Peak filling rate assessed by myocardial perfusion imaging predicts adverse outcomes in women with chronic coronary syndromes

Introduction

Chronic coronary syndromes (CCS) comprise a heterogeneous spectrum of clinical conditions arising from structural and functional abnormalities of the epicardial coronary arteries and the coronary microcirculation and remain a leading contributor to global morbidity and mortality (1). Large-scale registries and randomized trials consistently identify reduced left ventricular ejection fraction (EF) and increased ischemic burden as strong indicators of adverse cardiovascular risk (1,2). On this basis, many landmark studies have selected reduced EF, commonly defined as below 40%, as a key inclusion criterion.

However, despite the widespread use of systolic function and perfusion abnormalities for risk stratification, a substantial proportion of adverse cardiovascular events still occur in patients with preserved or mildly reduced systolic function (3,4). This limitation is particularly relevant in women, who often present with less obstructive epicardial disease despite persistent symptoms and unfavorable outcomes (5,6). Accumulating evidence indicates that women with suspected coronary syndromes more frequently exhibit coronary vasomotor abnormalities and microvascular dysfunction rather than stenosis (5,6). These pathophysiological characteristics are often insufficiently reflected by conventional measures of systolic performance or angiographic stenosis severity. Thus, reliance on left ventricular EF and ischemic burden alone may underestimate risk in selected patient populations and highlights the need for additional functional parameters that better capture myocardial impairment.

Left ventricular diastolic dysfunction has emerged as an important determinant of progression, and prognosis across a wide range of cardiovascular conditions (7,8). Current clinical guidelines emphasize the role of noninvasive imaging techniques to enhance diagnostic accuracy and improve risk stratification in patients with CCS (1). Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) enables the integrated assessment of myocardial perfusion, ventricular function, and mechanical synchrony. Gated acquisition further allows the derivation of diastolic filling indices, including peak filling rate (PFR), mean filling rate over the first third of the end-systole to end-diastole phase (MFR/3), and time to peak filling from end-systole (TTPF) (9). Despite these capabilities, evidence supporting the prognostic utility of SPECT-derived diastolic parameters remains limited compared with echocardiography and cardiac magnetic resonance imaging (10).

Moreover, whether the prognostic significance of MPI-derived diastolic indices differs between men and women has not been systematically examined. In this context, we performed a comprehensive resting MPI analysis in patients with CCSs and preserved EF, aiming to clarify the sex-specific prognostic value of diastolic functional parameters. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0323/rc).

Methods

Study population and endpoints

We retrospectively analyzed 6,386 patients, who underwent gated resting SPECT MPI between 2016 and 2021, at the First Hospital of Shanxi Medical University. Inclusion criteria: (I) diagnosed or suspected CCS underwent clinically indicated SPECT MPI; (II) presence of echocardiographic left ventricular EF within 3 months; (III) without structural heart disease, severe chronic obstructive pulmonary disease, arrhythmia, respiratory failure, severe infections, cancers, autoimmune diseases, liver and kidney diseases, and other diseases that may affect left ventricular EF significantly. Exclusion criteria: (I) imaging data missing or unanalyzable; (II) diagnosed acute coronary syndromes that followed 6 weeks; (III) echocardiographic left ventricular EF <40%; (IV) without follow-up results (the lost rate: 2.2%). Eventually, this study enrolled 1,446 patients. Of these, 519 (35.9%) patients experienced major adverse cardiovascular events (MACEs) (Figure 1). For this study, we included demographic and clinical information, including age, sex, body mass index (BMI), chest pain symptoms, cardiovascular risk factors such as hypertension, diabetes, dyslipidemia status, family history, and echocardiography-derived left ventricular EF. The aforementioned information was collected within 1 week before or after the MPI. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participants were informed of the purpose of this study by face-to-face conversation or telephone and provided written informed consent. This study was approved by the Institutional Ethics Committee of the First Hospital of Shanxi Medical University (No. 2022-K-128, approval date: September 2022).

Figure 1 Study design. CCS, chronic coronary syndromes; EF, ejection fraction; MPI, myocardial perfusion imaging; PS, propensity score; SPECT, single-photon emission computed tomography; TPD, total perfusion deficit.

Endpoints were identified through an electronic medical records system, phone calls to patients or their relatives, or consultation from their referring physician. The follow-up period for all patients took place from April to August 2022. MACEs were defined as a composite of all-cause mortality, nonfatal myocardial infarction, late revascularization (more than 90 days after index imaging), and cardiovascular re-hospitalization.

