Chronotropic Incompetence and Pacing in HPEF Heart Failure with Preserved Ejection Fraction

Introduction

There are approximately 550,000 new cases added to the at least 5 million Americans living with heart failure (HF) each year. Of these cases, approximately 40% to 50% are classified as diastolic HF or more currently heart failure with preserved ejection fraction (HFpEF). HFpEF is defined by abnormalities in LV relaxation, diastolic distensibility, and stiffness. Histologically these physiologic abnormalities may manifest as myocyte hypertrophy, increased myofibrillar density, elevated myocyte relative thickness, and increased myofilamentary calcium sensitivity. Accurate diagnosis of HFpEF can be difficult, but patients typically have at least one abnormal measurement on hemodynamic heart catheterization or echocardiography supporting this diagnosis.

Diastolic filling is influenced by many physiologic variables as briefly mentioned. The cardiac cycle length and the relative timing of atrial and ventricular contractions are also major contributors, to diastolic function. Permanent pacemakers (PPM) influence cardiac cycle timing and have been shown to induce and treat HFpEF. Influencing this relationship are various PPM programming modes and pacing locations. In this chapter the relationship between PPM and diastolic function will be explored with emphasis on the pathophysiology, diagnosis, treatment, and future technologies.

Basic Function of Permanent Cardiac Pacemakers

A permanent pacemaker is a system composed of a pulse generator and various forms of leads, which deliver an electrical pulse to the myocardium—within either the endocardium or epicardium. This electrical charge, if above a critical threshold, prompts myocardial cell action potential propagation. This propagation moves away from the electrode in a radial direction. A critical foundational concept is the coupling between electrical and mechanical activation. Myocardial contraction follows electrical stimulation and is impacted by many hemodynamic principles.

The most basic PPM configuration consists of a pulse generator within a prepectoral pocket (typically the patient’s left side) and a single lead coursing through the subclavian vein into the right ventricular apex. This configuration leads to a ventricular activation sequence originating in the ventricular apex and coursing posteriorly and toward the base. LV activation occurs after the wave of depolarization traverses the septal myocardium. This sequential (RV followed by LV) activation inherently leads to mechanical dyssynchrony and can affect systolic and diastolic function. An obvious drawback to this configuration of pacing is the lack of attention paid to the atrial activity. Without understanding atrial activity there can be a loss of AV coupling, which can decrease cardiac output by creating suboptimal diastolic filling times, provide an inadequate atrial contribution to LV filling, create poorly tolerated symptoms of palpitations, and predispose the patient to cardiac arrhythmias. Dual-chamber pacemakers circumvent these problems by adding a second lead from the pulse generator, which stimulates the right atrium. There, the lead can sense intrinsic atrial depolarizations and provide AV synchrony with prespecified AV delays.

Cardiac resynchronization therapy pacing adds another dimension to pacing’s influence on the cardiac cycle—intraventricular synchrony. CRT requires placement of at least two leads onto the ventricular myocardium. Most commonly a transvenous RV apex lead and a transvenous lead placed onto the LV posterolateral wall via a coronary sinus branch. If coronary sinus anatomy is not favorable or does not permit passage of a lead, epicardial leads can be placed onto the posterolateral LV wall. Historically this technology has been recommended for patients with NYHA Class III/IV symptoms and an LV EF of 35% or less refractory to drug therapy. These patients should have a left bundle branch block (BBB) QRS morphology and a QRS interval of at least 120 msec and preferably more than 150 msec (an indicator of interventricular [VV] dyssynchrony). While left BBB has traditionally been targeted with CRT devices, right BBB QRS morphologies have also been targeted, however with disappointing results. Despite some success, there is still a paucity of data in this area. In addition to a wide (QRS >120 msec) and left BBB pattern QRS on electrocardiogram, patients with significant intraventricular and interventricular dyssynchrony can be identified with standard echocardiography. This technology may not only assist in diagnosis but also provides opportunities to refine device settings to optimize both systolic and diastolic function. Data from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study group have shown improvements in quality of life, 6-minute walk distances, LV EF, and LV reverse remodeling following the implementation of CRT.

Diastolic Dysfunction

As mentioned earlier, diastolic dysfunction is defined as an abnormality in myocardial relaxation, filling, or distensibility. Diastolic HF requires one of these parameters of diastolic dysfunction and signs or symptoms of HF. The diastolic phase of the cardiac cycle begins with isovolumetric relaxation and ends after the atrial contribution to ventricular filling is completed. On a microscopic level, calcium is taken into the sarcoplasmic reticulum during this phase allowing the relaxation of the myocytes and a rapid decrease in LV pressure. Any aberrancy in these cellular processes causes a decrease in LV preload. According to the Frank-Starling law, this condition yields a decrease in peak pressure and the rate of LV relaxation (lusitropy).

On a more macroscopic level, diastolic dysfunction can be due to abnormal relaxation or an increase in myocardial stiffness. Typically, abnormal relaxation precedes increases in stiffness because stiffness is a marker of a fibrotic ventricle. On a ventricular pressure-volume loop, this is visualized as the slope of the diastolic portion of the loop (changes in LV pressure plotted against changes in diastolic LV volume [dP/dV]). Increased stiffness is inversely proportional to the pressure deceleration time. These measurements and relationships are exploited by echocardiography and assist in accurate diagnosis of variations in diastolic filling parameters.

Chronotropic Incompetence in Diastolic Heart Failure

As mentioned, the diastolic phase of the cardiac cycle is complex and depends at least in part on the timing of atrial and ventricular depolarizations. When the speed or timing of the cardiac cycle is inadequate to meet the cardiac output requirements of a patient, they are deemed to have chronotropic incompetence. Due to variability in normal values, there are wide ranges in the estimated incidence of chronotropic incompetence (25%–70% of HF patients). This is further impacted by the widespread use of beta blockers, which are now standard of care for HF patients.

Given the complexities associated with normal diastology, it has been difficult to determine the relative contributions of each factor. Chronotropic incompetence is estimated to reduce cardiac output by at least 20%. Kosmala et al. examined 207 patients with stage C HF and 60 patients with stage B HF in an attempt to answer this question. For each study subject, they performed echocardiograms at rest and immediately following a cardiopulmonary exercise test. One of their conclusions was that the development of chronotropic incompetence was an important factor leading asymptomatic patients to symptom development. The severity of diastolic HF correlated to the severity of chronotropic incompetence.

The estimated contribution of chronotropic incompetence is supported by work by Brubaker and colleagues published in 2007. In their report, cardiac output was measured in subjects at rest and during exertion. During exercise, cardiac output was noted to increase nearly 4-fold; of the 4-fold increase, there was a 2.2-fold increase in heart rate (HR), 1.5-fold increase in AV oxygen differences (oxygen extraction), and a 0.3-fold increase in stroke volume. Researchers also measured heart rate recovery (HRR) and linked this to mortality in asymptomatic patients. HRR is defined as the difference in HR between the time of termination of exercise to a prespecified time point following the termination of exercise while supine (1-minute and 2-minute HRR are common). Normal values are at least 12 bpm at 1 minute and at least 42 bpm at 2 minutes. This has also been demonstrated with Framingham data of 3000 patients followed 15 years. Those patients in the top quintile of HRR at 1 minute had the lowest risk of cardiovascular disease (HR 0.61).

Pathophysiology