The evolving state of cardiac resynchronization therapy and conduction system pacing: 25 years of research at EP Europace journal

Abstract

Cardiac resynchronization therapy (CRT) was proposed in the 1990s as a new therapy for patients with heart failure and wide QRS with depressed left ventricular ejection fraction despite optimal medical treatment. This review is aimed first to describe the rationale and the physiologic effects of CRT. The journey of the landmark randomized trials leading to the adoption of CRT in the guidelines since 2005 is also reported showing the high level of evidence for CRT. Different alternative pacing modalities of CRT to conventional left ventricular pacing through the coronary sinus have been proposed to increase the response rate to CRT such as multisite pacing and endocardial pacing. A new emerging alternative technique to conventional biventricular pacing, conduction system pacing (CSP), is a promising therapy. The different modalities of CSP are described (Hirs pacing and left bundle branch area pacing). This new technique has to be evaluated in clinical randomized trials before implementation in the guidelines with a high level of evidence.

Keywords: Cardiac conduction system pacing; Cardiac resynchronization therapy; Clinical trials.

Figure 1

Processes contributing to the structural, electrical, and contractile remodelling in the dyssynchronous heart as seen on functional measurements (left) and on a cellular and molecular level (right). Red colour indicates the situation during dyssynchrony. Dyssynchrony causes asymmetric and eccentric hypertrophy, and (in the failing heart) fibrosis as well as apoptosis. Some of the molecular factors are mentioned. Similarly, some of the processes involved in altered excitation–contraction coupling are displayed in the inset, illustrating a part of the plasmalemma, T-tubule, and sarcoplasmatic reticulum (SR). BNP, B-type natriuretic peptide; CRT, cardiac resynchronization therapy; CTGF, connective tissue growth factor; Cx43, connexin43; LBBB, left bundle branch block; LVfw, LV free wall; MHCa, myosin heavy chain a; MMP, matrix metalloproteases; OPN, osteopontin; PLN, phospholamban; SR, sarcoplasmic reticulum; SERCA, SR Ca2fl ATP-ase; TGFβ, transforming growth factor beta; TNFα, tumour necrosis factor alpha. From Nguyen et al. [5].

Figure 2

Expected survival (in years) after CRT-P or CRT-D undertaken in the period 2015–2017 according to sex. Expected survival in the general population is shown in blue. Adapted from Leyva et al.

Figure 3

Sudden cardiac death (SCD) in heart failure (HF) trials. The left-sided graph shows the residual risk of SCD in the intervention arm of HF trials, expressed as annualized risk (%). The most recent trials, namely PARADIGM-HF and DAPA-HF, are shown in red. Patients with an ICD have not been excluded. The right-sided graph shows the proportion of SCDs as a proportion of total mortality in HF trial, excluding patients receiving an ICD. Reproduced with permission from Leyva F, Israel CW, Singh J. Declining Risk of Sudden Cardiac Death in Heart Failure: Fact or Myth? Circulation 2023; 147: 759–767. Left-sided graph: CIBIS-II, Cardiac Insufficiency Bisoprolol Study II; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS, Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; HF, heart failure; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; RALES, Randomized Aldactone Evaluation Study; SCD, sudden cardiac death; SOLVD, Study of Left Ventricular Dysfunction; TRACE, Trandolapril Cardiac Evaluation; and Val-HeFT, Valsartan Heart Failure Trial. Right-sided graph: CIBIS-II, Cardiac Insufficiency Bisoprolol Study II; CORONA, Controlled Rosuvastatin Multinational Trial in Heart Failure; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; HF, heart failure; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; RALES, Randomized Aldactone Evaluation Study; SCD, sudden cardiac death; Val-HeFT, Valsartan Heart Failure Trial.

Figure 4

Choice between CRT-D and CRT-P according to the 2021 joint position statement from the European Heart Failure Association, European Heart Rhythm Association, and European Association of Cardiovascular Imaging of the European Society of Cardiology.

Figure 5

Model of heart failure progression according to the 2021 joint position statement from the European Heart Failure Association, European Heart Rhythm Association, and European Association of Cardiovascular Imaging of the European Society of Cardiology.

Figure 6

Incremental QRS narrowing with hybrid cardiac resynchronization modality: Left bundle branch-OpTimized cardiac resynchronization therapy (LOT-CRT). Reproduced with permission from Jastrzębski et al.

Figure 7

Conduction system pacing based cardiac resynchronization therapy (CSP-CRT) can be guided by the paced QRS metrics. Native peak time and paced V6 R-wave peak time (V6RWPT) are the same due to the physiological activation pathway of the lateral wall of the left ventricle during conduction system pacing. Lower panel shows distribution of V6RWPT values during His bundle pacing (HBP) and left bundle branch pacing (LBBP). Note that despite activation of the conduction system, V6RWPT is non-physiological in some patients indicating that the electrical synchrony is not restored to normal. Modified with permission from Jastrzebski et al.^,

Figure 8

Summary of indications for CRT according to the 2021 ESC guidelines. AF, atrial fibrillation; AVB, atrioventricular block; AVJ, atrioventricular junction; BiV, biventricular; EF, ejection fraction; HF, heart failure; LBBB, left bundle branch block. Adapted with permission from Mr J. Mascheroni.

Figure 9

Summary of indications for CRT according to the 2021 ESC guidelines. AF, atrial fibrillation; AVB, atrioventricular block; AVJ, atrioventricular junction; BiV, biventricular; EF, ejection fraction; HF, heart failure; LBBB, left bundle branch block. Adapted with permission from Mr J. Mascheroni.