www.ipej.org 379 Editorial AV Interval Optimization - A Step Towards Physiological Pacing in Patients with Normal Left Ventricular Function Shomu Bohora, MD U.N. Mehta Institute for Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, India Address for Correspondence: Shomu Bohora, MD, Assistant Professor, U.N. Mehta Institute for Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, India. E-mail: shomubohora/at/yahoo.com Keywords: AV Interval Optimization, Physiological Pacing "In wilderness I sense the miracle of life, and behind it our scientific accomplishments fade to trivia." Charles A. Lindbergh. Pacemakers have evolved over a period of time trying to mimic the normal response rates, conduction and activation characteristics, though are still far from what nature has bestowed upon us. Better understanding of cardiac physiology and hemodynamics has led to current available pacing technology and we do recognize now that to achieve physiological pacing we should have an appropriate heart rate response, ventriculo-ventricular (VV) synchronization and atrio- ventricular (AV) synchronization. Patients receiving rate responsive pacemakers for sinus node dysfunction, in spite of using various sensors and rate response algorithms, [1-5] still do not truly have an appropriate heart rate response, especially in absence of physical stress. There is a need to develop sensors, based on which an algorithm can be developed to achieve a heart rate response, which truly mimics to what a normal sinus node would behave in response to both physical and mental stress. In patients with heart block who have atrial sensing based ventricular pacing, the heart rate response remains appropriate if the sinus node is normal. Right ventricular (RV) pacing represents a non-physiological activation of the heart causing wide QRS (left bundle branch block) with electrical and mechanical VV dyssynchrony.[5] Higher percentage of ventricular pacing in patients with intact AV node has been found to be associated with increased incidence of atrial fibrillation and heart failure on follow up. [6-10] Algorithms to prevent ventricular pacing are effective in reducing unnecessary ventricular pacing in patients with normal AV conduction and sick sinus syndrome. However these algorithms cannot be applied to patients with advanced heart block in which there is need for mandatory ventricular pacing. To avoid detrimental effects of VV synchrony alternate site RV pacing [11-15] and biventricular pacing have been described. [16,17] Alternate site pacing studies have shown mixed results. [11-15] Left sided lead placement, non-physiological epicardial pacing and procedure and pacing related complications with the higher overall cost involved in doing biventricular pacing procedure represents a significant limitation for advising it as a routine. VV dyssynchrony possibly would remain a limitation in achieving total physiological pacing till further conclusive evidence of newer pacing methods is demonstrated. Optimal AV interval at rest ranges from 100 to 150 milliseconds. In normal individuals the AV Indian Pacing and Electrophysiology Journal (ISSN 0972-6292), 10 (9): 379-382 (2010) Shomu Bohora, “AV Interval Optimization - A Step Towards Physiological Pacing 380 in Patients with Normal Left Ventricular Function” interval shortens with increased heart rate during exercise in a predictable and linear fashion. Most pacemakers have a programmable shortening of AV delay at higher rates, the hemodynamic benefits of which have not yet been shown. [1] The aim of optimizing AV delay in patients with heart failure is to increase diastolic filling and at the same time maintain biventricular pacing so as to maximize cardiac output. In patients with heart failure and LV dysfunction even a small improvement in cardiac output, as obtained by optimizing AV delay, may result in significant clinical improvement. AV optimization is routinely done using echocardiographic techniques of which Ritter's method is the most commonly used. [18] Device based algorithms like QuickOpt is also available and is currently being evaluated for its effectiveness in comparison to echocardiographic methods. [19] Optimizing AV synchrony and hence AV delay is routinely not advised in patients receiving pacemakers without heart failure. An electrocardiogram based method to determine optimal AV interval is described by Sorajja et al [20] in this issue of the journal, in which P wave duration correlates with a correction factor of 1.26 with an optimal AV interval, as determined by Ritter's method of AV optimization on echocardiography. Such simple technique can be used for effectively programming optimal AV delay routinely once