Research Progress and Clinical Value of Subendocardial Viability Ratio

ABSTRACT

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with ischemic heart disease being a major contributor, either through coronary atherosclerotic plaque‐related major vascular disease or coronary microvascular dysfunction. Obstruction of coronary blood flow impairs myocardial perfusion, which may lead to acute myocardial infarction in severe cases. The subendocardial viability ratio, also known as the Buckberg index, is a valuable tool for evaluation of myocardial perfusion because it reflects the balance between myocardial oxygen supply and oxygen demand. The subendocardial viability ratio can effectively evaluate the function of the coronary microcirculation and is associated with arterial stiffness. This ratio also has potential value in predicting adverse cardiovascular events and mortality in various populations. Moreover, the subendocardial viability ratio has demonstrated clinical significance in a range of diseases, including hypertension, aortic stenosis, peripheral arterial disease, chronic kidney disease, diabetes, and rheumatoid arthritis. This review summarizes the applications of the subendocardial viability ratio, its particular progress in the relevant research, and its clinical significance in cardiovascular diseases.

Nonstandard Abbreviations and Acronyms

DPTI

diastolic pressure time index

PWV

pulse wave velocity

SCORE

Systematic Coronary Risk Evaluation Project

SEVR

subendocardial viability ratio

SPTI

systolic pressure time index

TAVR

transcatheter aortic valve replacement

Cardiovascular disease (CVD), in particular ischemic heart disease, remains the leading cause of death and disability worldwide. ¹ In most cases, ischemic heart disease is caused by atherosclerotic plaque–related coronary artery disease. However, in recent years, increasing attention has been focused on ischemic heart disease caused by dysfunction in the coronary microcirculation. ² Nonetheless, whether macrovascular or microvascular, ischemic heart disease is essentially caused by dysfunction of the coronary circulation leading to impaired myocardial perfusion. This results in impaired metabolism in myocardial cells, which leads to myocardial ischemia and, in severe cases, myocardial infarction. ³ The oxygen supply to the myocardium depends on the coronary arterial blood flow and oxygen‐carrying capacity. The endocardial myocardium is more sensitive to ischemia and hypoxia than is the epicardial myocardium. ³ The subendocardial viability ratio (SEVR) can reflect the balance of myocardial oxygen supply and demand, and is an effective and accurate indicator of myocardial perfusion. ⁴ This review summarizes the applications of SEVR, especially the progress made in research and its clinical significance in CVDs (Figure 1).

Figure 1. Measurement, affecting factors, and clinical value of the subendocardial viability ratio (SEVR).

 

DEFINITION OF SEVR

SEVR, also known as the Buckberg index, was first mentioned in the 1970s by Buckberg and Hoffman ⁵ and was calculated using invasive hemodynamic methods. It is defined as the ratio of the diastolic pressure time index (DPTI) to the systolic pressure time index (SPTI). Early invasive hemodynamic studies in animals demonstrated that the SPTI reflects myocardial oxygen demand, ⁶ with a higher SPTI value indicating greater myocardial oxygen consumption and an increased risk of myocardial ischemia. ⁷ The DPTI is an important determinant of subendocardial perfusion, reflecting myocardial oxygen supply. ⁸ Coronary blood flow is influenced by myocardial contractility ⁹ ; during systole, left ventricular (LV) pressure reaches its peak, resulting in maximal resistance to subendocardial coronary perfusion and minimal or even complete cessation of coronary blood flow. Subendocardial myocardial perfusion is almost entirely dependent on diastolic coronary perfusion and the duration of diastole, which are reflected by the DPTI. ⁸ , ¹⁰ Therefore, a low SEVR indicates a severe imbalance between myocardial oxygen supply and demand, suggesting reduced subendocardial myocardial perfusion. ⁵ , ¹¹

Initially, SEVR was derived from analysis of pressure curves recorded in the left ventricle and ascending aorta during cardiac catheterization; however, the invasive and cumbersome nature of this method greatly limited the application of SEVR in clinical practice. Later, arterial tension was measured by noninvasive recording of central blood pressure (BP), which allowed for morphological analysis of the waveform of central arterial pressure, known as pulse wave analysis. SEVR and other central hemodynamic parameters such as augmentation pressure and the augmentation index can also be obtained using pulse wave analysis and provide valuable information beyond traditional cardiovascular risk factors for assessment of cardiovascular risk. ¹² , ¹³

