Intraventricular conduction delays are associated with dyssynchronous left ventricular (LV) contraction caused by regional delays in the electrical activation of the chamber. This phenomenon occurs in 15 to 30 percent of patients with heart failure due to dilated cardiomyopathy and reduced systolic function while increasing systolic volume [1].

In short-term studies, biventricular stimulation in the form of cardiac-resynchronisation therapy (CRT) has been shown to improve symptoms, enhance the quality of life, increase exercise tolerance, and partially reverse maladaptive remodeling [2].

When evaluating the responsiveness to CRT, it is preferable to consider decreased end-systolic volume to clinical parameters (such as New York Heart Association (NYHA) class, 6-minute walking test (6MWT), and quality of life score). Quality of life and reverse remodeling do not always align, as patients may experience improvement in one parameter without the other. Therefore, clinical parameters should not be disregarded, as an increase in quality of life or improvement in NYHA class can be just as significant as patient survival [3].

So, we aimed to study the short-term response to CRT regarding electrocardiography (ECG), cardiac remodeling and functional status to evaluate the overlap or the gap between these parameters which determine the response after device implantation.

A single center, prospective, observational study included 50 patients with non-ischaemic cardiomyopathy who were candidate for CRT implantation at National Heart Institute, Egypt in the period from October 2017 to June 2019. All patients had cardiac-resynchronisation therapy-pacemaker (CRT-P) devices (St. Jude) (the only available device at our institute). The study was approved by the local ethics committee and all patients signed informed consent.

Inclusion criteria:

Exclusion criteria:

ECG acquisition and analysis

All patients had standard 12-lead ECGs (paper speed =25 mm/s, voltage gain =10 mm/mV) once prior to CRT implantation to assess QRSd then 3 months after implantation for assessment electrical response.

Echocardiography

All patients were examined using GE Vivid 7 machine M4S matrix sector array probe with a frequency range of 1.5 to 3.6 MHz (GE Vingmed Ultrasound, Horten, Norway) with integrated ECG recording [4] mostly with the patients lying in the left lateral decubitus position for assessment of:

6 min walk test

This is a simple objective measurement to assess patient’s functional capacity.

6MWT was performed indoors in a long, flat, straight, enclosed corridor with a hard surface. The walking course was 30 m in length. The length of the corridor is marked every 3 m. The turnaround point is marked with a cone. A starting line, which marks the beginning and end, is marked on the floor using brightly colored tape.

Reasons for immediately stopping a 6MWT include the following: chest pain, intolerable dyspnea, leg cramps, staggering, diaphoresis, and pale or ashen appearance. If a test is stopped for any of these reasons, the patient sits or lie supine as appropriate depending on the severity or the event and the technician’s assessment of the severity of the event and the risk of syncope [5].

CRT implantation data

All patients had CRT-P devices (St. Jude medical, PM3140 DDDRV S/N 123456). Pacing leads were inserted through standard subclavian vein approach. Direct puncture of the subclavian vein was performed (Seldinger technique) with separate puncture for each lead (3 punctures in total). Dilators and peel-away sheaths were used to advance all pacing and defibrillation leads. Operators implanted right ventricle (RV) lead (pacing or implantable cardioverter-defibrillator) first, then the LV lead and finally the right atrium lead.

Device implantation

The generator was positioned over or under the pectoral muscle in CRT-P patients. The RA lead was placed in RA appendage, The RV lead tip was placed in the apex of the right ventricle. The LV lead tip was placed in the postero-lateral cardiac vein when possible or in an alternative posterior or lateral vein. The location chosen for LV lead was that giving the greatest spatial separation from the tip of the RV lead, with stable LV capture and without diaphragmatic capture at four times threshold voltage. Device programming using Merline St. Jude was done during follow up of the patients in the outpatient clinic to assess lead impedances, pacing, sensing thresholds, optimisation of AV and VV delays and detection of device malfunction [6].

We included only de novo implantation of devices and did not include generator changes, redo procedures, revisions.

Criteria of CRT response

All patients were evaluated after one month for device programming and after 3 months for evaluation of the response to CRT.

