Accelerated physiologic pacing in patients with heart failure with preserved ejection fraction: An argument in support of therapeutic heart rate modulation

Key Findings▪The longstanding belief that slow heart rates benefit patients with heart failure with preserved ejection fraction (HFpEF) must be reconsidered.▪An important mechanism by which continuous, moderately accelerated physiologic pacing alleviates symptoms in patients with HFpEF at rest is by reducing cardiac filling pressures.▪With fully physiologic pacing (combining Bachmann bundle area atrial pacing with His-bundle or left bundle branch ventricular pacing), moderately accelerated pacing could be tailored to the individual patient without the offsetting effects of pacemaker-mediated dyssynchrony.▪Just as HFpEF and atrial fibrillation increase sharply with age, the prevalence of bradyarrhythmias due to cardiac conduction disease are projected to increase as the global population ages. Pacing is the only way to selectively increase the heart rate in patients with bradyarrhythmias at that occur at baseline or result from use of atrioventricular nodal blocking agents needed for another indication.▪Continuous accelerated physiologic pacing is a promising potential therapy for patients with HFpEF based on physiologic principles and hemodynamic pacing studies. Further multicenter, randomized studies are needed to prove and validate these hypotheses and findings. ▪The longstanding belief that slow heart rates benefit patients with heart failure with preserved ejection fraction (HFpEF) must be reconsidered.▪An important mechanism by which continuous, moderately accelerated physiologic pacing alleviates symptoms in patients with HFpEF at rest is by reducing cardiac filling pressures.▪With fully physiologic pacing (combining Bachmann bundle area atrial pacing with His-bundle or left bundle branch ventricular pacing), moderately accelerated pacing could be tailored to the individual patient without the offsetting effects of pacemaker-mediated dyssynchrony.▪Just as HFpEF and atrial fibrillation increase sharply with age, the prevalence of bradyarrhythmias due to cardiac conduction disease are projected to increase as the global population ages. Pacing is the only way to selectively increase the heart rate in patients with bradyarrhythmias at that occur at baseline or result from use of atrioventricular nodal blocking agents needed for another indication.▪Continuous accelerated physiologic pacing is a promising potential therapy for patients with HFpEF based on physiologic principles and hemodynamic pacing studies. Further multicenter, randomized studies are needed to prove and validate these hypotheses and findings. In the earliest heart failure guidelines, the primary therapeutic goal for patients with diastolic heart failure was "to reduce symptoms by lowering the elevated filling pressures without significantly reducing cardiac output."1Guidelines for the evaluation and management of heart failureReport of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure).J Am Coll Cardiol. 1995; 26: 1376-1398Crossref PubMed Scopus (0) Google Scholar Ten years earlier, a case series described a new clinical syndrome in elderly hypertensive patients with concentric hypertrophy, a small left ventricular (LV) cavity, and a supranormal left ventricular ejection fraction (LVEF) ≥65% who presented with dyspnea or chest discomfort.2Topol E.J. Traill T.A. Fortuin N.J. Hypertensive hypertrophic cardiomyopathy of the elderly.N Engl J Med. 1985; 312: 277-283Crossref PubMed Google Scholar Nine of the 21 patients received a beta-blocker or a calcium channel blocker and experienced symptomatic improvement. The authors likened this to the favorable response patients with hypertrophic cardiomyopathy experienced with these medications, thought to be due to "improvements in relaxation time and filling rate, a decrease in heart rate and thus prolongation of diastole, and an increase in end-systolic volume because of negative inotropic action."2Topol E.J. Traill T.A. Fortuin N.J. Hypertensive hypertrophic cardiomyopathy of the elderly.N Engl J Med. 1985; 312: 277-283Crossref PubMed Google Scholar The initial heart failure guidelines recommended beta-blockers and non–dihydropyridine calcium channel blockers to improve LV diastolic filling, relaxation, and compliance in patients with heart failure with preserved ejection fraction (HFpEF) while acknowledging that limited data supported this therapeutic strategy.1Guidelines for the evaluation and management of heart failureReport of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure).J Am Coll Cardiol. 