validation by large trials occur, so as to achieve better hemodynamics without the need for time consuming echocardiographic techniques or till the time echocardiographic optimization is routinely planned. This study, though with its limitations of having a small cohort of elderly patients and optimization evaluated only at rest, presents an attractive alternative to echocardiography based techniques to calculate and program optimal AV delay. Based on echocardiographic parameters and natriuretic peptide levels, AV delay optimization is found to be beneficial in patients with normal LV function in short term small studies. [21-25] There exists hardly any long term study to demonstrate benefits of routine optimization of AV delay in patients having normal LV function and receiving pacemakers for heart block. Hence it would be difficult to justify echocardiography based AV optimization in all such patients. However it seems appropriate to aim to program an optimal AV delay in all patients receiving pacemakers, based on data from heart failure patients and short term studies. Can the findings of this study be extrapolated for use in AV optimization in patients treated with devices for heart failure? Larger studies in patients with and without LV dysfunction and heart failure would be required to validate the results of this pilot study for incorporating it in clinical practice to achieve better long term outcomes. We still have a long way to go before we can mimic with pacemakers the normal electrical activity of the heart. Adopt the pace of nature: her secret is patience - Ralph Waldo Emerson Look deep into nature, and then you will understand everything better - Albert Einstein References 1. Buckingham TA, Janosik DL, Pearson AC. Pacemaker hemodynamics: clinical implications. Prog Cardiovasc Dis. 1992 ;34:347-66. 2. Israel CW, Hohnloser SH. Current status of dual-sensor pacemaker systems for correction of chronotropic incompetence. Am J Cardiol. 2000;86(9A):86K-94K. 3. Dell'Orto S, Valli P, Greco EM. Sensors for rate responsive pacing. Indian Pacing Electrophysiol J. 2004;4:137-45. 4. Chandiramani S, Cohorn LC, Chandiramani S. Heart rate changes during acute mental stress with closed loop stimulation: report on two single-blinded, pacemaker studies. Pacing Clin Electrophysiol. 2007;30:976-84. Indian Pacing and Electrophysiology Journal (ISSN 0972-6292), 10 (9): 379-382 (2010) Shomu Bohora, “AV Interval Optimization - A Step Towards Physiological Pacing 381 in Patients with Normal Left Ventricular Function” 5. Lau CP, Tai YT, Leung WH, Wong CK, Lee P, Chung FL. Rate adaptive pacing in sick sinus syndrome: effects of pacing modes and intrinsic conduction on physiological responses, arrhythmias, symptomatology and quality of life. Eur Heart J. 1994 Nov;15(11):1445-55. 6. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol. 2009 Aug 25;54(9):764- 76. 7. Albertsen AE, Nielsen JC. Selecting the appropriate pacing mode for patients with sick sinus syndrome: evidence from randomized clinical trials. Card Electrophysiol Rev. 2003 Dec;7(4):406-10. 8. Hesselson AB, Parsonnet V, Bernstein AD, Bonavita GJ. Deleterious effects of long-term single-chamber ventricular pacing in patients with sick sinus syndrome: the hidden benefits of dual-chamber pacing. Am Coll Cardiol. 1992 Jun;19(7):1542-9. 9. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002 Dec 25;288(24):3115-23. 10. Wilkoff BL, Kudenchuk PJ, Buxton AE, Sharma A, Cook JR, Bhandari AK, Biehl M, Tomassoni G, Leonen A, Klevan LR, Hallstrom AP. The DAVID (Dual Chamber and VVI Implantable Defibrillator) II trial. J Am Coll Cardiol. 2009 Mar 10;53(10):872-80. 11. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol. 2006 Jan 17;47(2):282-8. 12. Siu CW, Wang M, Zhang XH, Lau CP, Tse HF. Analysis of ventricular performance as a function of pacing site and mode. Prog Cardiovasc Dis. 2008 Sep-Oct;51(2):171-82. 13. Ng AC, Allman C, Vidaic J, Tie H, Hopkins AP, Leung DY. Long-term impact of right ventricular septal versus apical pacing on left ventricular synchrony and function in patients with second- or third-degree heart block. Am J Cardiol. 2009 Apr 15;103(8):1096-101. 14. Kaye G, Stambler BS, Yee R. Search for the optimal right ventricular pacing site: design and implementation of three randomized multicenter clinical trials. Pacing Clin Electrophysiol. 2009 Apr;32(4):426-33. 15. Tse HF, Wong KK, Siu CW, Zhang XH, Ho WY, Lau CP. Upgrading pacemaker patients with right ventricular apical pacing to right ventricular septal pacing improves left ventricular performance and functional capacity. J Cardiovasc Electrophysiol. 2009 Aug;20(8):901-5. 