MEASUREMENT OF SEVR

SEVR can be measured invasively and noninvasively. Using the invasive method (Figure 2A), SEVR is calculated by the pressure curve of the aorta and left ventricle measured by cardiac catheterization. DPTI is estimated as the area between the pressure curve of the aorta and the left ventricle in diastole, representing the myocardial oxygen supply index. SPTI is estimated as the area under the LV systolic pressure curve, representing the oxygen demand index for the LV myocardium. Using the noninvasive method, the central arterial pressure waveform is obtained by extracorporeal applanation tonometry for calculation of SEVR, mainly through direct measurement of carotid artery pressure. The validity and repeatability of the central arterial pressure waveform estimated from the pressure transfer function after radial artery pressure measurement have been confirmed. ¹⁴ , ¹⁵ The traditional noninvasive method (Figure 2B) estimates the area below the central arterial pressure waveform during the diastolic period as DPTI, and the area below the central arterial pressure waveform in the systolic period as a substitute for SPTI. This method is simple, convenient, and noninvasive, and has been widely validated as an alternative to invasive SEVR. ¹⁶ , ¹⁷ However, this traditional method of evaluating SEVR does not take into account LV pressure during the cardiac cycle, resulting in significant overestimation of SEVR. ¹⁸

Figure 2. Three methods for measurement of the subendocardial viability ratio (SEVR).

SEVR=diastolic pressure time index (DPTI)/systolic pressure time index (SPTI). DPTI and SPTI are, respectively, the areas of blue and yellow in the figure. A, Invasive method. The DPTI is the area between the diastolic aortic pressure curve and the left ventricular (LV) pressure curve, and the SPTI is the area under the systolic LV pressure curve. B, Traditional noninvasive method. The DPTI is the area under the systolic central artery pressure curve, and the SPTI is the area under the systolic central artery pressure curve. C, New noninvasive method. The DPTI is the area under the central pressure curve in diastole minus the estimated isovolumic systolic and isovolumic diastolic LV pressure and LV filling pressure, and the SPTI is the area under the central arterial pressure curve in diastole and isovolumic systole. ICT indicates isovolumic contraction time; IRT, isovolumic relaxation time; and LVET, left ventricular ejection time.

Considering the importance of LV diastolic pressure, LV isovolumic systole, and isovolumic diastole in evaluation of SEVR, ¹⁹ , ²⁰ a new noninvasive method (Figure 2C) has been developed using a verified algorithm to address this limitation. DPTI is estimated as the area under the central pulse pressure curve in the diastolic period minus the area corresponding to the area under the ventricular pressure curve during the isovolumic contraction and isovolumic relaxation phase and the area related to LV diastolic pressure. SPTI is estimated from the area below the systolic phase of the central pulse pressure curve, to which is added the area relating to the isovolumic contraction time. The average difference±SD between SEVR obtained by this new noninvasive method and that obtained by the invasive method is 0±8%, indicating better consistency. ¹⁸ This new method has been applied in clinical research. ²¹ , ²² , ²³

However, the above‐mentioned measurement methods still have limitations and cannot perfectly reflect the balance between myocardial oxygen supply and demand. One limitation is that SEVR is also related to myocardial mass. ²⁴ As myocardial mass increases, as with LV hypertrophy, oxygen demand increases. In recent years, Buckberg and Hoffman have suggested that when calculating SPTI, the original SPTI should be multiplied by the relative LV mass determined by echocardiography to estimate SPTI more accurately. ⁴ However, this method may entail an additional echocardiography examination, and its additional accuracy has not been confirmed. Therefore, it has not yet been applied in the clinical setting. Another limitation is that the supply of oxygen under the endocardium also depends on arterial oxygen saturation. ²⁵ Calculation of SEVR may be affected in the event of severe anemia or hypoxia. ²⁶ Some studies have multiplied SEVR by the arterial oxygen content to obtain the adjusted SEVR corrected by the arterial oxygen concentration. ²³ However, the existing evidence does not indicate that SEVR corrected for arterial oxygen content has better application value, ²⁶ , ²⁷ and the invasive and complex nature of acquisition of the arterial blood oxygen concentration limits its clinical application.

