Left ventricular systolic function and myocardial wall stress in conditions predisposing to diastolic heart failure

Abstract

Myocardial wall stress (MWS) is a crucial factor linked to myocardial hypertrophy, which can lead to heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Shortening-deactivation of cardiac myocytes could provide a mechanism linking systolic to diastolic dysfunction whereby an impairment of early systolic ejection leads to sustained myocardial contraction, preserving overall ejection fraction at the expense of diastolic dysfunction. We formulated a novel index of first phase ejection fraction (EF1), the fraction of left ventricular volume ejected from the start of systole to the time of the first peak in LV pressure (corresponding to the time of maximal ventricular shortening) to examine the relationship of early phase ejection to duration of myocyte contraction and diastolic relaxation. We also obtained time-varying ejection-phase MWS, a function of ventricular pressure, myocardial wall volume, and cavity volume, using carotid tonometry to get central aortic pressure and 2- dimentional echocardiographic wall tracking to get LV volumes. In the first part of this thesis, we examined EF1 and MWS in children with chronic kidney disease (CKD) who are at high risk of developing adverse cardiovascular events related to secondary hypertension and LVH. We found that peak, mean and end-systolic MWS were higher in children with CKD and increased across stages of CKD, which can be explained by a form a LV dysfunction whereby dynamic values of the ratio of wall volume/cavity size during systole were lower in children with CKD than without. EF1 and EF were preserved in both healthy children and those with CKD. In the second part of this thesis, we studied EF1 and MWS in adults with hypertension with varying degrees of diastolic dysfunction but in whom overall ejection fraction was preserved. EF1 and time of onset of ventricular relaxation (TOR, as determined from the temporal pattern of myocardial wall stress) were strongly correlated (standardized regression coefficients -0.36 and 0.35 respectively, each P<0.0001) with diastolic relaxation (transmitral : tissue Doppler E/E’ ratio) irrespective of adjustment for age, sex, anti-hypertensive treatment, measures of afterload and ventricular geometry. In the final part of this thesis, we repeated all measurements in part two after administration of nitroglycerin, a drug known to influence ventricular dynamics, in a sub-sample (n=18) of patients. We found that nitroglycerine had no significant effect on EF but increased EF1, decreased TOR and improved diastolic relaxation (E/E’) significantly. Thus, this thesis provides novel insight into aspects of LV function that may predispose to HFpEF: a) Children with CKD exhibit blood pressure independent LV remodeling which results in increased systolic MWS and which may dispose to LVH in later life. b) Our novel indices: EF1 and TOR provide a potential mechanistic link through the shortening deactivation phenomenon, between early systolic dysfunction, sustained myocardial contraction and impaired diastolic relaxation. EF1 may be an important diagnostic measurement and therapeutic target to prevent progression to heart failure, particularly that associated with hypertension and preserved ejection fraction.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Philip Chowienczyk (Supervisor)