Myocardial Work in Coronary Artery Disease

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1		Alexandra-Catalina Catalina Frisan	--	3037	2024-02-22 20:13:42	\|
2	references update and layout	Fanny Huang	Meta information modification	3037	2024-03-05 10:13:11	\|

This entry is adapted from the peer-reviewed paper 10.3390/medicina60020199

Myocardial ischemia caused by coronary artery disease (CAD) and the presence of metabolic abnormalities and microvascular impairments detected in patients with diabetes mellitus (DM) are a common cause of left ventricular (LV) dysfunction. Transthoracic echocardiography is the most-used, non-invasive imaging method for the assessment of myocardial contractility. The accurate evaluation of LV function is crucial for identifying patients who are at high risk or may have worse outcomes. Myocardial work (MW) is emerging as an alternative tool for the evaluation of LV systolic function, providing additional information on cardiac performance when compared to conventional parameters such as left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) because it incorporates deformation and load into its analysis. The potential of MW in various conditions is promising and it has gained increased attention.

myocardial work left ventricular ejection fraction global longitudinal strain coronary artery disease

1. Introduction

Coronary artery disease (CAD) is one of the primary causes of death worldwide, mostly caused by atherosclerosis. Over the last four decades, a decrease in the mortality rate caused by CAD has been observed. However, it still accounts for about one third of deaths in individuals over the age of 35. Almost half of the reduction in mortality is due to the upgraded management of acute coronary syndromes (ACS) which encompasses improved prevention and therapeutic strategies ^[1]. Management of CAD includes the quantitative, accurate and reproducible evaluation of ventricular function. Early detection and treatment of ventricular dysfunction equals a chance to improve the outcome and prognosis of patients with ischemic heart disease. Type 2 diabetes mellitus (DM) is a major risk factor for cardiovascular diseases, and diabetic patients’ risk for heart failure development is two times higher as compared to nondiabetic patients. Moreover, patients with DM have worse cardiovascular outcomes and poorer prognoses ^[2]. Echocardiography is an essential tool in clinical practice for the evaluation of cardiac function, providing diagnostic and prognostic information in several clinical settings. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) are the most-used echocardiographic parameters for the assessment of left ventricular (LV) systolic function, but their dependence on loading conditions is a major limitation that could lead to the misinterpretation of myocardial contractility. Recently, myocardial work (MW) based on two-dimensional speckle tracking echocardiography has been proposed as a method for assessing myocardial function through the integration of myocardial deformation and afterload, thereby offsetting the disadvantages of conventional parameters.

2. Myocardial Work in Coronary Artery Disease

Cardiovascular diseases, which resulted in 20.5 million deaths in 2021, account for nearly one-third of all global deaths ^[3]. Ischemic heart disease is the leading cause of premature death worldwide. The advances made in cardiovascular medicine during the last 50 years decreased the globally age-standardized death rate, but the world is far from achieving the goals of diagnosis, treatment, prevention and management of cardiovascular diseases ^[4]. CAD involves the formation of atherosclerotic plaques in the lumen of coronary arteries, leading to a demand-supply mismatch of oxygen to the myocardium ^[5]. Non-invasive detection of early ischemia is challenging and is still being investigated. Two-dimensional speckle-tracking echocardiography has been demonstrated to detect early subclinical dysfunction, and it also provides detailed information about global and segmental LV systolic function even when the resting LV wall motion and LVEF are preserved. However, strain parameters remain load-dependent ^[6]. Recently, a new method that considers loading conditions was validated as being able to non-invasively assess the LV systolic function using longitudinal strain and a standardized LV pressure curve for determining myocardial work. While the loading conditions of LV may not be affected by CAD, the impaired oxygen metabolism in ischemic myocardium segments can have an impact on MW. Accordingly, several studies in the last five years have aimed to investigate the role of MW in patients with CAD.

2.1. Chronic Coronary Syndromes

To prevent adverse cardiac outcomes, early detection and treatment in patients with significant coronary artery stenosis is very important. LVEF is preserved at rest in most patients with significant CAD, and regional wall-motion abnormalities may not be seen in the early stages of the disease. GLS, assessed by speckle-tracking echocardiography, provides an incremental diagnostic value in detecting CAD in patients with normal LVEF and the absence of regional wall-motion abnormalities ^[6]. GLS is reduced in the areas of the myocardium affected by ischemia, but an increase in afterload was also demonstrated to be associated with a reduction in LV longitudinal strain. In consequence, in patients with increased afterload conditions (e.g., hypertension), the evaluation of strain may lead to false interpretations of ischemia ^[7]. Taking afterload into account, MW may be superior to GLS in detecting the myocardial dysfunction caused by CAD.