A noninvasive SEVR has better prospects for application because it has the advantages of being noninvasive and easy to perform, having good repeatability, and involving low cost. Currently, the device most commonly used for noninvasive measurement of SEVR is the SphygmoCor device (AtCor Medical, Sydney, Australia), which measures carotid artery pressure. A more recent method for measurement of carotid artery pressure is the PulsePen device (DiaTecne, San Donato Milanese, Italy). ¹⁶ Considering that an operation involving the carotid artery causes discomfort to the patient and measurement of carotid artery pressure requires a relatively high level of skill, the traditional noninvasive SEVR obtained by the SphygmoCor, ²⁸ HEM‐9000AI (Omron Healthcare Co. Ltd., Kyoto, Japan), ²⁹ or IIM‐9000A device (Institute of Intelligent Machines, Hefei, China) ³⁰ by measuring pressure in the radial artery and calculation of pressure conduction function, also has an application in clinical practice (Table 1). In conclusion, although SEVR measurement methods have limitations, they are still valuable tools for evaluation of myocardial perfusion and assessment of cardiovascular risk. Further research is needed to improve the accuracy and clinical application of SEVR measurement methods.

Table 1.

Methods and Devices Commonly Used to Measure the SEVR in Clinical Practice and Their Advantages and Disadvantages

	Device	Cutoff value	Advantages	Disadvantages
Invasive method	Cardiac catheterization	45% 4	Accuracy; other invasive indicators can be obtained at the same time.	Invasive; complicated and cumbersome; difficult to repeat.
Noninvasive method
Traditional
Carotid	SphygmoCor	130% 66	Noninvasive; easy to operate; good repeatability; wide range of applications; low cost.	Results may be overestimated; result is easily disturbed; operation may cause discomfort.
Radial	SphygmoCor, HEM‐9000AI, IIM‐9000A	130% 66	Noninvasive; easy to operate; good repeatability; wide range of applications; low cost; more comfortable and convenient.	Results may be overestimated; result is easily disturbed.
New
Carotid	PulsePen	…*	Noninvasive; easy to operate; good repeatability; wide range of applications; low cost; relatively high accuracy.	Results may be overestimated; result is easily disturbed; Operation may cause discomfort.

^*There is currently no established cutoff value for the new noninvasive method. However, a study has shown a mean±SD difference of 0.4±7.8% in comparison with invasive methods. ¹⁸

SEVR indicates subendocardial viability ratio.

FACTORS AFFECTING SEVR

SEVR is affected by various factors, including sex, age, heart rate, systolic pressure, mean arterial pressure, central pulse pressure, peripheral pulse pressure, ejection time, diastole time, and many biochemical indicators. Several studies have found that SEVR is lower in women than in men. ³¹ , ³² , ³³ , ³⁴ In a study of 350 healthy individuals by Hayward et al, ³⁴ there was no significant sex difference in SPTI in any age group, but DPTI was lower in women compared with men. In a study of 962 healthy adults, Tagawa et al ³³ found that the aortic diastolic pressure attenuation index was significantly higher in women than in men, while SEVR was significantly lower in women. The potential mechanism for the lower SEVR in women may be attributed to the accelerated attenuation of aortic diastolic pressure and a shorter diastolic duration. There is a significant negative correlation between SEVR and age. ³¹ , ³² , ³⁵ Compared with their younger counterparts, elderly individuals have a lower SEVR. Namasivayam et al ³² investigated 3682 healthy individuals and found that their SEVR decreased gradually with age in both sexes, while Gómez‐Sánchez et al ³⁵ found that this change was more pronounced in men. Heart rate also has a significant negative effect on SEVR. SEVR gradually decreases with increasing resting heart rate, ¹⁹ , ³¹ , ³⁶ possibly because of the decrease in myocardial perfusion caused by shortening of the diastolic duration as a result of the increase in resting heart rate. ³⁷ Furthermore, Chemla et al ¹⁹ measured SEVR in 203 healthy and hypertensive elderly individuals and found that SEVR was positively correlated with diastolic time and diastolic/systolic time but not with systolic time, central pulse pressure, mean aortic diastolic pressure, or systolic pressure. However, multiple studies have shown a significant correlation between SEVR and ejection time, mean aortic pressure, central pulse pressure, and central and peripheral systolic BP. ²¹ , ³¹ , ³⁵ , ³⁸ In addition to the above‐mentioned factors, many studies have found that certain laboratory biochemical indicators are related to SEVR, including renal function and urinary albumin levels, ²² , ³⁹ , ⁴⁰ hemoglobin, ²¹ , ⁴¹ C‐reactive protein, ⁴² cholesterol, ⁴³ serum cystatin C, ⁴⁴ urinary liver‐type fatty acid–binding protein, ⁴⁵ serum fibrinogen, ²¹ and troponin I. ⁴¹

