Background
Tissue Doppler Imaging (TDI) echocardiography is a sensible and feasible tool to detect subclinical left ventricular (LV) systolic dysfunction (LVSD). In particular, the assessment of mitral annular peak systolic velocity (peak S’) by Tissue-Doppler pulsed wave spectral analysis, reveals the longitudinal LVSD in several settings of patients at increased risk for cardiovascular (CV) adverse events such as those with type 2 diabetes mellitus, arterial hypertension, ischemic heart disease and/or heart failure with preserved LV ejection fraction (LVEF) [
1‐
7]. As a result, peak S’ has emerged as one of the strongest predictors for CV disease in the domain of non-invasive cardiac imaging.
We prospectively studied a large cohort of patients at increased CV risk without history of cardiac disease to test the hypothesis that longitudinal LVSD measured as lower peak S’ at baseline echocardiographic evaluation can predict inducible myocardial ischemia during exercise stress echocardiography (ExSEcho) in these patients. Furthermore, we verified whether other echocardiographic parameters were prognosticators of inducible myocardial ischemia measured at baseline evaluation preceding ExSEcho.
Discussion
The main result emerged by the present study was that in patients at increased risk for CV events, without history of cardiac disease, a reduced longitudinal LV systolic function measured at baseline evaluation was closely associated with inducible myocardial ischemia during ExSEcho, independent of the traditional confounding factors. Furthermore, the coexistence of high CESS and high LASF with a reduced longitudinal LV systolic function predicted the development of inducible myocardial ischemia during ExSEcho in a substantial portion (one third) of the ischemic patients. This is what does our study finding add beyond current day ExSEcho. Unexpectedly, no clinical or laboratory variable including diabetes mellitus, hypertension or renal dysfunction was associated with inducible ischemia in our population.
Peak S’ reduction was already identified as an early marker of longitudinal LV systolic dysfunction in different conditions [
2]. Several authors found in diabetic patients a 10–20 % reduction of peak S’ [
18,
19] evident either at rest or during ExSEcho in comparison with controls [
18,
20]. Similarly, 10 % of asymptomatic hypertensive patients showed a reduction of peak S’, closely correlated with LV hypertrophy and LVSD [
21,
22]. Also in patients with coronary artery disease (CAD), peak S’ at rest was reduced [
23,
24], and the reduction was positively correlated with the severity of CAD [
24]. In other studies [
23,
25], significant CAD was associated with higher LV mass, and with several parameters of diastolic and systolic dysfunction. Our results are partially in line with the previous ones: in our population, indeed, TDI identified the presence of inducible myocardial ischemia by the lower values of peak S’ in ischemic patients than controls at rest, but all other Doppler parameters as well as LV mass were not significantly different between the ischemic and non-ischemic groups. Collectively, our findings clearly indicate that patients who developed myocardial ischemia during ExSEcho have an intrinsic and specific LVSD at rest detectable by measuring the global longitudinal function using TDI echocardiography. Furthermore, during ExSEcho, the longitudinal LV function expressed as peak S’ increased significantly less in ischemic than in non-ischemic ones. One reason could be that we induced mainly subendocardial ischemia during ExSEcho and at endocardial layer the longitudinal component of the myocardial fibers shortening is prevalent. Thus, it is not surprising the association between subendocardial ischemia and reduced increase in longitudinal LV systolic function. Evidently, both conditions and their close relationship also exist at rest, although overt signs/symptoms of subendocardial ischemia are lacking.
In our study population, diabetes, hypertension and obesity were widely present. Thus, as predictable, these pathological conditions could not emerge as prognosticators of ExSEcho-induced myocardial ischemia in this setting of patients. No difference, indeed, existed in clinical characteristics between the two study groups. Some difference in drug therapy was present at baseline evaluation but no medication significantly influenced the development of ischemia during ExSEcho.
Together with longitudinal LVSD, another condition independently associated with the inducible myocardial ischemia was the higher LASF. With increased LV stiffness and reduced LV compliance, LASF increases to preserve LV filling and has to be considered as a sensible marker of LV diastolic function [
25,
26]. Furthermore, increased LASF is a prognosticator of a higher CV risk in patients with chronic heart failure with preserved LVEF [
16], hypertension [
27] and aortic stenosis [
28]. Our findings may be interpreted as the expression of the inter-dependence between LV systolic and diastolic function, two active processes requiring energy closely coupled in the cardiac cycle which exert a mutual negative influence in presence of excessive LV mass growth and/or myocardial ischemia [
29]. Interestingly, LASF increased much less in ischemic than non-ischemic patients during the intermediate phase of ExSEcho and it was significantly lower in the former than in the latter at the peak exercise. Two reasons may justify this behavior recognized by our analysis: 1) the development of atrial ischemia leading to a reduction of systolic atrial performance in ischemic patients 2) the significant increase in LV filling pressures during exercise in ischemic patients leading to a reduction of the peak velocity of the blood at atrial contraction during late diastole despite a preserved atrial systolic force: this condition actualizes a reduction of A wave of the trans-mitral flow and consequently, a reduction of LASF values.
Also an increased LV CESS, row index of LV afterload, was independently associated with inducible myocardial ischemia in our patients. CESS was studied in patients at high CV risk, where it was found increased in presence of hypertension and LV hypertrophy [
30]. In our study a new relation between increased CESS at basal echocardiography and inducible myocardial ischemia was found, suggesting higher levels of LV afterload a derivative hemodynamic status of myocardial ischemia or, alternatively, a condition inducing myocardial ischemia. The available data do not allow us to definitely assess the real pathophysiological pathway, so that we can only make speculative inferences about this finding.
Taking one by one the three echocardiographic parameters emerged at multivariate regression analysis as prognosticators of inducible myocardial ischemia (peak S’, LASF and CESS), the sensibility and specificity for the event prediction was around 60 %, slightly better for peak S’. Furthermore, there is significant overlap between the S’ values between the two study groups, resulting in a relatively high number of both false positive and false negative results where S’ value would be considered as continuous variable. But combining the three variables together, on the basis of the cut-off got from ROC analysis, we could better predict inducible myocardial ischemia during ExSEcho at baseline echocardiography. The echocardiographic methods for the assessment of these variables are easy and feasible using standard echocardiography, so that the proposed evaluation can be performed in every echo-Lab without high technology.
Limitations and strengths of the study
Lacking follow-up data, no prognostic inference in regards to the detection of longitudinal LVSD in patients candidate to ExSEcho can be made. Although our statistical models were extensive, some confounders explaining the observed relations could be left out. The tissue Doppler S’ is an angle dependent measure, so that we cannot exclude that this aspect may have influenced at least in part our results. Finally, the analyses did not consider any parameter of vascular function. Strengths of our study include the large number of participants prospectively enrolled, the reliable, appropriate and validated methods for the assessment of longitudinal LVSD, LASF and CESS as well as the other numerous echocardiographic variables considered in this investigation, the comprehensive nature of the dataset and the capability to correct for the most clinically relevant CV risk factors.
Abbreviations
ACE, Angiotensin-converting enzyme; ARB, Angiotensin receptor blockers; ASE, American Society of Echocardiography; CAD, Coronary artery disease; CESS, Circumferential end-systolic stress; CV, Cardiovascular; ExSEcho, Exercise stress echocardiography; LASF, Left atrial systolic force; LV, Left ventricular; LVEF, Left ventricular ejection fraction; LVSD, Left ventricular systolic dysfunction; ROC, Receiver operating characteristic; S’, Mitral annular peak systolic velocity; TDI, Tissue Doppler Imaging.
Funding
These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. No financial support was provided.