An interesting study by Edwards et al. ^[8] included 114 patients referred to angiography who had preserved EF (LVEF ≥55%), no resting regional wall-motion abnormalities and no clinical symptoms of ischemia; this study evaluated whether MW can predict significant CAD. The results showed that global MW was reduced in patients with significant CAD as compared to those without CAD. A receiver operating characteristic (ROC) analysis demonstrated that MW was superior to GLS and was the most powerful predictor of significant CAD. The cutoff value for global MW in predicting CAD was 1810 mmHg% (sensitivity: 92% and specificity: 51%). The low specificity underlines the fact that MW should be used along with other parameters to identify patients with significant CAD. Sabatino et al. ^[9] further extended the previous results of Edwards et al.’s study and found that GWI, GCW and GWE were significantly reduced in patients with critical CAD (stenosis >70%) as compared to the controls. The novelty of this study was the assessment of the regionalized MW indices. In particular, regional GWE had the highest diagnostic performance for predicting critical CAD (AUC = 0.920, p < 0.001), and this might solve one of the limitations of Edwards’ study, namely, the low specificity. Similar to the aforementioned studies, Zhang et al. ^[10] explored the value of global and regional MW indices in predicting high-risk, stable CAD in patients without wall-motion abnormalities and preserved LVEF. They demonstrated that GWI and GCW could predict high-risk, stable CAD at cutoff values of 1808 mmHg% and 2038 mmHg%, respectively, and that decreased GWI and GCW were independently related to high-risk, stable CAD in multivariable analyses. Compared to previous studies, the MW indices could not be proven as superior to GLS in identifying high-risk, stable CAD with statistical significance, and the limited sample size of the cohort included in this study could be a possible reason.

Another study ^[11] included patients with CAD (stenosis ≥ 50% in at least one major coronary artery), with heart failure (mid-range or reduced LVEF), without heart failure (preserved LVEF) and controls (healthy individuals). The CAD patients were divided into hypertension and no-hypertension subgroups. In this study, MW was more predictive for assessing LV function as compared to LVEF and GLS. The GWI and GCW values were decreased in CAD patients with heart failure and increased in the subgroup of CAD patients with preserved EF and hypertension subgroup vs. the controls. In hypertensive patients, LV must spend more energy to eject blood against an increased afterload, and this could explain the increased values in the hypertension subgroups. GWW was increased and GWE was decreased in all CAD subgroups.

When comparing the resting MW indices with stress myocardial perfusion (assessed by coronary-computed tomography angiography and dynamic-stress-computed tomography myocardial perfusion imaging) in patients with angina and non-obstructive CAD (lumen stenosis < 50%), the potential advantages over LVEF have been demonstrated ^[12]. Impaired stress myocardial perfusion in patients with non-obstructive CAD may be a consequence of coronary microvascular dysfunction. GLS, GCW, GWI and GWE were reduced and GWW was increased in patients with reduced stress perfusion, suggesting that these parameters could detect myocardial ischemia earlier and more accurately than LVEF. In the multivariable logistic regression, GWI and GWE were independently associated with reduced global-stress myocardial perfusion, while GLS was not. Among the analyzed variables, GWE had the highest AUC value (AUC = 0.858, p < 0.05), with an optimal cutoff value of 95% (specificity 90%, sensitivity 70%), which demonstrated that it is the most powerful parameter for detecting reduced global stress myocardial perfusion.

Recently, Zhou et al. ^[13] proposed a new method of predicting severe CAD (stenosis ≥ 50% in the left main coronary artery and ≥70% in at least one major coronary artery), a method named “positive region identification” according to the assignment of segments of the coronary artery territories and the values of the myocardial work segments in the bull’s-eye diagram of myocardial work in the LV. Using this method, the results of this study showed that, when compared with the regional values of GLS, regional GWI predicted severe CAD with higher sensitivity (95.2% vs. 70.2%) and similar specificity (97.5 vs. 91.1%) and performed better in accurately detecting the culprit coronary artery with severe stenosis. The “positive region identification” method proposed in this study performed better in predicting severe stenosis in the culprit coronary artery as compared to the traditional method (regional average values in the anterior, lateral and inferior wall segments of the bull’s-eye plot, corresponding to the left anterior descending artery, left circumflex and right coronary artery); therefore, it may improve the accuracy of diagnosis and could have a strong clinical practicability.

In summary, the MW parameters could provide incremental diagnostic information for identifying patients with chronic CAD who may benefit from early therapeutic strategies. Further studies with large-scale and multicenter samples should be performed to improve the diagnostic and prognostic value of MW in stable coronary heart disease.