POTENTIAL CLINICAL USES OF SEVR

Evaluation of Myocardial Perfusion

Buckberg and Hoffman ⁵ used the microsphere method to measure blood flow in a model of heart disease in anesthetized dogs and found that SEVR was significantly correlated with the LV subendocardial and subepicardial blood perfusion ratio, which represented myocardial perfusion. A lower SEVR indicates lower myocardial perfusion, suggesting the presence of myocardial ischemia. SEVR is now recognized as an index that can evaluate myocardial perfusion and has been used in many clinical studies. ⁴ Dillinger et al ⁴⁶ investigated the effect of ivabradine on myocardial perfusion in patients with stable coronary artery disease and found that it could significantly increase SEVR and improve myocardial perfusion. SEVR has also been used to assess myocardial perfusion in athletes. Knez et al ⁴⁷ performed a comparative study in 44 super‐endurance athletes and normal athletes and found that SEVR was higher in the super‐endurance athletes, indicating better subendocardial myocardial perfusion. Zhang et al ⁴⁸ found that SEVR was significantly higher in basketball players than in controls, indicating that the balance between myocardial oxygen supply and demand is better in athletes than in nonathletes and that exercise may improve myocardial perfusion. Therefore, as an index reflecting the balance between myocardial oxygen supply and demand, SEVR can be used to evaluate myocardial perfusion.

Evaluation of Coronary Microcirculation

Under physiological conditions, coronary blood flow is regulated by coronary artery tension, and impairment of the coronary microcirculation weakens the increase in coronary blood flow regulated by tension. Severe impairment of the coronary microcirculation may cause an imbalance of myocardial oxygen supply and demand, leading to subclinical or clinical myocardial ischemia. ⁴⁹ As an indicator of the balance between myocardial oxygen supply and demand, SEVR can evaluate coronary blood perfusion. Tsiachris et al ⁵⁰ assessed 36 patients with hypertension who had myocardial ischemia without coronary stenosis and found that SEVR decreased by 24.5% in patients with hypertension and reduced coronary flow reserve. Furthermore, coronary flow reserve was positively correlated with SEVR in patients with hypertension who had reduced coronary flow reserve, and SEVR was an independent predictor of coronary flow reserve.

Many studies have used SEVR as a noninvasive surrogate index of coronary microvascular function. ³⁸ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ However, only one study has explored the relationship between SEVR and the function of the coronary microcirculation in the hypertensive population, and the sample size was small. ⁵⁰ SEVR may have the potential to be a reliable tool to evaluate coronary microcirculation, and further research is needed to confirm its utility as a surrogate evaluation index.