1995; 26: 1376-1398Crossref PubMed Scopus (0) Google Scholar,3Hunt S.A. Baker D.W. Chin M.H. et al.ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.Circulation. 2001; 104: 2996-3007Crossref PubMed Google Scholar,4Remme W.J. Swedberg K. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of CardiologyGuidelines for the diagnosis and treatment of chronic heart failure.Eur Heart J. 2001; 22: 1527-1560Crossref PubMed Scopus (1548) Google Scholar Over the past 2 decades, clinical trials evaluating pharmacologic heart rate suppression in patients with HFpEF (now defined as LVEF ≥50%) have been neutral.5Cleland J.G.F. Bunting K.V. 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Bourge R.C. et al.Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 935-944Crossref PubMed Scopus (339) Google Scholar This trial demonstrated that small but chronic filling pressure reduction significantly benefited these patients. A common thread among the handful of HFpEF clinical trials meeting their primary efficacy endpoint—pulmonary artery pressure–guided medical management,15Adamson P.B. Abraham W.T. Bourge R.C. et al.Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 935-944Crossref PubMed Scopus (339) Google Scholar therapeutic weight loss,16Kitzman D.W. Brubaker P. 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Claggett B. et al.Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.Eur Heart J. 2023; 44: 2930-2943Crossref Scopus (14) Google Scholar Obesity is a risk factor for HFpEF through various mechanisms, one of which involves hemodynamic derangements related to an increase in total blood volume and abnormal blood volume distribution.13Borlaug B.A. Sharma K. Shah S.J. Ho J.E. Heart failure with preserved ejection fraction: JACC scientific statement.J Am Coll Cardiol. 2023; 81: 1810-1834Crossref PubMed Scopus (68) Google Scholar,21Sorimachi H. Burkhoff D. Verbrugge F.H. et al.Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction.Eur J Heart Fail. 2021; 23: 1648-1658Crossref PubMed Scopus (68) Google Scholar,22Reddy Y.N.V. Anantha-Narayanan M. Obokata M. et al.Hemodynamic effects of weight loss in obesity: a systematic review and meta-analysis.JACC Heart Fail. 2019; 7: 678-687Crossref PubMed Scopus (74) Google Scholar Among the pleiotropic effects of weight loss in obese patients with HFpEF are the significant improvements in biventricular and atrial filling pressures.17Borlaug B.A. Kitzman D.W. Davies M.J. et al.Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial.Nat Med. 2023; 29: 2358-2365Crossref PubMed Scopus (8) Google Scholar,22Reddy Y.N.V. Anantha-Narayanan M. Obokata M. et al.Hemodynamic effects of weight loss in obesity: a systematic review and meta-analysis.JACC Heart Fail. 2019; 7: 678-687Crossref PubMed Scopus (74) Google Scholar A hallmark of diastolic dysfunction in HFpEF is an exponential rise in the end-diastolic pressure–volume relationship (Figure 1).25Aurigemma G.P. Zile M.R. Gaasch W.H. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function.Circulation. 2006; 113: 296-304Crossref PubMed Scopus (223) Google Scholar With the prolongation of diastole that occurs with low heart rates, slight increases in left ventricular end-diastolic volume (LVEDV) and stroke volume come at the expense of exponential increases in left ventricular end-diastolic pressure (LVEDP) (Figure 1).19Silverman D.N. Rambod M. Lustgarten D.L. Lobel R. LeWinter M.M. Meyer M. Heart rate-induced myocardial Ca(2+) retention and left ventricular volume loss in patients with heart failure with preserved ejection fraction.J Am Heart Assoc. 2020; 9e017215Crossref Scopus (20) Google Scholar,26Liu C.P. Ting C.T. Lawrence W. Maughan W.L. Chang M.S. Kass D.A. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. 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Westermann D. et al.Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure.Eur Heart J. 2009; 30: 3027-3036Crossref PubMed Scopus (96) Google Scholar This translates to elevation in left atrial and upstream pressures with resultant atrial remodeling and secondary pulmonary hypertension, predisposing patients to atrial fibrillation (AF) and right ventricular dysfunction in the long term as well as pulmonary congestion in the near term.19Silverman D.N. Rambod M. Lustgarten D.L. Lobel R. LeWinter M.M. Meyer M. Heart rate-induced myocardial Ca(2+) retention and left ventricular volume loss in patients with heart failure with preserved ejection fraction.J Am Heart Assoc. 2020; 9e017215Crossref Scopus (20) Google Scholar,31Edelmann F. Gelbrich G. Duvinage A. et al.Differential interaction of clinical characteristics with key functional parameters in heart failure with preserved ejection fraction—results of the Aldo-DHF trial.Int J Cardiol. 2013; 169: 408-417Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 32Guazzi M. Borlaug B.A. Pulmonary hypertension due to left heart disease.Circulation. 2012; 126: 975-990Crossref PubMed Scopus (350) Google Scholar, 33Habel N. du Fay de Lavallaz J. et al.Lower heart rates and beta-blockers are associated with new-onset atrial fibrillation.Int J Cardiol Cardiovasc Risk Prev. 2023; 17200182Crossref PubMed Scopus (6) Google Scholar An important mechanism by which physiologic accelerated pacing alleviates symptoms in patients with HFpEF at rest is by reducing cardiac filling pressures through heart rate modulation. Studies over the past 3 decades (Tables 1 and 2) consistently demonstrate that pacing at moderately higher heart rates moves the end-diastolic pressure–volume relationship curve down and to the left (Figure 1), reducing left-sided cardiac pressures.19Silverman D.N. Rambod M. Lustgarten D.L. Lobel R. LeWinter M.M. Meyer M. Heart rate-induced myocardial Ca(2+) retention and left ventricular volume loss in patients with heart failure with preserved ejection fraction.J Am Heart Assoc. 2020; 9e017215Crossref Scopus (20) Google Scholar,26Liu C.P. Ting C.T. Lawrence W. Maughan W.L. Chang M.S. Kass D.A. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants.Circulation. 1993 Oct; 88: 1893-1906Crossref Scopus (130) Google Scholar, 27Yamanaka T. Onishi K. Tanabe M. et al.Force- and relaxation-frequency relations in patients with diastolic heart failure.Am Heart J. 2006; 152: 966 e961-e967Crossref Scopus (27) Google Scholar, 28Sohn D.W. Kim H.K. Park J.S. et al.Hemodynamic effects of tachycardia in patients with relaxation abnormality: abnormal stroke volume response as an overlooked mechanism of dyspnea associated with tachycardia in diastolic heart failure.J Am Soc Echocardiogr. 2007; 20: 171-176Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 29Westermann D. Kasner M. Steendijk P. et al.Role of left ventricular stiffness in heart failure with normal ejection fraction.Circulation. 2008; 117: 2051-2060Crossref PubMed Scopus (376) Google Scholar, 30Wachter R. Schmidt-Schweda S. Westermann D. et al.Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure.Eur Heart J. 2009; 30: 3027-3036Crossref PubMed Scopus (96) Google ScholarTable 1Summary of atrial pacing hemodynamic studies in patients with HFpEF at restStudyStudy populationBaseline heart rate in sinus rhythm∗Values are given as mean ± SD or median [interquartile range] (bpm)Atrial pacing rates (BPM)Findings in HFpEF patients at faster heart rates compared with baselineLiu et al26Liu C.P. Ting C.T. Lawrence W. Maughan W.L. Chang M.S. Kass D.A. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants.Circulation. 1993 Oct; 88: 1893-1906Crossref Scopus (130) Google Scholar 1993Adults with HFpEF (n = 10) and controls without heart failure (n = 8)HFpEF: 80 ± 14Control: 71 ± 9100, 120, and 150•↓ in left ventricular end-diastolic pressure at faster rates•Stroke volumes ↓ to a similar extent between HFpEF patients and controls; cardiac output did not decrease•Improvement in parameters of active relaxation at faster ratesYamanaka et al27Yamanaka T. Onishi K. Tanabe M. et al.Force- and relaxation-frequency relations in patients with diastolic heart failure.Am Heart J. 2006; 152: 966 e961-e967Crossref Scopus (27) Google Scholar 2006Adults with HFpEF (n = 18) and HFrEF (n = 11)HFpEF: 80 ± 11HFrEF: 77 ±18+20 and +40 above baseline•↓ in left ventricular end-diastolic pressure at faster ratesSohn et al28Sohn D.W. Kim H.K. Park J.S. et al.Hemodynamic effects of tachycardia in patients with relaxation abnormality: abnormal stroke volume response as an overlooked mechanism of dyspnea associated with tachycardia in diastolic heart failure.J Am Soc Echocardiogr. 