2.2. Acute Coronary Syndromes

Acute coronary syndromes (ACS) represent a range of conditions characterized by a sudden, reduced blood flow to the heart and are often the first clinical manifestation of cardiovascular diseases. These conditions include unstable angina, which is when blood flow is decreased but is not severe enough to produce myocyte death, and myocardial infarction, which is characterized by a partially blocked coronary artery; a transient, complete block of a coronary artery (non-STEMI); or a total blockage of a coronary artery (STEMI), resulting in cell injury or the necrosis of part of the myocardium ^[14]. In the last 40 years, major progress has been made in the management and treatment of ACS, and the prognoses of patients have significantly improved. However, continuous efforts are still being made to predict the outcome of patients with ACS ^[15]. LV dysfunction is a key prognostic factor in patients presenting ACS. Current guidelines recommend routine echocardiography before hospital discharge to assess LV, right ventricle and valvular function that may influence outcomes in ACS survivors ^[16]. Several studies evaluated the usefulness of MW in patients with ACS.

2.2.1. Non-ST-Segment Elevation Myocardial Infarction

The changes in myocardial function were evaluated through MW assessment 1 day before and 1 month after percutaneous revascularization in 33 non-ST-segment elevation myocardial infarction (non-STEMI) patients as compared to 30 healthy subjects. Compared to the controls, the GLS, GWI, GCW and GWE values were decreased, while the GWW value was increased in non-STEMI patients 1 day before and 1 month after revascularization. The difference was statistically significant (p < 0.05), suggesting that the LV myocardial function was impaired. In the group treated by percutaneous coronary intervention, the values of GLS, GWI and GCW increased after 1 month as compared to those obtained 1 day before revascularization, showing that the LV systolic function was improved, while other echocardiographic parameters were not significantly different between the two groups ^[17]. Follow-up is necessary after revascularization to observe the value of MW and to estimate long-term prognosis.

Severe coronary artery stenosis leads to a decreased blood flow to the myocytes and to regional myocardial stunning. Hence, defining and quantifying LV risk areas is crucial for early interventions that may reduce mortality. Quin et al. ^[18] showed that patients with significant coronary artery stenosis had lower global and regional values of GLS, GWI, GCW and GWE and higher values of GWW as compared to patients without significant coronary artery stenosis. Regional GLS, GWI, GCW and GWE were significantly worse in territories of total coronary artery occlusion. The best parameter for predicting significant coronary artery stenosis was regional GWE, with a cut-off value of 96% (AUC = 0.80, sensitivity 73%, specificity 70% and p < 0.001).

Approximately 30% of patients with non-STEMI present acute coronary occlusion (ACO) that does not develop ST-segment elevation on the ECG ^[19]. Boe et al. ^[20] aimed to investigate the ability of the MW index to identify patients with ACO. The reduced MW index in ≥ 4 adjacent segments had good sensitivity and specificity for identifying ACO and was superior to other echocardiographic parameters. The cutoff value for GWI to identify segmental systolic dysfunction was <1700 mmHg%. Alterations in the loading conditions, such as high systolic blood pressure, lead to a decrease in the systolic shortening of a segment, which may be falsely interpreted as dysfunctional. The logistic regression analysis of this study demonstrated that an elevated systolic blood pressure decreased the ability of strain analysis to identify patients with ACO, while GWI was able to correct the falsely interpreted reduction in systolic function based on strain analysis.

2.2.2. ST-Segment Elevation Myocardial Infarction

Acute ST-segment elevation myocardial infarction (STEMI) survivors are at high risk for future cardiovascular events, including recurrent myocardial infarction, arrhythmias, heart failure and death; thus, more knowledge is needed regarding these patients’ prognosis after treatment with STEMI in daily clinical practice.

Butcher et al. ^[21] evaluated the prognostic value of MW indices in patients with STEMI and reduced LVEF. They found that higher values of GWI were associated with a greater probability of LVEF normalization after 6 months of follow-up, while lower values of GWI (<750 mmHg%) were independently associated with all-cause mortality, giving additional information that could be used to detect patients who may benefit from prompt initiation of therapy.

In patients with anterior STEMI treated by percutaneous coronary intervention, GCW was the best parameter for predicting segmental and global LV recovery and was more severely impaired in patients with in-hospital complications (defined as reinfarction, heart failure, LV thrombus and death) ^[22].