Correlation With Arterial Stiffness

Arterial stiffness is associated with an increased risk of cardiovascular events ⁵⁵ , ⁵⁶ and can be evaluated using various indicators, including carotid‐femoral pulse wave velocity (PWV), ⁵⁷ brachial‐ankle pulse wave velocity, ⁵⁸ augmentation index, ⁵⁹ and central BP. ⁶⁰ When arterial stiffness increases, vascular compliance decreases, leading to higher PWV. This results in increased systolic BP in the central aorta, prolonged systolic duration, and significantly shortened diastolic duration, leading to a decrease in SEVR, which indicates impaired myocardial perfusion. ⁶¹ Amah et al ⁶² assessed 213 patients with hypertension and found a significant negative linear correlation between SEVR and carotid‐femoral PWV in patients with extreme dipper hypertension as determined by ambulatory BP monitoring, but the correlation was not significant in patients with dipper hypertension. Anyfanti et al ³⁸ investigated 150 patients with various hypertension phenotypes and found that SEVR was significantly correlated with central systolic BP, peripheral pulse pressure, and the overall arterial compliance index in univariate analysis. After adjusting for heart rate and other factors, the correlation between SEVR and central and peripheral pulse pressure was still significant but there was no correlation between SEVR and carotid‐femoral PWV. Scandale et al ⁶³ studied 248 patients with peripheral artery disease (PAD) and 307 without PAD and found a significant negative correlation of SEVR with augmentation index corrected for heart rate and aortic pulse pressure in those with PAD. In a study of 75 elderly patients by Fantin et al, ²³ there was also a significant negative correlation between SEVR and carotid‐femoral PWV. In summary, there is a close correlation between arterial stiffness and myocardial ischemia. ²⁰ , ⁶⁴

APPLICATIONS OF SEVR IN CVD

Prediction of Cardiovascular Risk

As an indicator of myocardial perfusion, SEVR can effectively predict the risk of future cardiovascular events and death (Table 2). ⁶⁵ In patients with chronic kidney disease (CKD), low SEVR is associated with a significantly increased risk of future cardiovascular events, including cardiovascular death. Di Micco et al ²⁴ investigated 212 patients with asymptomatic CKD and found no significant change in SEVR in patients who survived but a 48% decrease in those who died and that a reduction in SEVR was a significant predictor of cardiovascular mortality. Ekart et al ⁶⁶ followed 98 patients with CKD who were not undergoing dialysis for an average of 5 years and detected a statistically significant increase in cardiovascular mortality in the group with a low SEVR. That study also found that the risk of fatal cardiovascular events was 16 times higher in the low SEVR group after adjusting for confounding variables (P=0.004) and that the risk of combined fatal and nonfatal cardiovascular events was 7 times higher (P=0.009). Similar findings have been reported for populations with hypertension and with diabetes. Aursulesei Onofrei et al ²¹ followed 56 patients with uncomplicated hypertension for 12 months and found that a low SEVR seemed to increase the risk of major cardiovascular events by increasing Systematic Coronary Risk Evaluation Project (SCORE) and Framingham Risk Score values, which have prognostic value in patients with hypertension. Theilade et al ⁶⁷ followed 636 patients with type 1 diabetes for a median of 2.8 years and found that reduction of SEVR predicted the occurrence of end‐stage renal disease and all‐cause mortality during follow‐up. Cardoso et al ⁶⁸ followed 467 patients with type 2 diabetes for a median of 7.3 years and found that SEVR was an independent predictor of nonfatal cardiovascular events, major adverse cardiovascular events, cardiovascular death, and all‐cause mortality (hazard ratio [HR], 0.7–0.8) and improved risk discrimination ability. Drawing from the aforementioned studies, SEVR can predict future cardiovascular risk in specific populations. However, Cardoso et al ⁶⁸ found that SEVR did not predict cardiovascular risk in 532 patients with refractory hypertension who were followed for a median of 4.4 years. In a prospective cohort study by Schott et al ⁶⁹ in which 1414 individuals in the general population with a median age of 67.3 years and an almost equal sex distribution were followed for a median of 10.5 years, there was a significant correlation between SEVR and all‐cause mortality (unadjusted HR, 3.52) and cardiovascular mortality (unadjusted HR, 1.81) in participants younger than 60 years but not in older patients. Furthermore, in subgroup analysis, the correlation was only significant in men. These findings suggest that SEVR may be a predictor of cardiovascular and all‐cause mortality in men younger than 60 years. However, larger studies are needed to explore the ability of SEVR to predict cardiovascular risk in the general population.

Table 2.