16. van Geldorp IE, Vernooy K, Delhaas T, Prins MH, Crijns HJ, Prinzen FW, Dijkman B. Beneficial effects of biventricular pacing in chronically right ventricular paced patients with mild cardiomyopathy. Europace. 2010 Feb;12(2):223-9. 17. Delnoy PP, Ottervanger JP, Luttikhuis HO, Elvan A, Misier AR, Beukema WP, van Hemel NM. Long-term clinical response of cardiac resynchronization after chronic right ventricular pacing. Am J Cardiol. 2009 Jul 1;104(1):116-21. 18. Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace. 2008 Nov;10 Suppl 3:iii88- 95. Indian Pacing and Electrophysiology Journal (ISSN 0972-6292), 10 (9): 379-382 (2010) Shomu Bohora, “AV Interval Optimization - A Step Towards Physiological Pacing 382 in Patients with Normal Left Ventricular Function” 19. Abraham WT, Gras D, Yu CM, Guzzo L, Gupta MS. Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial. Am Heart J. 2010 Jun;159(6):944-948.e1. 20. Dan Sorajja, Mayurkumar D Bhakta, Luis RP Scott, Gregory T Altemose, Komandoor Srivathsan. Utilization of Electrocardiographic P-wave Duration for AV Interval Optimization in Dual-Chamber Pacemakers. Indian Pacing and Electrophysiology Journal; 2010; 10(9):383-392. 21. Leonelli FM, Wang K, Youssef M, Hall R, Brown D. Systolic and diastolic effects of variable atrioventricular delay in patients with complete heart block and normal ventricular function. Am J Cardiol. 1997 Aug 1;80(3):294-8. 22. Cristina Porciani M, Fantini F, Musilli N, Sabini A, Michelucci A, Colella A, Pieragnoli P, Demarchi G, Padeletti L. A perspective on atrioventricular delay optimization in patients with a dual chamber pacemaker. Pacing Clin Electrophysiol. 2004 Mar;27(3):333-8. 23. Styliadis IH, Gouzoumas NI, Karvounis HI, Papadopoulos CE, Efthimiadis GK, Karamouzis M, Parharidis GE, Louridas GE. Effects of variation of atrioventricular interval on left ventricular diastolic filling dynamics and atrial natriuretic peptide levels in patients with DDD pacing for complete heart block. Europace. 2005 Nov;7(6):576-83. 24. Panou FK, Kafkas NV, Michelakakis NA, Matsakas EP, Dounis GB, Kouvousis NM, Perpinia AS, Zacharoulis AA. Effect of different AV delays on left ventricular diastolic function and ANF levels in DDD paced hypertensive patients during daily activity and exercise. Pacing Clin Electrophysiol. 1999 Apr;22 (4 Pt 1):635-42. 25. Ritter P, Padeletti L, Gillio-Meina L, Gaggini G. Determination of the optimal atrioventricular delay in DDD pacing. Comparison between echo and peak endocardial acceleration measurements. Europace. 1999 Apr;1(2):126-30. Indian Pacing and Electrophysiology Journal (ISSN 0972-6292), 10 (9): 379-382 (2010) Shomu Bohora, MD U.N. Mehta Institute for Cardiology and Research Centre, Civil Hospital Campus,  Ahmedabad, India Address for Correspondence: Shomu Bohora, MD, Assistant Professor, U.N. Mehta Institute for Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, India. E-mail: shomubohora/at/yahoo.com Keywords: AV Interval Optimization, Physiological Pacing "In wilderness I sense the miracle of life, and behind it our scientific accomplishments fade to trivia."  Charles A. Lindbergh. Pacemakers have evolved over a period of time trying to mimic the normal response rates, conduction and activation characteristics, though are still far from what nature has bestowed upon us. Better understanding of cardiac physiology and hemodynamics has led to current available pacing technology and we do recognize now that to achieve physiological pacing we should have an appropriate heart rate response, ventriculo-ventricular (VV) synchronization and atrio-ventricular (AV) synchronization. Patients receiving rate responsive pacemakers for sinus node dysfunction, in spite of using various sensors and rate response algorithms, [1-5] still do not truly have an appropriate heart rate response, especially in absence of physical stress. There is a need to develop sensors, based on which an algorithm can be developed to achieve a heart rate response, which truly mimics to what a normal sinus node would behave in response to both physical and mental stress. In patients with heart block who have atrial sensing based ventricular pacing, the heart rate response remains appropriate if the sinus node is normal. Right ventricular (RV) pacing represents a non-physiological activation of the heart causing wide QRS (left bundle branch block) with electrical and mechanical VV dyssynchrony.