2007; 20: 171-176Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 2007Adults with diastolic dysfunction (n = 11) and controls (n = 8)Not reported80 and 120•↓ in left ventricular end-diastolic and left ventricular mean pressure at faster ratesWestermann et al29Westermann D. Kasner M. Steendijk P. et al.Role of left ventricular stiffness in heart failure with normal ejection fraction.Circulation. 2008; 117: 2051-2060Crossref PubMed Scopus (376) Google Scholar 2008Adults with HFpEF (n = 70) and controls (n = 20)HFpEF: 71 [65–82]Control: 76 [65–85]120•↓ in left ventricular end-diastolic pressure (from median 16 mm Hg to 8 mm Hg)•Improvement in parameters of active relaxation•Stroke volumes ↓ but cardiac output ↑ compared with baseline (from median 6.8 to 8.2 L/min)Wachter et al30Wachter R. Schmidt-Schweda S. Westermann D. et al.Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure.Eur Heart J. 2009; 30: 3027-3036Crossref PubMed Scopus (96) Google Scholar 2009Adults with HFpEF (n = 17) and controls (n = 7)HFpEF: 66 [60–68]Control: 72 [67–90]100 and 120•↓ in left ventricular end-diastolic pressure (from median 17 mm Hg to 8 mm Hg)•Improvement in parameters of active relaxation at faster rates•Cardiac index ↑ compared with baseline (but not statistically significant)Silverman et al19Silverman D.N. Rambod M. Lustgarten D.L. Lobel R. LeWinter M.M. Meyer M. Heart rate-induced myocardial Ca(2+) retention and left ventricular volume loss in patients with heart failure with preserved ejection fraction.J Am Heart Assoc. 2020; 9e017215Crossref Scopus (20) Google Scholar 2020Adults with HFpEF (n = 10) and controls presenting for AF ablation (n = 12)HFpEF: 70 ± 9Control: 65 ± 795 and 125•↓ in left ventricular end-diastolic pressure (from mean 17 mm Hg to 9 mm Hg)•↓ in mean left atrial pressure (from mean 17 mm Hg to 12 mm Hg)•Systemic blood pressure did not change at faster ratesAF = atrial fibrillation; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction.∗ Values are given as mean ± SD or median [interquartile range] Open table in a new tab Table 2Cardiac hemodynamics during atrial pacing in patients with heart failure with preserved ejection fraction at restHemodynamic measures assessedHemodynamic values by paced heart ratesSohn et al36Rimoldi S.F. Messerli F.H. Cerny D. et al.Selective heart rate reduction with ivabradine increases central blood pressure in stable coronary artery disease.Hypertension. 2016; 67: 1205-1210Crossref PubMed Scopus (32) Google Scholar 2007Paced at 80 bpmPaced at 120 bpm Stroke volume (mL)51 ± 1330 ± 7∗Significantly different compared with baseline. LV end-diastolic dimension (mm)44 ± 339 ± 3 LV mean diastolic pressure (mm Hg)∼8 ± 3∼5 ± 3.5∗Significantly different compared with baseline.Westermann et al37Williams B. Lacy P.S. Thom S.M. et al.Differential impact of blood on central pressure and clinical results of the Evaluation 2006; 113: PubMed Scopus Google Scholar 71 bpmPaced at 120 bpm (mm different compared with baseline. Stroke volume different compared with baseline. output different compared with baseline. different compared with baseline. different compared with et G. P. D. et and of and receptor in the PubMed Scopus (0) Google Scholar 66 bpmPaced at 120 bpm (mm different compared with et Y.N.V. Anantha-Narayanan M. Obokata M. et al.Hemodynamic effects of weight loss in obesity: a systematic review and meta-analysis.JACC Heart Fail. 2019; 7: 678-687Crossref PubMed Scopus (74) Google Scholar 70 ± 9 bpmPaced at bpm left atrial pressure (mm ± ± different compared with baseline. (mm ± ± different compared with baseline. area ± ± different compared with baseline. area ± ± different compared with are given as mean ± SD or median [interquartile = left = left ventricular end-diastolic = left ventricular end-diastolic = left ventricular end-systolic different compared with baseline. Open table in a new tab AF = atrial fibrillation; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection Values are given as mean ± SD or median [interquartile LV = left = left ventricular end-diastolic = left ventricular end-diastolic = left ventricular end-systolic Heart rate been a of myocardial the that cardiac increases with faster heart rates A occurs with faster heart rates