Cardiac Resynchronization Therapy for Congestive ...

Life Science Journal , 3( 1) , 2006 , W ang , Cardiac Resy nchronization T herapy

Cardiac Resynchronization Therapy for Congestive Heart Failure Lexin Wang School o f B iomedical Sciences , Charles S tu rt U niversity , New Sout h Wales, A ustralia Abstract: Congestive heart failure (CH F) is a leading cause of morbidit y and mor tality worldwide . Many CHF patien ts have in traventricular conduction delays such as right or left bundle branch block or non-specific QRS widening on the body surface ECG .In traven tricular conduction delays cause dyssynchrony of the ven tricles , leading to regional movement abnormalities and worsening of cardiac function .R ecent clinical t rials have indicated t hat cardiac resynchronization therapy improves cardiac function class, exercise tolerance , maximum oxygen consumption and qualit y of life in patien ts wit h moderate to severe heart failure .I t is also associated with a significant reduction in mortalit y and hospital admissions for hear t failure . [ Life Science Journal . 2006 ; 3(1 ) : 1 - 4] ( ISSN : 1097 - 8135 ) . Keywords: hear t failure; cardiac resynchronization therapy ; cardiac elect rophysiology

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Introduction

Congestive hear t failure ( CHF ) is a common cardiovascular disease and a leading cause of morbidity and mortality around t he world . Despite major advances in pharmacological t herapy in the past 2 decades , CHF is still associated with a high morbidity and mor tality rate ( The CONSENSUS Trial St udy Group , 1987 ; Bristow , 2000 ) . Recen tly, t he effects of cardiac resynchronization therapy , or biven tricular pacing , on hear t failure have been investigated in a number of clinical t rials ( Leclercq, 1998 ; Alonso , 1999 ; Auricchio, 1999 ; Gras, 1998 ; Leclercq, 2000 ; Etienne , 2001 ; Lau, 2000 ; Cazeau , 2001 ; Braunschweig , 2000 ; Abraha m, 2002 ; Higgins , 2003 ; Bristow, 2004 ; Cleland, 2005 ) . The rationale for t he resynchronization therapy is that many of t he hear t failure patients have in traventricular conduction delays , leading to poor coordination of ventricular con traction and relaxation ( dyssynchrony) and worsening cardiac function ( Farwell, 2000 ; Aaronson , 1997 ; Shenkman, 2002 ; Xiao , 1992 ; Littmann , 2000 ) . Results from major clinical st udies have demonstrated t hat cardiac resynchronization t herapy provides significant improve men t in cardiac function, exercise tolerance and quality of life ( Leclercq , 1998 ; Alonso , 1999 ; Auricchio, 1999 ; Gras , 1998 ; Leclercq , 2000 ; Etienne, 2001 ; Lau, 2000 ; Cazeau , 2001 ; Braunschweig , 2000 ) . M IRACLE trial, one of t he largest clinical trials on cardiac resynchronization therapy, presen ts some convincing evidence on t he efficacy of cardiac resynchronization t herapy in t reating moderate to

severe CHF ( Abraham , 2002 ) . However , no clear benefits on short-term mortality are observed in the st udy . T wo recent t rials, the COMPAN ION (Bristow , 2004) and CARE-H F (Cleland , 2005 ) , have demonstrated that cardiac resynchronization therapy, wit h or without implantable defibrillator , not only improves patient’s qualit y of life but also reduces t he mor tality in short- and medium-term . The primary aims of this paper are to review the most recen t landmark clinical trials and evaluate the therapeutic effects of cardiac resynchronization on CHF . 2

Rationale of Cardiac Resynchronization Therapy

In traven tricular conduction delays , such as right or left bundle branch block ( RBBB or LBBB) , or non-specific wide QRS complex , occurs in more than 20 % of patients with CHF ( Far well, 2000 ; Shenkman , 2002 ) . Such conduction delays are the prim ary causes of dyssynchrony of t he vent ricles . They have a negative impact on t he failing heart to eject blood and are major con tributors of worsening clinical symptoms . QRS duration is closely related to the level of ejection fraction , the wider t he QR S duration , the lower t he ejection fraction ( Shenkman , 2002 ) . LBBB alone is associated wit h a 13 % increase in t he left ventricular end-systolic diameter and 40 % reduction in left ven tricular ejection fraction . Left ventricular dyssynchrony also enhances the severity of the mit ral regurgitation in CHF patients ( Xiao , 1992 ; Litt mann , 2000 ; Saxon , 1998 ; Ker win , 2000 ) . Furthermore, intravent ricular conduction de-