Selection of Studies Investigating SEVR as a Potential Predictor of Cardiovascular Risk

Reference	Population			SEVR			Follow‐up, y	Main results
	Men, n (%)	Disease	Age, y	Device	Method	Baseline value, %
Theilade, 2014 67	363 (55)	Type 1 diabetes	54±13	SphygmoCor	Noninvasive traditional	150	2.8	SEVR can predict end‐stage renal disease and death (HR, 2.2; P=0.002).
Di Micco, 2014 24	212 (61)	Stage 3 or 4 CKD	57.9±12.2	NA	NA	133 survivors, 116 nonsurvivors	3	A major reduction of SEVR during the study (third tertile) significantly predicts cardiovascular mortality (P<0.0001).
Aslanger, 2017 65	50 (90)	Coronary artery disease planned for cardiac rehabilitation	54 in the low SEVR group (range, 47–65) and 57 in the high SEVR group (range, 47–68)	SphygmoCor	Noninvasive corrected traditional	145	…	SEVR >145% group showed significant improvements in peak VO2 (P<0.001), percent of predicted peak VO2 (P=0.001), oxygen pulse (πO2) (P<0.001), and circulatory power (P=0.004).
Ekart, 2019 66	98 (NA)	Nondialysis CKD	60 (22–88)	SphygmoCor	Noninvasive traditional	150	5	SEVR <130% can predict fatal cardiovascular events (HR, 16.171; P=0.004) and combined cardiovascular events (HR, 7.472; P=0.009).
Cardoso, 2023 68	467 (36.6)	Type 2 diabetes	59.3±9.3	SphygmoCor	Noninvasive traditional	132	7.3	SEVR is an independent predictor of cardiovascular/mortality outcomes (HR, 0.7–0.8; P<0.05) and improved risk discrimination (relative IDI, 8%–15%; P<0.05).
Cardoso, 2023 68	532 (27.1)	Resistant hypertension	67.5±11.1	SphygmoCor	Noninvasive traditional	147	4.4	SEVR is not an independent predictor of cardiovascular/mortality outcomes (P>0.05).
Schott, 2023 69	1414 (55.1)	General population	67.3	SphygmoCor	Noninvasive traditional	173 with SEVR >130%; 118 with SEVR ≤130%	10.5	SEVR ≤130% can predict cardiovascular (HR, 1.81) and all‐cause mortality (HR, 3.52) in men younger than 60 y.

Data are provided as n(%), mean±SD, or median (interquartile range). CKD indicates chronic kidney disease; HR, hazard ratio; IDI, integrated discrimination index; NA, not available; SEVR, subendocardial viability ratio; and VO₂, oxygen consumption.

Hypertension

Hypertension is a traditional risk factor for CVD. It may lead to increased arterial stiffness and decreased myocardial perfusion, resulting in a significantly increased risk of CVD. London et al ⁷⁰ found that SEVR was significantly lower in patients with essential hypertension than in controls with normotension. SEVR also varies according to the hypertension phenotype. Anyfanti et al ³⁸ investigated 150 untreated patients with suspected hypertension and found that the group with normotension had the highest SEVR, while the true, white‐coat, and occult hypertension groups had similar SEVRs, all of which were lower than SEVR in the group with normotension. Amah et al ⁶² performed ambulatory BP monitoring in 213 patients with treated hypertension and divided them into a dipper hypertension group and a hyperdipper hypertension group. They found that SEVR was significantly reduced in the hyperdipper hypertension group, suggesting that a low SEVR may be related to reduction of nighttime BP. These findings indicate that hypertension can significantly affect SEVR and that SEVR may be a useful indicator for assessing the risk of CVD in patients with hypertension.