The response to CRT can be divided into 2 main categories:

The improvement in 6MWT and NYHA class were considered as improved functional status.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation. Paired and unpaired and Student’s t-test and nonparametric tests were used for comparisons between baseline and follow up. Categorical variable were expressed as numbers or percentages were analyzed with the chi-square test. D’Agostino-Pearson test for normal distribution was done and accordingly, non-parametric test was chosen when distribution was non-normal. Comparison between continuous data before and after CRT was done using paired t-test. Comparison between continuous data in responders and non-responders was done using unpaired t-test or Mann-Whitney test as appropriate. Correlations were made using Pearson correlation coefficient or Spearman r (S) as appropriate. P value was considered significant if <0.05.

All patients were evaluated before CRT implantation and 3 months after for assessment of electrical remodeling, cardiac remodeling and functional status. All patients were in sinus rhythm, mean age was 54.88±7.48 years, 35 males (70%) and 15 female (30%), 24 patients (48%) were hypertensive, 22 patients (44%) had diabetes mellitus, 30 patients (60%) had dyslipidemia and 10 patients (20%) were smokers, all patients had DCM of non-ischaemic etiology.

ECG response to CRT

There was statistically significant improvement in QRS duration 3 months after CRT implantation in 41 patients (82%); where duration improved from 145.33±16.29 ms to 133.33±17.15 ms, P<0.001.

NYHA class improvement

Before CRT implantation; 72% of the patients were NYHA class III and 28% were NYHA class IV. After 3 months of CRT; 78% showed increase in NYHA by at least one class (fig. 1).

Six minutes walk test

The mean 6MWT distance at baseline was 168.5 meters reaching 280.0 meters 3 months after CRT implantation (p-value <0.001) (fig. 2). The improvement in the distance was detected in 40 cases (80%) that was considered as clinical response.

Cardiac remodeling and transthoracic echocardiographic response to CRT

There was statistically significant improvement in LVEF in 37 patients (74%), where EF% increased from 28.6±2.7 to 34.5±3.1 (p value <0.001). There was statistically significant improvement in LVEDV (267.0±45.7 to 221.8±41.9 ml, p=0.002), and LVESV (137.4±47.2 to 105.0±42.7 ml, p=0.003). The improvement occurred in 39 patients representing 78% of study cases.

Mitral regurgitation severity as assessed by vena contracta improved by one class (from moderate to mild) in 29 patients which represents 58% of study cases.

The correlation analysis between all parameters (ECG, echocardiographic and functional status)

Correlations between ECG parameter (QRSd) and changes in NYHA class, 6MWT and echocardiographic parameters revealed that; There was statistically significant correlation between changes in QRSd with NYHA class, QRSd with 6MWT and QRSd with LVEF, but it was insignificant for LVEDV and LVESV (table 1). Only seven patients showed improvement in the 3 parameters: LVESV, QRS duration and 6MWT (fig. 3).

LV desynchrony was initially recognized as a phenomenon related to electrical conduction delay in patient with systolic heart failure with wide QRS complexes which is associated with worsening of symptoms and poor prognosis so; CRT is an important non-pharmacological therapy in end-stage heart failure if optimal heart failure therapy failed [7].

All patients in the present study had CRT-P according to the device availability and data available as it not clear whether adding implantable cardioverter-defibrillator as prophylactic therapy would be beneficial in patients who have advanced heart failure with severe left ventricular dysfunction or in those with non-ischaemic cardiomyopathies. Nor is it clear that in these settings, any benefit would be additive to those of CRT. According to COMPANION trial, the addition of a defibrillator to CRT did not appreciably affect the combined outcomes of death from or hospitalisation for any cause, which are heavily influenced by the hospitalisation components [8].

The researchers of COMPANION trial concluded that the decision of which of these two therapeutic options is appropriate for a particular setting is best determined on an individual basis by patients and their physicians [8].

Y. Liang et al., conducted a survey study where majority of CRT implantations were CRT-D, which occupied over 70-80% of all CRT devices in developed countries. However, this wide clinical application of CRT-D was not supported by solid evidence showing its superiority over CRT-P [9].