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lays have been found to correlate with an increased risk of deat h in CH F patien ts ( Xiao , 1996 ; Shamim , 1999 ; Hesse , 2001 ) . The highest 5-year mortalit y has been found in t hose wit h QRS duration between 120 - 140 ms ( Shenkman , 2002 ) . Bot h LBBB and RBBB are associated wit h elevated and equal all-cause mortality rates in a general population ( Hesse, 2001 ) . The current indications for cardiac resynchronzation t herapy are that patients are in New York Hear t Association class Ⅲ or Ⅳ despite standard pharmacological therapy , with a left vent ricular ejection fraction of less than 35 per cent and left ventricular end-diastolic dimension of at least 30 mm ( Cleland, 2005 ) . The duration of QRS complex must be more than 120 ms . Additional criteria to be met are an aortic pre-ejection delay of more t han 140 ms , an intervent ricular mechanical delay of more t han 40 ms or delayed activation of t he posterolateral left vent ricular wall ( Higgins , 2003 ; Bristow , 2004 ; Cleland , 2005 ) . Currently , resynchronization is achieved by pacing or sensing t he righ t atrium , pacing the right and left ventricles . This involves t he positioning of pacing leads in to t he righ t atrium , righ t ven tricle and the left vent ricle , respectively ( Wang , 2003) . The positioning of left vent ricular pacing lead is t he key for a successful resynchronization therapy . This is achieved by inser ting a pacing lead into one of t he distal coronary venous branches where t he left vent ricle is paced from the epicardium . The pacing locations for the best hemodynamic out comes are t he lateral or posterolateral left vent ricular walls ( Wang , 2003 ) . There is a considerable variabilit y in the presence, diameter , angulation and tor tuosit y of coronary veins ( Meisel, 2001 ) . For this reason t he coronary veins must be st udied by injecting con trast media into the coronary sinus before t he positioning of left ventricular lead . Overall, t he success rate for implantation of left-sided leads ranges from 75 % to 93 % ( Leclercq, 1998 ; Alonso, 1999 ; Auricchio, 1999 ; G ras , 1998 ; Leclercq , 2000 ; Etienne, 2001 ; Lau , 2000 ; Cazeau , 2001 ; Braunschweig, 2000 ; Abraham, 2002 ; Higgins , 2003 ; Bristow , 2004 ; Cleland , 2005 ) . Color tissue Doppler imaging ( TDI ) has emerged as a noninvasive tool for selection of proper left vent ricular pacing sites and for evaluation of myocardial con traction synchrony . TDI has been proven useful in detecting quantitatively t he regional systolic and diastolic times and velocities within t he myocardium ( Hatle, 2000 ) .T DI is able to accurately identify the vent ricular site of most delayed activation ( Ansalone , 2002 ) . Pacing from t hese

most delayed sites results in the greatest improvement in ven tricular resynchronization and ventricular function ( Ansalone, 2002 ) . Cardiac resynchronization therapy is generally well tolerated by patients .However , implantation and maintenance of biventricular pacing devices are associated with greater risks t han a conventional pacing device . Apart from the common adverse effects seen in a pacemaker implantation , a very small proportion of patien ts ( < 0 .1 % ) undergoing cardiac resynchronization procedure develop complete heart block that requires permanent cardiac pacing , or progressive hypotension or asystole during t he procedures ( Abraham , 2002 ) . Ot her major adverse effects include coronary sinus dissection ( 4 % ) and cardiac vein or coronary sinus perforation ( 2 % ) ( Abraham , 2002 ) . After implan tation, approximately 6 % - 11 % of t he patients require repositioning or replacement of the left ven tricular lead due to lead dislodgement during long-term pacing ( Abraham , 2002 ; Alonso, 2001 ) . However, this complication does not result in the discontinuation of t reatment in any patien t . 3

Effects of Cardiac Resynchronization Therapy

The primary goals of any heart failure treatment are to improve t he lengt h or quality of the patien t’s life . Trials of cardiac resynchronization therapy have shown improvemen ts in functional status of t he hear t, t he distance patients can walk in 6 min , and hospital admission for heart failure (Braunschweig, 2000 ; Abraham , 2002 ; Higgins , 2003 ; Bristow , 2004 ; Cleland , 2005 ) . Cardiac resynchronization therapy also reduces left ventricular end-systolic diameter , and increases stroke volume and thus , cardiac ou tpu t and vent ricular systolic function ( Leclercq, 1998 ; Alonso , 1999 ; Auricchio, 1999 ; Gras , 1998 ) . T here is also an increase in t he systolic and pulse pressure , and a decrease in pulmonary wedge pressure ( Leclercq , 1998 ; Alonso, 1999 ; Auricchio, 1999 ; Gras , 1998 ) . The acute hemodynamic benefits of the cardiac resynchronization are largely due to improved septal con tribution to ven tricular ejection , increased diastolic filling times , and reduced mitral regurgitation . Another important and unique benefit of resynchronization therapy is that bivent ricular pacing acutely enhances systolic function but modestly lowering myocardial oxygen consumption ( Nelson , 2000 ) . Most other heart failure therapy, however , increase energy cost of t he myocardium w hile enhancing systolic function . M USTIC st udy ( Linde , 2002 ) was a randomised , crossover clinical trial w here patien ts un-