Gated resting MPI-derived parameters

Patients underwent gated resting SPECT MPI (Symbia T16, Siemens Medical System, Germany) by injecting 740–925 MBq of ^99mTc-methoxyisobutylisonitril at resting. Eat fatty foods 15–20 minutes before imaging. Placement of electrodes on the patient’s chest for gated information. Patients were imaged in a supine position with arms raised above the head, and the acquisition of 8 min started 60 min after the injection. Images were acquired using a 128×128 matrix, step-and-shoot mode, and 8-frame per cardiac cycle. The ordered subsets expectation maximization algorithm reconstructed all images.

Automatic acquisition of quantitative parameters through quantitative gated SPECT and quantitative perfusion SPECT software (Cedars-Sinai Medical Center, Los Angeles, CA, USA) following SPECT MPI guidelines. Quantitative parameters, including perfusion-related total perfusion deficit (TPD), shape-related end-diastolic volume (EDV) and end-systolic volume (ESV), phase-related entropy, systolic function-related left ventricular EF, and diastolic function-related PFR, MFR/3, and TTPF (one case showed in Figure 2).

Figure 2 Example. (A) Short-axis, horizontal long-axis, and vertical long-axis images of the left ventricle. (B) Polar map. (C) Mechanical synchrony analysis. Left: phase histogram (X-axis: 0°–360° cardiac cycle; Y-axis: proportion of myocardium initiating contraction at each phase angle). Right: global left ventricular thickening curve (X-axis: 0°–360° cardiac cycle; Y-axis: relative myocardial thickening). (D) Time-activity curve. X-axis: time of one cardiac cycle (s). Black curve: ventricular volume (mL, left Y-axis). Purple curve: instantaneous filling/ejection rate (mL/s, right Y-axis). Positive values = diastolic filling; negative values = systolic ejection. The maximum value of the purple waveform represents PFR. (E) The table summarizes the patient’s baseline characteristics and selected semi-quantitative parameters. The patient was a 51-year-old man with no prior medical history who presented with chest tightness. SPECT myocardial perfusion imaging demonstrated reduced perfusion in the mid and basal segments of the inferior wall, posterior wall, and inferoseptal wall of the left ventricle, consistent with right coronary artery involvement. Subsequent coronary angiography during follow-up revealed long-segment disease in the proximal and mid right coronary artery with 90–95% luminal stenosis at the most severe site and impaired distal flow, and three stents were implanted in the right coronary artery. BMI, body mass index; EDV, end-diastolic volume; EF, ejection fraction; EI, eccentricity index; ESV, end-systolic volume; HLA, horizontal long-axis; MFR/3, mean filling rate over the first third of the end-systole to end-diastole phase; PFR, peak filling rate; SPECT, single-photon emission computed tomography; TTPF, time to peak filling from end-systole; VLA, vertical long-axis.

Statistical analysis

Baseline characteristics of the entire cohort were evaluated according to sex. Continuous data were expressed as the mean ± standard deviation (SD) compared using the Student’s t-test and Wilcoxon signed-rank test as appropriate. Comparisons of categorical variables were made using Pearson’s χ² test, and variables were reported as numbers (percentages). We used the receiver operating characteristic (ROC) curves and Youden’s indexes to set the cut-off value for PFR, MFR/3, TTPF, and the combination of these three parameters. The risk of MACE was analyzed using the Kaplan-Meier method and compared by a log-rank test. We performed a Cox regression analysis to identify the factors related to MACE. Before analysis, we checked basic assumptions and tested for multicollinearity for underlying interrelated variables.

To adjust for bias in choices between men and women, we performed propensity score (PS) matching analyses. For all patients, we performed PS matching with a caliper 0.2 and without replacement in a 1:1 ratio based on age, BMI, hypertension, diabetes, dyslipidemia status, and family history of cardiovascular disease. Then, we compared the independent predictors of MACE between men and women, respectively.

In addition, we set two subgroups of TPD ≥10% and EF ≥50%, given the major sex differences in perfusion abnormalities and systolic function. Then, we used PS matching and Cox regression analysis with the same method to determine the reproducibility of the results. Statistical analyses were performed using SPSS (version 26.0, SPSS, Inc, Chicago, IL, USA) and R (V.4.3.0; The R Foundation, www.R-project.org). A 2-sided P<0.05 was considered statistically significant.

