Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue
Justus StenzigMarc D. LemoineAaltje Maria Stella StoterKinga M. WronaMarta LemmeWesam MullaYoram EtzionThomas EschenhagenMarc N. Hirt
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BackgroundOne third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT.MethodsCardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously.ResultsAsymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca2+-sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca2+-signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5–0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower.ConclusionsThis model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT.Keywords:
Afterload
Objective To investigate the correlation between the QRS duration and mechanical dyssynchrony in patients with congestive heart failure and complete left bundle branch block(CLBBB).Methods Fifty-one chronic heart failure patients with CLBBB were studied.The patients were divided into two groups,group Ⅰ with QRS duration ≤160 ms and group Ⅱ with QRS duration longer than 160 ms.All the patients underwent conventional echocardiography and tissue Doppler imaging.Results In patients with heart failure and CLBBB,the left ventricular pre-ejection time(LVPT)correlated significantly with QRS duration(r=0.56,P0.01).The LVPT was significantly longer in group Ⅱ than in group Ⅰ.However,the tissue Doppler-derived parameters Ts-SD,Ts-12 and Ts-sep-lat did not show significant difference between the two groups.Conclusions In patients with congestive heart failure and CLBBB,the QRS duration correlated significantly with left ventricular pre-ejection delay,but not intra-ventricular dyssynchrony.
Bundle branch block
Ventricular dyssynchrony
Doppler imaging
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Objective
To assess short-term and long-term effects of cardiac resynchronization therapy (CRT) in heart failure patients.
Methods
We continuously assessed forty-five end-stage heart failure patients. NYHA grade, left ventricular diastolic diameter (LVED), left ventricular ejection fraction (LVEF) and B-type natriuretic peptides (BNP) before cardiac resynchronization therapy and at six months, one year, two years after cardiac resynchronization therapy were evaluated.
Results
Compared to the results before cardiac resynchronization, six months, one year and two years after CRT, NYHA grade, LVEF, LVED, BNP improved significantly (all P 0.05).
Conclusions
CRT could improve the short-term and long-term myocardial function of hear failure patients.
Key words:
Cardiac resynchronization therapy; Myocardial function; B-type natriuretic peptides
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Doppler imaging
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【Objective】 To observe the short-term curative effects of biventricular cardiac resynchronization therapy in patients of chronic congestive heart failure.【Methods】 Biventricular cardiac resynchronization therapy(CRT) underwent in six cases of primary dilated cardiomyopathy with chronic congestive heart failure and prolonged QRS duration(QRS duration≥120 ms).During the 6 months of following-up period.The following parameters were recorded and analyzed: the pacing parameters of left ventricle electrode,the QRS wave width,left ventricular end-diastolic dimension(LVEDD),left ventricular end-systolic dimension(LVESD),left ventricular ejection fraction(LVEF),6-minutes walking test(6 MWT).【Results】 All of 6 cases were implanted CRT devices successfully.Except one case died from stroke three days after the operation,5 cases were completed the 6 months of follow-up.By the end of the 6th month after the operation,the pacing parameters of left ventricle electrode(the pacing voltage,the resistance and the sensitivity) are stable very much.Compared to before the operation,the width of QRS wave is obviously narrower,the LVEDD,LVESD and the LVEF were significantly improved,6 MWT was significantly increased.【Conclusion】 CRT is one of the effective therapies for the patients of chronic congestive heart failure accompanying electromechanical dissynchrony.
Dilated Cardiomyopathy
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The number of patients who suffer from heart failure is rapidly increasing. In about one‐third of heart failure patients, conduction delays cause dyssynchronous left ventricular contractions, which leads to reduction in left ventricular function, adverse cardiac remodelling and finally increased mortality. Cardiac resynchronization involves simultaneous pacing of both ventricles, and improves left ventricular contractile function. Although resynchronization does not restore myocardial function, multiple studies have shown that cardiac resynchronization therapy improves quality of life, exercise capacity, symptoms of heart failure, left ventricular ejection fraction, morbidity and mortality. The use of cardiac resynchronization therapy has increased significantly, since its initial approval in 2001, in patients with advanced heart failure.
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Objective To investigate the effect of cardiac resynchronization therapy on improving heart function and reversing left ventricular remodeling in chronic heart failure patients. Methods Eleven patients with NYHA class Ⅲ to Ⅳ heart failure, ejection fraction ≤35% and QRS duration ≥130 ms were implanted synchronous biventricular pacemaker. Serial assessment was performed before and up to 1-36 months after pacing. Results There were significant improvement of LVEF、 LVFS; and decrease in MR、 LVED and QRS duration. The NYHA class of heart function was improved from Ⅲ-Ⅳ to Ⅰ-Ⅱ. Six-minute hall walk distances were also improved. Conclusion For patients with NYHA class Ⅲ to Ⅳ heart failure and ventricular conduction delay, cardiac resynchronization therapy could reverse left ventricular remodeling and improve heart function.
Ventricular remodeling
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Objective to evaluate the short-term and long-term effects of cardiac resynchronization therapy in heart failure patients. Methods We continuous assessed forty-eight heart failure patients who underwent CRT implantation in our hospital from January 2008 to December 2012, evaluate/measure NYHA grade, left ventricular diastolic diameter (LVEDd), left ventricular ejection fraction (LVEF) and B-type natriuretic peptides (BNP) before cardiac resynchronization therapy and half year, one year, two years after cardiac resynchronization therapy. Results Compared to the results before cardiac resynchronization, half year, one year and two years later, NYHA grade, LVEF, LVEDd, BNP improved significantly (P <0.05); Compared to the results of half year after cardiac resynchronization therapy, one year and two years later, NYHA grade, LVEF, LVEDd, BNP also improved significantly (P<0.05); However, compared the results between one year and two years later after cardiac resynchronization therapy, there were no difference as to NYHA grade, LVEF, LVEDd and BNP (P>0.05). Conclusions CRT could improve cardiac function in patients with congestive heart failure, however, when we followed up the patients for two years, cardiac function did not improve further.
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Doppler imaging
Ventricular dyssynchrony
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The aim of the study: to evaluate the clinical and hemodynamic effects of resynchronization therapy in patients with congestive heart failure. Materials and Methods: seventy-six consecutive patients underwent echocardiography, NYHA classification, 6-minute walk test before and after cardiac resynchronization therapy. All had complete left bundle branch block, with a QRS complex duration greater than 130 ms. and left ventricular ejection fraction less than 35%. Also, all patients had received optimal medical therapy for at least 3 months before inclusion to the study. Results: we observed significant increase in left ventricular ejection fraction (on 35.4 ± 3.7%, p < 0.001, compared with baseline) and decrease in end-systolic volume of the left ventricle (on 20.2 ± 3.0%, p < 0.001 compared with baseline). Improvement in functional class of congestive heart failure by NYHA classification by more than 1 was observed in 68.4% of individuals, in 26.3% of participants demonstrated no change and 5.3% of patients had worsening of CHF symptoms. Conclusions: the response of patients with congestive heart failure to cardiac resynchronization therapy is heterogeneous. The relationship between left ventricular reverse remodeling and the functional class of the congestive heart failure was not significant.
Bundle branch block
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