[5] Higher percentage of ventricular pacing in patients with intact AV node has been found to be associated with increased incidence of atrial fibrillation and heart failure on follow up. [6-10] Algorithms to prevent ventricular pacing are effective in reducing unnecessary ventricular pacing in patients with normal AV conduction and sick sinus syndrome. However these algorithms cannot be applied to patients with advanced heart block in which there is need for mandatory ventricular pacing. To avoid detrimental effects of VV synchrony alternate site RV pacing [11-15] and biventricular pacing have been described. [16,17] Alternate site pacing studies have shown mixed results. [11-15] Left sided lead placement, non-physiological epicardial pacing and procedure and pacing related complications with the higher overall cost involved in doing biventricular pacing procedure represents a significant limitation for advising it as a routine. VV dyssynchrony possibly would remain a limitation in achieving total physiological pacing till further conclusive evidence of newer pacing methods is demonstrated. Optimal AV interval at rest ranges from 100 to 150 milliseconds. In normal individuals the AV Shomu Bohora, “AV Interval Optimization - A Step Towards Physiological Pacing 380 in Patients with Normal Left Ventricular Function” interval shortens with increased heart rate during exercise in a predictable and linear fashion. Most pacemakers have a programmable shortening of AV delay at higher rates, the hemodynamic benefits of which have not yet been shown. [1] The aim of optimizing AV delay in patients with heart failure is to increase diastolic filling and at the same time maintain biventricular pacing so as to maximize cardiac output. In patients with heart failure and LV dysfunction even a small improvement in cardiac output, as obtained by optimizing AV delay, may result in significant clinical improvement. AV optimization is routinely done using echocardiographic techniques of which Ritter's method is the most commonly used. [18] Device based algorithms like QuickOpt is also available and is currently being evaluated for its effectiveness in comparison to echocardiographic methods. [19] Optimizing AV synchrony and hence AV delay is routinely not advised in patients receiving pacemakers without heart failure. An electrocardiogram based method to determine optimal AV interval is described by Sorajja et al [20] in this issue of the journal, in which P wave duration correlates with a correction factor of 1.26 with an optimal AV interval, as determined by Ritter's method of AV optimization on echocardiography. Such simple technique can be used for effectively programming optimal AV delay routinely once validation by large trials occur, so as to achieve better hemodynamics without the need for time consuming echocardiographic techniques or till the time echocardiographic optimization is routinely planned. This study, though with its limitations of having a small cohort of elderly patients and optimization evaluated only at rest, presents an attractive alternative to echocardiography based techniques to calculate and program optimal AV delay. Based on echocardiographic parameters and natriuretic peptide levels, AV delay optimization is found to be beneficial in patients with normal LV function in short term small studies. [21-25] There exists hardly any long term study to demonstrate benefits of routine optimization of AV delay in patients having normal LV function and receiving pacemakers for heart block. Hence it would be difficult to justify echocardiography based AV optimization in all such patients. However it seems appropriate to aim to program an optimal AV delay in all patients receiving pacemakers, based on data from heart failure patients and short term studies. Can the findings of this study be extrapolated for use in AV optimization in patients treated with devices for heart failure? Larger studies in patients with and without LV dysfunction and heart failure would be required to validate the results of this pilot study for incorporating it in clinical practice to achieve better long term outcomes. We still have a long way to go before we can mimic with pacemakers the normal electrical activity of the heart. Adopt the pace of nature:  her secret is patience  - Ralph Waldo Emerson Look deep into nature, and then you will understand everything better  - Albert Einstein References 1. Buckingham TA, Janosik DL, Pearson AC. Pacemaker hemodynamics: clinical implications. Prog Cardiovasc Dis. 1992 ;34:347-66. 2. Israel CW, Hohnloser SH. Current status of dual-sensor pacemaker systems for correction of chronotropic incompetence. Am J Cardiol. 2000;86(9A):86K-94K. 3. Dell'Orto S, Valli P, Greco EM. Sensors for rate responsive pacing. Indian Pacing Electrophysiol J. 2004;4:137-45. 4. Chandiramani S, Cohorn LC, Chandiramani S. Heart rate changes during acute mental stress with closed loop stimulation: report on two single-blinded, pacemaker studies. Pacing Clin Electrophysiol. 