The present study included 50 patients referred for CRT implantation who were evaluated twice (before CRT and 3 months after) to evaluate cardiac remodeling, factional status and electrical remodeling after CRT implantation.

All CRT responders in this study had significant reduction in LVESV and LVEDV which is considered the hallmark of LV reverse remodeling, improved functional status (NYHA functional class, 6 min walk test) which was correlated with ECG changes (QRSd).

The results of our study are in agreement with C. Ypenburg et al. [10] who evaluated the clinical response to CRT where there was about 57% of the patients improved by one NYHA functional class and 12% showed an improvement of two NYHA functional classes while 31% remained unchanged for 6 months follow-up after CRT. The reason for unresponsiveness to CRT in this study was attributed to presence of a large percentage of ischaemic patients in the whole study which accounted for 68% compared to non-ischaemic patients.

C. Stellbrink et al. [11] studied 25 patients with advanced heart failure for 6 months follow up after CRT implantation with echocardiographic measurements of both dimensions and volumes, they found that the mean LVESV and LVEDV were significantly reduced after CRT. They concluded that spherical shape in dilated hearts was associated with increased wall stress, and that a change in LV sphericity have been correlated to an increase in exercise capacity and may involve a reduction in regional wall stress, myocardial oxygen demand and functional mitral regurgitation.

Mitral regurgitation is one of the echocardiographic changes that predict CRT reverses remodeling and clinical improvement. This improvement in mitral regurgitation could be explained by the effect of resynchronisation on the papillary muscles and the better coaptation of the leaflets. Also, the decrease in the contraction time possibly leads to a decrease in the degree of mitral regurgitation. The reverse remodeling and reduction of the LV dimensions can explain further improvement at follow-up [3].

In the present study clinical responders show corresponding increase in 6MWT coinciding with functional class improvement. The study of C. M. Yu [12] was in concordant to our study, where echocardiography show improvement in LVESV and LVEDV and improved 6MWT distance after pacing for 3 months that was associated with objective measurement of clinical improvement.

Our results agreed with the study of S. Cazeau et al. [13] who studied 100 patients with successful CRT implantation, they found that 63 patients had a decrease in QRS complex post CRT implantation and as the percentage of decrease in QRS width after implantation increased; there was an improvement in LVEF and clinical outcome post implantation.

Also, in a recent study by T. Nakai et al. [14] who studied 260 patients with a QRS duration >120 ms and a LVEF ≤35% with follow up for 6 months, they found that after CRT implantation, the functional response definition of CRT response is associated with a higher response rate and better clinical outcomes than that of the echocardiographic response definition, and therefore it is reasonable to use the functional definition to assess CRT response.

A recent study examined the degree of agreement between echocardiographic and patient-reported health status response to CRT 6 months after implantation in 109 patients, and evaluated the differences in pre-implantation characteristics of patients with concordant and discordant echocardiographic and health status responses. They found that 25 (22.9%) had an echocardiographic response but no health status response and 29 (26.6%) had a health status response but no echocardiographic response [15]. Results of the PSYHEART-CRT study found that there is large discrepancy between echocardiographic and patient-reported health status response to CRT. The most important predictor of health status response was the pre-implantation health status score. These results emphasize that disease-specific health status measures may have additional value over ‘objective’ measures of CRT response and should be incorporated in clinical practice [15].

Clinical implication

The nonresponse rate for CRT is a significant concern. However, depending on the definition of response, there might not be as many non-responders as expected. In addition, functional responders can correctly predict better prognoses. So, we should evaluate the response to CRT regarding functional class improvement in association with ECG and echocardiography parameters.

Study limitation

Single center study that was conducted on small number of patients and the study was also limited by short term follow up.

The implantation of CRT-P was associated with significant improvement in QRSd, NYHA class, 6MWT and LV volumes already in the short-term period. QRSd improvement was significantly correlated functional status and left ventricle ejection.

Отношения и Деятельность. Нет.

Relationships and Activities. None.

Финансирование: Исследование проведено при поддержке Университета Бенха и Национального кардиологического института (Арабская Республика Египет).

Funding: The study was performed with the support of Benha University and National Heart Institute (Egypt).