Mahdiudi et al. ^[23] demonstrated in their study that the GWE values in patients with STEMI treated by percutaneous intervention were lower compared with patients who have cardiovascular risk factors and normal controls. Consistent with these findings, Lustosa et al. ^[24] demonstrated that lower values of GWE (<86%), measured by transthoracic echocardiography within 48 h of admission in patients with STEMI, were associated with higher rates of all-cause mortality. Furthermore, it had an incremental prognostic value over baseline clinical characteristics, such as LVEF and GLS. Similar to the results of Lustosa et al., GWE <91% was independently associated with a higher risk of major events (unplanned coronary revascularization, hearth failure and cardiovascular death), in a study by Coisne et al. ^[25] that explored the prognostic value of MW 1 month after an acute myocardial infarction (Table 1). The slight difference in the GWE thresholds between the two studies may be due to the time when the GWE was analyzed (48 h vs. 1 month) and to medical therapy optimization. Another difference was that Coisne et al. included both patients with non-STEMI and STEMI in their study. Ischemia after STEMI leads to reduced adenosine triphosphate formation, changes in myocardial metabolism, LV contractility dysfunction and a decrease in regional longitudinal strain, which can all lead to a decrease in LV myocardial efficiency ^[23].

Table 1. Association of GWE and GWI with adverse outcomes in patients with ACS in different studies.

Myocardial Work Parameter	Value	Role
GWE	<86%	Independent association with all-cause mortality in patients with STEMI (HR 3.167 [95% CI, 1.679–5.927]; p < 0.001) ^[24].
GWE	<91%	Independent association with higher risk for major events in patients after an acute myocardial infarction (HR 2.94 [95% CI, 1.36–6.35]; p < 0.041) ^[25].
GWI	<750 mmHg%	Independent association with all-cause mortality in patients with STEMI (HR 3.85 [95% CI, 1.94–7.67]; p < 0.0001) ^[21].

GWE = global work efficiency; GWI = global work index; STEMI = ST-elevation myocardial infarction; HR = hazard ratio; CI = confidence interval.

An important risk factor for the development of heart failure and all-cause mortality in patients with STEMI is LV remodeling, which is caused by microvascular obstruction, inflammation and infarct size, and is defined as an increase in LVEDV ≥20% from the baseline ^[26]. It was demonstrated that GWI, GCW and GWE were reduced and GWW was increased in patients with LV remodeling 3 months after STEMI as compared to patients without LV remodeling. Interestingly, a minority of patients without remodeling also showed some degree of impaired MW, which may be related to further reverse remodeling at longer-term follow-ups ^[27].

Another study that aimed to evaluate the role of MW in patients with STEMI from the baseline to the 3-month follow-up found that the values of GWI, GCW and GWE were significantly improved at the follow-up, which may reflect the myocardial stunning (delayed myocardial function recovery after reperfusion in patients with STEMI), while GWW did not change between the baseline and the 3-month follow-up, which may reflect the development of non-viable, irreversible scar tissue ^[28].

Even after successful revascularization of the obstructed coronary artery, there is a relatively high incidence of coronary microvascular dysfunction that may affect outcomes in STEMI patients. Jin et al. ^[29] aimed to explore the role of MW in identifying impaired microvascular perfusion in patients with STEMI within 48 h after PCI and found that GWI, GCW, GWE and GLS were significantly reduced in the impaired microvascular perfusion group as compared to the normal microvascular perfusion group. In this study, GWI was the only independent predictor for impaired microvascular perfusion among the MW parameters, with a cutoff value of 1145 mmHg% (sensitivity, 86.8%, specificity, 53.7%). Several studies demonstrated the value of MW indices in predicting CAD (Table 2).

Table 2. Cutoff values of the myocardial work indices in different studies.

Myocardial Work Parameter	Cutt-Off Value	Sensitivity (%)	Specificity (%)	Role
GWE	78%	90.5	85.7	To predict critical coronary artery stenosis ^[9]
GWE	95%	70	90	To detect reduced global stress myocardial perfusion in patients with angina and non-obstructive coronary artery disease ^[12]
Regional GWE	96%	73	70	To predict obstructive coronary artery stenosis ^[18]
GWI	1145 mmHg%	86.8	53.7	To predict microvascular perfusion impairments in patients with STEMI ^[29]
GWI	1810 mmHg%	92	51	To predict significant coronary artery disease ^[8]
GWI	1808 mmHg%	52.6	87.8	To predict high-risk, stable coronary artery disease ^[10]
GCW	2308 mmHg%	80.7	64.9	To predict high-risk, stable coronary artery disease ^[10]

GWE = global work efficiency; GWI = global work index; GCW = global constructive work; STEMI = ST-elevation myocardial infarction.

A recently published meta-analysis aimed to compare the diagnostic accuracy of MW parameters in predicting CAD. Five studies, which included a total of 501 patients, were evaluated. The results showed that GCW had the highest diagnostic accuracy among all MW indices in the prediction of CAD (AUC = 0.86), with an excellent reproducibility ^[30].

In conclusion, the evaluation of MW could be a promising tool in clinical practice for assessing the necessity of early revascularization and predicting the outcomes of patients with CAD.

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