB, obtaining clear patterns of dyssynchrony for CLBBB in relation to normalcy and CRBBB. Another significant element of analysis in our work was whether there was a difference or not between CRBBB and normal ECG carriers when analyzing the parameters of dyssynchrony. This line of investigation became quite relevant since it could provide more information on endemic pathologies, as chagasic cardiomyopathy in its prognostic risk stratification and its potential use in CRT.

We could not objectify differences in the parameters of dyssynchrony between CRBBB and normal ECG carriers. Thus, there are coincidences found with the last guidelines for CRT by the Committee of the Heart Failure Society of America, where it was mentioned that the benefit by CRT in patients with CRBBB would be from little to none [19].

The PA analyzed by Gated SPECT may evaluate these parameters of dyssynchrony with an excellent reproducibility and repeatability presenting according to preliminary studies, the ability to differentiate between patients with normal conduction and affected ventricular function, from those with left ventricular dysfunction, CLBBB, CRBBB or right ventricular pacemaking [20,21] (Figure 7, examples A, B and C).

Figure 7. Outline of three examples of cases
A. Patient with low probability of CAD, referred for evaluation by doubtful prior stress test and atypical symptoms.

 
 
B. Female patient, carrier of Chagas disease, severe involvement of ventricular function, carrier of pacemaker.
 
C. Patient carrier of ischemic heart disease, with myocardial infarction evolved over 3 years, referred for control.
 

BW: Band width; SD: Standard deviation; Ep: Entropy; SSS: Summed Stress Score; SRS: Summed Resting Score; SDS: Summed Difference Score; LVEF: Left ventricular ejection fraction; PPM: Permanent pacemaker.

 

As to the analysis of cardiomyopathies in our population, we highlight the group of patients with necrotic ischemic cardiomyopathy and idiopathic dilated cardiomyopathy, observing patterns of global dyssynchrony by BW, SD and Ep in both groups, which were clearly differentiated.

In ischemic heart disease, the natural history of the disease uses the nuclear diagnostic methodology by Gated SPECT for the diagnosis of the disease, its developmental follow-up and risk stratification. We can establish necrotic ischemic cardiomyopathy as the final developmental point of this entity. Data from epidemiological studies and clinical trials estimate that 60-70% of patients with HF have coronary disease, where Gated SPECT very likely has some participation in the follow-up of these patients.

In our registry, we used the interpretation of perfusion images with semi-quantification scores, Summed Stress Score (SSS), Summed Rest Score (SRS) and Summed Difference Score (SDS), a modality widely validated and well-known in many published papers [16,22,23,24,25] that allow establishing degrees of involvement in perfusion (ischemic, necrotic or mixed) and classify them considering different patterns; thus we could verify the correlation existing between the different degrees of dyssynchrony and the severity of necrosis, as also the clear involvement of myocardial function (idiopathic dilated cardiomyopathies) without a marked decrease of perfusion with significant associated dyssynchrony (Figure 8).

Figure 8. Dyssynchrony differences according to necrotic amount.

 

It is relevant to be able to differentiate, mainly in ischemic cardiomyopathy, whether the presence of dyssynchrony is considered just by finding extensive necrosis, where stimulation through the coronary sinus would lack a proper response and even not improving the synchrony in contraction at all; or considered by the presence of conduction disorder such as CLBBB (mechanical dyssynchrony by electric dyssynchrony) and the necrosis being mild, where resynchronization therapy could be more successful.

This evaluation modality could optimize CRT in HF from the conception and integration of a basal evaluation of the LV mechanical dyssynchrony involvement, the site of the last mechanical activation and myocardial scar by the study of conventional myocardial perfusion.

The incorporation in the evaluation of a perfusion test and in it, the different locations of the possible perfusion defects (namely necrosis) could be associated to the topographic region of dyssynchrony (by polar map of the LV) and if it is related or not, obtaining in a single study of comprehensive and conceptual interpretation, a possible response or failure for CRT.

In regard to our average follow-up of 12±4 months, the presence of greater dyssynchrony displayed a tendency to a worse evolution in patients analyzed in our registry.

Al Jaroudi et al, evaluated the impact of dyssynchrony in a population with advanced chronic renal insufficiency, that was considered for renal transplantation. Here it showed that dyssynchrony was associated to a greater mortality. The same author reported in another paper, 70 patients with ICD without revascularization procedure between Gated SPECT (within 6 months), with LVEF<40% and evaluated them along with a control group constituted by 157 patients with prior PA. Between both groups, he found that patients with a higher degree of dyssynchrony, evaluated by PA were in a greater risk of cardiovascular events (death or effective electric shock by ICD) and 1/3 of patients presented SD of up to 50º and were free from all events, while 2/3 with SD>50º, all suffered some event (0 vs. 18 p=0.02).

We emphasize the limitation of a work with a small number of patients, but it yields an interesting hypothesis for greater prospective population studies [26,27].

It has been proven that patients with HF who receive CRT with a matching positioning of the pacing catheter (catheter located at the site of the last mechanical activation evaluated by PA) have a better rate of response to CRT than those with a mismatching positioning [28].

Our work considers only the acquisition of images in rest with practical purposes; while there are lines of investigation that consider rest and stress, with interesting results. In another paper by Al Jaroubi et al, who studied 489 patients with protocols of rest and stress, carriers of HF, there was a worsening in dyssynchrony in the peak of strain in comparison to rest and was an independent predictor in all-cause death, just as the degree of ischemia [29].

Although there is currently an increasingly acceptance of 1 day protocols (just stress) with the aim of decreasing the dose of radiation [30]; in our area most acquisitions are in rest and stress.

Limitations
Besides what was already mentioned in regard to the size of the sample (n=160), the population studied presents the bias of belonging to a single non-hospital institution.

Clinical Usefulness
The addition of PA through Gated SPECT is a new modality of evaluation of cardiac dyssynchrony that supplements other imaging techniques. The application of this practical tool, widely available, which is used in a scenario of the usual protocols of acquisition of images of most of our nuclear medicine centers in Argentina, will not result in greater costs on conventional Gated SPECT.

The participation in an increasingly greater number of clinical investigations, will allow approaching strategies that will provide useful supplementary information in those patients candidates to CRT.


CONCLUSIONS
In our work we could verify that the population with a greater dyssynchrony, evaluated by phase analysis of Gated SPECT, was carrier of CLBBB, LVEF deterioration and greater extension of the objectified myocardial scar by myocardial perfusion.

A tendency to a worse clinical evolution could also be observed in the group of asynchronous patients.

 

 

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Publication: June 2013

 
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8vo. Congreso Virtual de Cardiología

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XXXI Congreso Nacional de Cardiología

30-31 Mayo,
1º Junio, 2013
Organiza: Región Patagónica
 

 
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Revista de FAC

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Contenidos Científicos
y Académicos

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