Peripheral Artery Disease

Most studies have shown a negative correlation between the severity of PAD and SEVR value. Mosimann et al ⁷¹ investigated 65 patients with stable PAD in Rutherford stages I to III and found a significant correlation of the ankle‐brachial index with SEVR. Scandale et al ⁶³ studied 248 patients with PAD and 307 controls without PAD and found that SEVR correlated with augmentation index and aortic pulse pressure corrected for heart rate in the patients with PAD. This finding indicated that there may be a correlation between arterial stiffness and impaired myocardial perfusion in patients with PAD. Piko et al ⁷² investigated 123 patients with ischemic cardiomyopathy and found that SEVR was associated with ankle‐brachial index in univariate analysis but not in a multiple regression model, which may reflect the fact that the study population did not include patients with confirmed PAD. However, in a more recent study, Kaczmarczyk et al ⁷³ followed up 72 patients with stable PAD in Rutherford stages II or III who underwent percutaneous transluminal angioplasty and reported unexpected results. They found that a higher baseline SEVR was associated with a worse clinical outcome during the 12‐month follow‐up period. The reason for this result is unclear, and further studies in larger sample sizes may be needed to confirm their findings.

Aortic Stenosis

SEVR may be used to evaluate the severity of valvular stenosis and the efficacy and prognosis of aortic valve replacement or plasty in patients with severe aortic stenosis. Müller et al ⁷⁴ investigated 40 patients with severe aortic stenosis who underwent transcatheter aortic valve replacement (TAVR) and found that SEVR was significantly correlated with the peak transvalvular velocity over the aortic valve and medium pressure gradient, which indicate the severity of aortic stenosis. Their study also found that SEVR increased significantly after TAVR. Michail et al ⁷⁵ and Smucker et al ⁷⁶ similarly found that SEVR increased significantly after aortic valve replacement or plasty, suggesting that myocardial perfusion was improved after relief of aortic stenosis. In a study of 90 patients with severe aortic stenosis by Terentes‐Printzios et al, ⁷⁷ SEVR not only increased significantly immediately after TAVR but was also improved further by 1 year of follow‐up. These findings indicate that patients with valvular stenosis not only obtain significant short‐term improvement in myocardial perfusion after treatment but also improve further in the long‐term. Patsalis et al ⁷⁸ studied 167 patients undergoing TAVR and found that the invasive SEVR ≤0.7 calculated by cardiac catheterization could effectively predict death related to paravalvular regurgitation after TAVR.

ASSOCIATION BETWEEN SEVR AND OTHER DISEASES

Endocrine Diseases

SEVR has also demonstrated clinical significance in endocrine diseases, especially diabetes. Patients with diabetes, whether type 1 ⁷⁹ or type 2, ⁸⁰ and even those with prediabetes, ⁸¹ have an SEVR that is lower than that in the population without diabetes. Laugesen et al ⁸² found that after adjusting for age, systolic BP, heart rate, diabetes, smoking, and other factors, SEVR in patients with type 2 diabetes, especially women, was significantly reduced and that SEVR was associated with certain cardiovascular risk markers. Studies by Prince et al ⁴⁰ and Secrest et al ⁸³ found that cardiovascular autonomic neuropathy in patients with type 1 diabetes was associated with a lower SEVR. Patients with metabolic syndrome also tend to have a lower SEVR. ⁸⁴ , ⁸⁵ Fantin et al ²² investigated 55 patients with metabolic syndrome and found that they not only had a lower SEVR after adjustment for confounding factors but they also showed a gradual decrease in SEVR with increases in the components of metabolic syndrome. From the perspective of pathophysiological mechanisms, diabetes and metabolic syndrome are frequently linked with an abnormal coronary microcirculation in the early subclinical stage, which leads to onset and progression of CVD. ⁸⁶ As an index of the functional status of the coronary microcirculation, a low SEVR is often found in patients with diabetes and metabolic syndrome and may indicate an abnormal coronary microcirculation and a potential risk of CVD. Several studies in other endocrine diseases have found that SEVR is lower in patients with primary aldosteronism, ⁸⁷ hyperthyroidism, ⁸⁸ and secondary hyperparathyroidism ⁸⁹ than in controls, indicating potential impaired myocardial perfusion and suggesting a possible increased risk of CVD.