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derwent 3 mon ths’active pacing then switched to a non-pacing period of t hree mont hs . It was found t hat patien ts’exercise capacity improved only during active pacing period , wit h a more than 23 % increase in 6-min walking distance . The clinical symptoms were improved by 32 % during active t reat ment and the maximal oxygen consumption was up by 8 % . M USTIC study ( Linde, 2002 ) also investigated the long-term effects of cardiac resynchronization therapy in patien ts with sinus rhyt hm and t hose wit h atrial fibrillation .At the end of t he 12mont h active pacing period , there was a significant improvemen t in 6-min walk distance, peak oxygen consumption and t he quality of life . The NYHA class improved by 25 % - 27 % and the ejection fraction was up by 4 % - 5 % ( Linde , 2002) . Mitral regurgitation in t hese patients was almost halved at t he end of the t rial . These data indicate t he clinical benefits of cardiac resynchronization can be main tained for at least 12 mon ths . M IRACLE trial randomized 228 patients to biven tricular pacing t herapy and 225 to a placebo con trol arm for six mon ths ( Abraham , 2002) . All patients were in normal sinus rhyt hm and had an ejection fraction of less than 35 % .Compared wit h t he cont rol group , patients assigned to cardiac resynchronization experienced an improvement in t he distance walked in 6 min , NYHA functional class and quality of life ( Abraham , 2002 ) . The time on the t readmill exercise testing and t he ejection fraction were also improved during active pacing periods .F urt hermore, patients treated wit h cardiac resynchronization required less hospitalisation or int ravenous medication for heart failure ( Abraha m, 2002 ) . However , t he clinical benefits were observed on only about two thirds of the patien ts received t he resynchronization therapy . F ur thermore, alt hough the overall cardiac event rate was 40 % lower in t he cardiac resynchronization group, t he mortalit y rate was similar between t he pacing and con trol groups in the first 6 mont hs of t herapy ( Abraham , 2002 ) . The CARE-H F trial is the largest trial so far, to assess the effect of cardiac resynchronization t herapy on mortality rates in short- and mediumterm ( Cleland , 2005 ) . A total of 813 patien ts were enrolled and followed for more t han 29 mont hs . At t he end of the st udy, t he mor tality rate in the cardiac resynchronization t herapy and medication group was 20 % and 30 % , respectively, indicating t hat resynchronization reduces mortality more t han 2 years after the treat ment . As compared wit h medical therapy , cardiac resynchronization reduced t he in terven tricular mechanical delay , the end-sys-

tolic volume index and t he area of the mit ral regurgitant jet ( Cleland , 2005 ) . There was also a greater increase in ejection fraction , improvement in quality of life and symptoms in t he resynchronization group ( Cleland , 2005) . A nother major trial, COM PAN ION, compared the effect of drug therapy, cardiac resynchronization , and cardiac resynchronzation plus implantable defibrillator on mor tality and hospital admission in 1 , 250 patients ( Bristow , 2004 ) . Compared wit h the drug therapy group, the risk of the combined end point of death or hospitalization for heart failure was reduced by 34 percen t in t he resynchronization group and by 40 percen t in the resynchronization-defibrillator group (Bristow , 2004 ) .These results suggest t hat a combination of resynchronization therapy and implantable defibrillator offers furt her survival benefits for patients wit h severe CH F . 4

Conclusions

Cardiac resynchronization therapy offers a new approach for t reating patients wit h ventricular dyssynchrony and moderate to severe heart failure . Clinical t rials have demonstrated that t his new therapy improves patient’s symptoms , quality of life and short- to medium-term survival .H owever , up to 30 % of patients w ho receive resynchronization devices will not show clinically significan t responses to t his t herapy . Given t he significant costs associated with the therapy, it is important to have fur ther st udies to establish measures of iden tifying the non-responders before t he t herapy is implemented . Correspondence to: Lexin Wang , MD, PhD . School of Biomedical Sciences Charles Sturt U niversity Wagga Wagga, NSW Australia . T elephone: 612-6933-2909 Fax: 612-6933-2587 Email: lwang@ csu .edu .au References 1 .Aaronson KD, Schwar tz JS, Chen TM , et al . Developmen t and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation . Circulation 1997 ; 95 : 2660 - 7 . 2 .Abraham WT , Fisher WG, Smit h AL , et al . Cardiac resynchronization in chronic heart failure . N E ngl J Med 2002 ; 346 : 1845 - 53 . 3 .Alonso C , Leclercq C , Victor F , et al . Electrocardiographic predictive factors of long-term clinical improvemen t wit h multisite biven tricular pacing in advanced heart failure . Am J Cardiol 1999 ; 84 : 1417 - 21 . 4 .Alonso C , Leclercq C , d’Allonnes FR , et al . Six years

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Received Novem ber 1 , 2005