Results

Sex differences in baseline characteristics and MPI-derived diastolic function

A total of 1,446 patients with CCS and preserved EF were included, with a mean age of 60.99±12.80 years; 532 were women and 914 were men (Table 1). During follow-up, the overall incidence of MACE did not differ significantly between sexes. However, distinct sex-related differences in clinical profiles were observed. Women were older (P<0.001) and had a lower BMI than men (P=0.003). Hypertension was more prevalent in women (P=0.004), whereas men more frequently had a history of obstructive coronary artery disease (P=0.003), dyslipidemia (P=0.005), and a family history of cardiovascular disease (P=0.012). Furthermore, the rate of revascularizations (including percutaneous coronary intervention or coronary artery bypass grafting) in female subjects was significantly lower compared to male subjects (17.5% vs. 40.2%, P<0.001).

All MPI-derived parameters differed significantly between men and women. Notably, women demonstrated more favorable diastolic filling profiles, characterized by higher PFR and MFR/3, together with shorter TTPF (all P<0.05). These diastolic indices were strongly correlated with one another (all P<0.001, Figure S1), indicating a coherent representation of early diastolic performance.

Clinical outcomes and distribution of MACE

Over a median follow-up of 3.05 (1.71–4.97) years, 519 (35.9%) patients experienced MACE, of which 296 (20.5%) had readmissions,117 (8.1%) had late coronary angiographies, 66 (4.6%) had late revascularization, 7 (0.5%) had a nonfatal myocardial infarction, and 33 (2.3%) had all-cause mortality (12, 0.8%, cardiovascular death). Among patients who developed events, the sex-related distribution of baseline characteristics remained consistent with that of the overall population (Table S1).

Prognostic performance of diastolic parameters

The ROC curve test of diastolic parameters was assessed using the area under the ROC curve as an index performance (Figure S2). The area under the ROC curve were no statistical differences (P=0.956). ROC curve-based best threshold value between MACE vs. non-MACE was defined as the cut-off value. For the clinical endpoint, the cut-off value for estimating MACE was calculated to be <2.1 EDV/s for PFR, <0.68 EDV/s for MFR/3, and >251 ms for TTPF. When patients were classified according to these thresholds, impaired diastolic function was consistently associated with worse event-free survival, supporting the prognostic relevance of early diastolic abnormalities.

Sex-specific predictors of adverse outcomes

The endpoint of the overall population was poorer in men than in women during the follow-up (log-rank P<0.03, Figure S3A). Based on the definition of premature coronary atherosclerotic heart disease, we compared clinical outcomes of 2 age groups. MACE was significantly lower in patients before age 65 years in women or before age 55 years in men (log-rank P<0.001, Figure S3B). Importantly, diastolic dysfunction identified by MPI was associated with increased risk of adverse outcomes across the cohort (log-rank P<0.05, Figure S3C-S3E).

Based on ROC curve results and concerns regarding multicollinearity, only PFR among MPI-derived diastolic parameters was included in the multivariable analysis. After adjustment for demographic factors, cardiovascular risk factors, and MPI-derived parameters, PFR remained independently associated with MACE [hazard ratio (HR), 0.68; 95% confidence interval (CI), 0.51–0.91, P=0.009], alongside age, hypertension, diabetes, and ischemic burden (Table 2).

PS matched and sensitivity analyses

After PS matching, baseline clinical characteristics between men and women were well balanced (P<0.05, Table S2). Despite this adjustment, men continued to experience worse clinical outcomes. In contrast, PFR remained an independent predictor of adverse events exclusively in women (HR, 0.61; 95% CI, 0.39–0.95, P=0.028) (Figure 3). This sex-specific association persisted in multiple sensitivity analyses restricted to patients with higher ischemic burden (Figure S4, HR 0.36) or preserved systolic function (Figure S5, HR 0.57, all P<0.05), confirming the robustness of the finding.

Figure 3 Multivariate Cox regression analysis stratified by sex. Multivariate cox survival analysis of patients after PS matching to balance clinical covariates showed that: (I) advanced age and impaired PFR are independent predictors of MACE in women, (II) advanced age and extent of myocardial ischemia are independent risk factors for MACE in men. *, P<0.05; **, P<0.01; ***, P<0.001. MACE, major adverse cardiovascular event; PFR, peak filling rate; PS, propensity score;

Discussion

This study evaluated the prognostic significance of MPI-derived diastolic parameters in CCS according to sex. Using a comprehensive SPECT MPI approach, we demonstrated a distinct sex-specific association between diastolic function and long-term adverse cardiovascular events. PFR emerged as an independent predictor of MACE exclusively in women. This association remained consistent in the subgroups with significant myocardial ischemia (TPD ≥10%) and preserved systolic function (EF ≥50%). These findings suggest that diastolic dysfunction may represent a distinct risk dimension in women with CCSs, independent of myocardial ischemia and impaired systolic function.