Chronic Kidney Disease

Cardiovascular risk is significantly increased in patients with CKD, regardless of stage. ⁹⁰ SEVR may be a valuable tool for assessment of myocardial perfusion and prediction of cardiovascular risk in patients with CKD. Koskela et al ⁹¹ found that SEVR was significantly lower in patients with stage 5 CKD than in patients with hypertension or in the general population without cardiovascular or renal disease. In patients with CKD, SEVR was significantly correlated with proteinuria level, renal function, and hemoglobin level. Multiple studies by Ekart et al have found that SEVR is reduced in patients with CKD who have higher proteinuria levels and poor renal function but are not undergoing dialysis ³⁹ , ⁹² and in those with a reduced hemoglobin level. ⁴¹ Moreover, as described earlier, SEVR could be a valuable predictor of cardiovascular events and mortality in patients with CKD. ²⁴ , ⁶⁶

SEVR also has potential clinical applications in patients with end‐stage renal disease who require hemodialysis or peritoneal dialysis. Iwashima et al ⁹³ found that SEVR was an independent predictor of hypotension during hemodialysis, while Debowska et al ⁹⁴ found that the increase in SEVR during dialysis was associated with ultrafiltration rate, reduction in water flow, and decline in blood volume. It seems to indicate that SEVR can be used as an evaluation index before hemodialysis. Furthermore, Ekart et al ⁹⁵ found that SEVR was associated with pulmonary edema in patients undergoing peritoneal dialysis, and the more severe the pulmonary edema, the lower the SEVR.

Other Diseases

SEVR is also associated with other diseases, such as rheumatoid arthritis (RA). Sandoo et al ⁴² found that SEVR was associated with markers of disease activity in patients with RA and highly prevalent classical risk factors for CVD. Anyfanti et al ⁴³ found that SEVR was significantly lower in patients with RA than in controls, even in those without hypertension, diabetes, or CVD. This suggests that RA may be an independent risk factor for CVD and that SEVR can be used as an index for evaluation of cardiovascular risk in patients with RA. Moreover, some studies have found that SEVR is reduced in patients with obstructive sleep apnea ⁹⁶ and glaucoma, ⁹⁷ indicating that these diseases may lead to impaired myocardial perfusion and suggesting a potential cardiovascular risk.

ASSESSMENT OF DISEASE SEVERITY AND EFFECTIVENESS OF TREATMENT USING SEVR

SEVR has potential value in evaluation of the severity of a range of diseases and the effectiveness of surgical or medical intervention. As mentioned earlier, SEVR could be used to evaluate the severity of aortic stenosis and the efficacy of TAVR. ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ Siwicka‐Gieroba et al ⁵⁴ investigated 64 patients with severe brain injury and no history of heart disease and found that SEVR was significantly lower in nonsurvivors than in survivors at 24, 72, and 96 hours after admission and that it increased after decompressive craniectomy, suggesting that SEVR may be used to assess brain injury and the response to treatment. A study by Pieringer et al ⁹⁸ found that patients with RA (n=17) and ankylosing spondylitis (n=13) showed a decrease in SEVR after treatment with infliximab, suggesting that infliximab may have a negative impact on myocardial perfusion. Treatment with lipid‐lowering drugs, such as simvastatin and rosuvastatin, led to a significant increase in SEVR, suggesting that these agents may have the potential effect of improving myocardial perfusion. ⁹⁹ , ¹⁰⁰ Drawing from the aforementioned studies, SEVR may also be used to monitor the response to some drug treatments.

SUMMARY AND PROSPECTS

SEVR is a reliable indicator of the balance between oxygen supply and oxygen demand in the subendocardial myocardium. SEVR obtained by noninvasive methods has shown great potential for clinical application. However, a noninvasive SEVR is still affected by many factors and may not accurately reflect myocardial perfusion. It is hoped that in the future, a more precise SEVR can be obtained by further analysis of the pulse wave using artificial intelligence. In addition to evaluating myocardial perfusion, SEVR may also play an important role in evaluating the coronary microcirculation function. It is hoped that using SEVR to evaluate the function of the coronary circulation and myocardial ischemia can be explored further in the future. Although SEVR has thus far been investigated in very few studies and only in specific disease populations, it has demonstrated an ability to predict the likelihood of future CVD and mortality. Larger‐scale, high‐quality clinical studies are now needed to explore the practical value of the SEVR in the primary and secondary prevention of CVDs.

Sources of Funding

This work was supported by the National Key Research and Development Program of China, 2021YFC2500500/2021YFC2500503.

Disclosures

None.