Letter by Kass Regarding Article, “Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction”
To the Editor:
In their recent study, Westermann et al1 examined detailed hemodynamics using pressure-volume analysis in patients with heart failure symptoms despite a preserved ejection fraction (HFpEF), the latter defined by an EF >50%. Their control group was individuals referred for chest discomfort without heart failure or significant coronary disease. The work represents the largest effort to date to detail rest and reserve function in HFpEF patients, and as such it is an important accomplishment. A primary conclusion was that diastolic chamber stiffening in HFpEF compromised stroke volume (because of reduced end-diastolic volume) at faster heart rates (≈75 to 120 bpm). However, this was in comparison to controls in whom end-diastolic volume and stroke volume actually rose at faster rates despite reduced end-diastolic pressure, and cardiac output doubled. Estimating systemic vascular resistance from end-systolic pressure and cardiac output data, this means resistance fell by half at the faster rate in the controls. It even declined by ≈25% in the HFpEF subjects.
These findings contrast to a large body of physiological data dating to the late 19th century when heart rate was first shown to inversely impair cardiac filling.2 This result was related to shortening of the diastolic time period at faster rates, behavior explored by Lewis Katz while a medical student.3 A molecular mechanism for this relationship was recently revealed in a study we performed using mice lacking the sarcomeric protein cardiac myosin binding protein C.2 As in humans, control mice showed a linear decline in filling and thus stroke volume at higher heart rates that correlated with shortening of the diastolic time period. Mice without cardiac myosin binding protein-C had little rate-dependent shortening of diastole, and filling remained similar despite faster rates.
In a prior clinical study4 using similar methodologies as those in Westermann et al,1 we documented an inverse dependence of end-diastolic volume and stroke volume on atrial paced heart rates. Furthermore, we found this dependence was similar between controls and patients with ventricular hypertrophy, many having presented with HFpEF. The HFpEF findings in Westermann et al1 are quite similar to these prior results; the difference lies in the controls. The unusual present findings raise the question of methodology problems (eg, catheter calibration), and an independent measure of cardiac output would have been useful. Given the very unusual nature of the control results, however, it remains difficult to interpret them as presented. As noted by Kitzman5 in his accompanying editorial, more study is needed to clarify these findings and their relevance to exertional limitations in HFpEF patients.
The author is a consultant for Boston Scientific and Principal Investigator for the Restoration of Chronotropic Competence in Heart Failure Patients With Normal Ejection Fraction (RESET) trial, a study evaluating rate-responsive atrial pacing for the treatment of heart failure with a preserved ejection fraction.
Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschöpe C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008; 117: 2051–2060.
Nagayama T, Takimoto E, Sadayappan S, Mudd JO, Seidman JG, Robbins J, Kass DA. Control of in vivo left ventricular contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation. 2007; 116: 2399–2408.
Katz LN. Factors modifying the duration of ventricular systole. J Lab Clin Med. 1921; 6: 291–311.
Liu CP, Ting CT, Lawrence W, Maughan WL, Chang MS, Kass DA. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy: systolic versus diastolic determinants. Circulation. 1993; 88: 1893–1906.
Kitzman DW. Diastolic dysfunction: one piece of the heart failure with normal ejection fraction puzzle. Circulation. 2008; 117: 2044–2046.