Among women undergoing coronary angiography for persistent ischemic symptoms, up to 62% have no obstructive coronary artery disease and instead exhibit coronary microvascular dysfunction (11,12). Emerging evidence suggests that left ventricular diastolic dysfunction develops early in the course of coronary microvascular dysfunction and may represent one of the earliest manifestations of microvascular ischemic injury (13,14). With advancing age, women are exposed to a cumulative burden of cardiometabolic comorbidities, including hypertension, dyslipidemia, and diabetes mellitus (15,16). Concurrent declines in estrogen withdrawal, increased salt sensitivity, endothelial inflammation, and metabolic dysregulation contribute to oxidative stress, endothelial dysfunction, impaired myocardial energetics, interstitial fibrosis, and cardiomyocyte stiffening, ultimately leading to impaired ventricular relaxation (12,17-19). In addition, women generally have smaller ventricular cavities and appear to rely more heavily on sympathetic activation and concentric remodeling to preserve systolic performance when exposed to comparable or even lower levels of ischemic burden and afterload (20). These adaptive responses may mask underlying microvascular dysfunction and diastolic impairment despite relatively mild ischemia and preserved or enhanced systolic function, thereby increasing susceptibility to heart failure with preserved EF (18,21,22). Collectively, these observations suggest that conventional assessments of ischemic burden and systolic function may not fully capture cardiovascular risk in women. As an imaging marker of ventricular filling dynamics, PFR may reflect the cumulative effects of microvascular dysfunction, myocardial stiffening, and impaired relaxation, providing complementary prognostic information beyond traditional measures of ischemia and systolic performance.

Hypertension further amplified the prognostic relevance of diastolic dysfunction in women. Female patients in this cohort showed a higher prevalence of hypertension, which independently predicted adverse outcomes. Prior studies have demonstrated that women develop concentric remodeling and diastolic impairment at lower blood pressure thresholds (e.g., diastolic blood pressure >85 mmHg and/or systolic blood pressure >100 mmHg) and respond less favorably to antihypertensive treatment (23,24). These findings advocate for stricter blood pressure targets and preferential use of sacubitril/valsartan or sodium-glucose cotransporter-2 inhibitors to target both blood pressure and fibrosis in women with CCS (25,26). Diabetes also emerged as a strong predictor of outcomes, with a more pronounced association in men, which is consistent with the results of a large-scale Swedish study (27). Together, these observations underscore the need for sex-specific interpretation of clinical risk factors and imaging markers.

In agreement with previous studies, women in our cohort were less likely to receive guideline-directed therapies, including pharmacological treatment and coronary revascularization (28). Sex-related differences in socioeconomic factors, clinical presentation, disease awareness, healthcare-seeking behavior, and treatment adherence have all been proposed as contributors to these disparities (29). Therefore, it is possible that the increased event risk observed among women with reduced PFR was partially amplified by lower rates of evidence-based treatment rather than reflecting biological aging alone. However, prior investigations have shown that the greater symptom burden and poorer cardiovascular health status observed in women cannot be fully explained by baseline clinical characteristics, achievement of risk factor targets, antianginal medication use, or completeness of revascularization (30). Women frequently experience adverse cardiovascular outcomes despite a lower prevalence of obstructive coronary artery disease and a lower ischemic burden (31). These observations suggest that additional mechanisms, including coronary microvascular dysfunction, ventricular stiffening, and impaired diastolic reserve, may contribute to the excess risk observed in women (21). Within this context, reduced PFR may identify a subgroup of women with heightened myocardial vulnerability that is not adequately captured by conventional treatment metrics or measures of ischemic severity. These findings underscore the importance of optimizing guideline-directed medical therapy in women while also highlighting the need for further investigation into sex-specific mechanisms underlying cardiovascular risk. Future studies with larger cohorts should evaluate the interaction between treatment target achievement, diastolic dysfunction, and long-term outcomes in women with CCSs (28).