2007;30:976-84. Shomu Bohora, “AV Interval Optimization - A Step Towards Physiological Pacing 381 in Patients with Normal Left Ventricular Function” 5. Lau CP, Tai YT, Leung WH, Wong CK, Lee P, Chung FL. Rate adaptive pacing in sick sinus syndrome: effects of pacing modes and intrinsic conduction on physiological responses, arrhythmias, symptomatology and quality of life. Eur Heart J. 1994 Nov;15(11):1445-55. 6. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol. 2009 Aug 25;54(9):764-76. 7. Albertsen AE, Nielsen JC. Selecting the appropriate pacing mode for patients with sick sinus syndrome: evidence from randomized clinical trials. Card Electrophysiol Rev. 2003 Dec;7(4):406-10. 8. Hesselson AB, Parsonnet V, Bernstein AD, Bonavita GJ. Deleterious effects of long-term single-chamber ventricular pacing in patients with sick sinus syndrome: the hidden benefits of dual-chamber pacing. Am Coll Cardiol. 1992 Jun;19(7):1542-9. 9. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002 Dec 25;288(24):3115-23. 10. Wilkoff BL, Kudenchuk PJ, Buxton AE, Sharma A, Cook JR, Bhandari AK, Biehl M, Tomassoni G, Leonen A, Klevan LR, Hallstrom AP. The DAVID (Dual Chamber and VVI Implantable Defibrillator) II trial. J Am Coll Cardiol. 2009 Mar 10;53(10):872-80. 11. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol. 2006 Jan 17;47(2):282-8. 12. Siu CW, Wang M, Zhang XH, Lau CP, Tse HF. Analysis of ventricular performance as a function of pacing site and mode. Prog Cardiovasc Dis. 2008 Sep-Oct;51(2):171-82. 13. Ng AC, Allman C, Vidaic J, Tie H, Hopkins AP, Leung DY. Long-term impact of right ventricular septal versus apical pacing on left ventricular synchrony and function in patients with second- or third-degree heart block. Am J Cardiol. 2009 Apr 15;103(8):1096-101. 14. Kaye G, Stambler BS, Yee R. Search for the optimal right ventricular pacing site: design and implementation of three randomized multicenter clinical trials. Pacing Clin Electrophysiol. 2009 Apr;32(4):426-33. 15. Tse HF, Wong KK, Siu CW, Zhang XH, Ho WY, Lau CP. Upgrading pacemaker patients with right ventricular apical pacing to right ventricular septal pacing improves left ventricular performance and functional capacity. J Cardiovasc Electrophysiol. 2009 Aug;20(8):901-5. 16. van Geldorp IE, Vernooy K, Delhaas T, Prins MH, Crijns HJ, Prinzen FW, Dijkman B. Beneficial effects of biventricular pacing in chronically right ventricular paced patients with mild cardiomyopathy. Europace. 2010 Feb;12(2):223-9. 17. Delnoy PP, Ottervanger JP, Luttikhuis HO, Elvan A, Misier AR, Beukema WP, van Hemel NM. Long-term clinical response of cardiac resynchronization after chronic right ventricular pacing. Am J Cardiol. 2009 Jul 1;104(1):116-21. 18. Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace. 2008 Nov;10 Suppl 3:iii88-95. Shomu Bohora, “AV Interval Optimization - A Step Towards Physiological Pacing 382 in Patients with Normal Left Ventricular Function” 19. Abraham WT, Gras D, Yu CM, Guzzo L, Gupta MS. Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial. Am Heart J. 2010 Jun;159(6):944-948.e1. 20. Dan Sorajja, Mayurkumar D Bhakta, Luis RP Scott, Gregory T Altemose, Komandoor Srivathsan. Utilization of Electrocardiographic P-wave Duration for AV Interval Optimization in Dual-Chamber Pacemakers. Indian Pacing and Electrophysiology Journal; 2010; 10(9):383-392. 21. Leonelli FM, Wang K, Youssef M, Hall R, Brown D. Systolic and diastolic effects of variable atrioventricular delay in patients with complete heart block and normal ventricular function. Am J Cardiol. 1997 Aug 1;80(3):294-8. 22. Cristina Porciani M, Fantini F, Musilli N, Sabini A, Michelucci A, Colella A, Pieragnoli P, Demarchi G, Padeletti L. A perspective on atrioventricular delay optimization in patients with a dual chamber pacemaker. Pacing Clin Electrophysiol. 2004 Mar;27(3):333-8. 23. Styliadis IH, Gouzoumas NI, Karvounis HI, Papadopoulos CE, Efthimiadis GK, Karamouzis M, Parharidis GE, Louridas GE. Effects of variation of atrioventricular interval on left ventricular diastolic filling dynamics and atrial natriuretic peptide levels in patients with DDD pacing for complete heart block. Europace. 2005 Nov;7(6):576-83. 24. Panou FK, Kafkas NV, Michelakakis NA, Matsakas EP, Dounis GB, Kouvousis NM, Perpinia AS, Zacharoulis AA. Effect of different AV delays on left ventricular diastolic function and ANF levels in DDD paced hypertensive patients during daily activity and exercise. Pacing Clin Electrophysiol. 1999 Apr;22 (4 Pt 1):635-42. 25. Ritter P, Padeletti L, Gillio-Meina L, Gaggini G. Determination of the optimal atrioventricular delay in DDD pacing. Comparison between echo and peak endocardial acceleration measurements. Europace. 1999 Apr;1(2):126-30.