The present results can be summarized as followings: 1) GLS changed during HG exercise in substantial patients with cardiovascular disease and preserved LVEF, 2) patients showing increase, not but decrease, in GLS were characterized as LV diastolic dysfunction manifested by stiffened left ventricle and reduced LA booster function, and 3) parameters of LV stiffness as well as that of LA booster function determined the increase in GLS independently of changes in hemodynamics by HG exercise. Notably, this was the first study to investigate the clinical significance of changes in GLS during the manipulation of the afterload in patients with cardiovascular diseases.
Gls As An Indicator Of Intrinsic Myocardial Dysfunction And Its Load Dependency
During these decades, numerous studies have been reported associations between reduced GLS and future adverse events in various conditions with preserved LVEF including hypertrophic cardiomyopathy[4], coronary artery disease[5], heart failure[6] and in general population [7]. Based on these findings, GLS has been recognized as an indicator of intrinsic myocardial dysfunction before the reduction of LVEF[18]. Because of the vulnerability of longitudinally-oriented inner myocardial layer to deleterious effects of the interstitial fibrosis[19] and hypoperfusion[20], GLS is considered to reflect the decreased longitudinal systolic function in various cardiovascular diseases before reduction of LVEF[21].
At the same time, load dependency of strain has been pointed[22]. Albeit slightly, inversely linear relationship between strain and wall stress has been reported in healthy subjects, in which afterload was manipulated by HG exercise[11]. Taken together with the relationship of reduced GLS and intrinsic myocardial dysfunction, GLS reduced by afterload augmentation is expected to become more sensitive marker of myocardial damage than that at rest in patients with preserved LVEF. However, we could not find any signs of LV dysfunction in patients showing reduced GLS during HG exercise in the present study. This might be due to the characteristics of the studied population in which severely reduced LV systolic function was not included. Importantly, we further found that increase, rather than decrease, in GLS was associated with advanced stage of LV diastolic dysfunction (Fig. 4).
Hg Exercise And Changes In Gls
Physiologically, several factors other than afterload can alter myocardial strain. Briefly, decrease in preload[8], increase in heart rate[9], reduction of sympathetic activation[10], along with increase of afterload[11] are known to reduce myocardial strain. Of these, HG exercise increases cardiac afterload, which is believed to be mainly brought by increase in heart rate[23, 24] through a circulatory reflex serving to increase perfusion pressure in contracting muscle[25].
In healthy subjects, HG exercise was reported to decrease GLS by 2.4–2.5% in absolute value[11, 26]. In heart failure patients, however, the data of alteration in GLS by HG exercise is quite limited. To date, there is only one study in which changes in cardiac magnetic resonance imaging-derived GLS by HG stress was tested[27]. The study reported that changes in absolute values of GLS, irrespective of increase or decrease, was higher in heart failure patients including various LV ejection fraction. They further found weak but significant correlations of the absolute value of changes in GLS to LVEF, NT-pro BNP levels, and Minnesota Living with Heart Failure questionnaire scores. This result suggests that not only reduction but also increase in GLS by HG exercise might reflect advanced stage of heart failure. Severe reduction of GLS by afterload augmentation can easily be expected in patients with severe myocardial dysfunction. On the other hand, how can the increase in GLS by HG exercise be associated with advanced stage of heart failure? This might be partly explained by blunted heart rate response in diastolic dysfunction. In the present study, we found a markedly blunted increase in heart rate and subsequent trend of gentle increase of blood pressure in patients showing increase in GLS by exercise. Therefore, lower heart rate together with inappropriate increase in blood pressure during HG exercise might work to prevent a reduction of GLS and unmask the enhanced contractility recruited by adrenergic stimulation[28] in these patients. Because chronotropic incompetence is one of the hemodynamic characteristics of heart failure with preserved LVEF, [29, 30] abnormal increase in GLS might have occurred in association with severe diastolic dysfunction in patients with preserved ejection fraction.
In the present study, however, parameters of LV stiffness and that of LA booster function determined increased GLS by HG exercise independently of changes in heart rate or that in systolic blood pressure. Since the precise mechanism of the direct relationships between LV stiffness or LA function and increase in GLS by exercise cannot be figured out from the present data, further study is warranted to elucidate this point.
Clinical Implication
Because of the general recognition in which myocardial strain must decrease with augmentation of afterload, increase of GLS by HG exercise has not been regarded as an unfavorable response to HG stress. Our findings thus could shed light on the meaning of GLS increase by HG exercise in patients with preserved LVEF. Although the clinical utility of HG stress testing in heart failure has not been well demonstrated, the present results is expected to add new insights on the understandings of pathophysiology in LV diastolic function and stress testing.
Limitation
First, our population consists of various cardiac etiologies with preserved LVEF and thus we need to confirm the present findings in well-differentiated heart failure with LVEF. Second, although the HG strength was set at 50% of maximal voluntary contraction in accordance with previous reports[11], the strength was slightly higher than other previous reports[26, 27]. Therefore, we need to establish a universal protocol for worldwide spread of HG exercise echocardiographic study. Finally, substantial proportion of the enrolled patients used beta-blockers, which might affect heart rate response to HG exercise. However, comparable frequency of beta-blocker use among the groups would relief this concern.