Gated SPECT MPI provides a reproducible and noninvasive assessment of perfusion and ventricular function within a single examination. 1.7–2.6 EDV/s is usually an anomaly threshold for PFR and can sensitively represent global left ventricular diastolic dysfunction (32,33). It should be noted that these reference ranges were primarily derived from gated resting MPI protocols acquired with 16 frames per gated scan. In contrast, our study employed an 8-frame scan acquisition. Several comparative studies have demonstrated strong correlations between 8-frame and 16-frame measurements of both systolic and diastolic parameters despite the presence of systematic differences (34,35). Owing to its lower temporal resolution, 8-frame acquisition may underestimate PFR relative to 16-frame imaging. Importantly, the previously reported range of 1.7–2.6 EDV/s was established to identify diastolic dysfunction, whereas the threshold identified in the present study (<2.1 EDV/s) was derived from outcome-based analyses. Thus, these thresholds serve different clinical purposes and are not directly interchangeable. Importantly, the use of uniform cut-off values for PFR without consideration of age or sex may limit diagnostic accuracy. Although Kaplan-Meier analyses based on fixed thresholds may underestimate risk in certain subgroups, the prognostic value of PFR as a continuous variable remained robust in multivariable models. This highlights the need for sex- and age-adapted reference ranges to balance sensitivity and specificity.

Current practice has emphasized the potential value of stress-induced diastolic impairment; however, accumulating evidence indicates that resting diastolic indices also carry prognostic information (7). Xu et al. reported that resting PFR (HR, 2.766; 95% CI, 1.244–6.150, P=0.013), rather than stress-related changes, independently predicted heart failure events (36), supporting the concept that baseline diastolic dysfunction reflects a chronic myocardial phenotype associated with adverse remodeling. Our findings are concordant with this observation, as resting PFR remained an independent predictor of MACE after comprehensive adjustment and across multiple sensitivity analyses, particularly in women. Taken together, these findings support incorporating resting PFR into routine SPECT MPI interpretation and reinforce its role as a clinically meaningful marker of diastolic vulnerability, particularly in women with CCS and preserved EF.

Notably, diastolic function can also be assessed by echocardiography and cardiac magnetic resonance imaging. In 2016, the American Society of Echocardiography and the European Association of Cardiovascular Imaging simplified the multiparametric echocardiographic method to evaluate and grade diastolic function (37). In the majority of studies, by a step-wise approach diastolic function grade has achieved remarkable success (37). However, the diagnosis of diastolic dysfunction can be challenging and insufficient because echocardiography-derived cardiac motion and hemodynamic indices can be significantly affected by other pathological features. Other noninvasive or invasive examinations appear to be necessary to define the etiology. cardiac magnetic resonance imaging is the gold standard for most parameters in the latest heart failure with preserved EF guidelines (10). But large-scale studies are still needed to validate the effectiveness of novel techniques and to establish standardized scan layouts. Furthermore, the analysis of phase, right ventricle function, myocardial motion, and thickening of SPECT MPI has also received increasing attention because it partially explains the etiology of diastolic dysfunction, including but not limited to myocardial scar, right ventricle dysfunction, pulmonary hypertension, and cardiac hypertrophy, and provides prognostic information (38-40). Attention should be paid to the differences in parameter thresholds caused by different scanning protocols.

Limitations

Several limitations should be acknowledged. First, this was a retrospective, single-center study, which may limit generalizability. To mitigate potential selection bias, we applied PS matching and multivariable adjustment; nevertheless, residual confounding cannot be completely excluded. Second, information on comprehensive echocardiographic parameters, socioeconomic status, educational background, and lifestyle factors was unavailable and therefore not included in the analyses, although these variables may influence long-term outcomes. Third, the discriminative performance of individual MPI-derived diastolic parameters on ROC analysis was modest, likely reflecting the multifactorial nature of adverse events in patients with CCS. Based on ROC results, prior literature, and concerns regarding multicollinearity, PFR was selected as the representative diastolic index (36,41,42). While the 8-frame per gated scan protocol may underestimate PFR, it remains widely used in routine clinical practice. Further research is needed to clarify the prognostic value and thresholds of parameters obtained from the 16-frame acquisition protocol. Despite these limitations, the consistency of findings across adjusted models, propensity-matched cohorts, and sensitivity analyses supports the robustness of our conclusions.

Conclusions

In patients with CCS without reduced EF, PFR derived from MPI demonstrates a clear sex-specific prognostic profile, with independent predictive value confined to women. Incorporation of diastolic functional assessment into routine SPECT interpretation may therefore improve risk stratification in this population. Our results also suggest that uniform diagnostic thresholds may not adequately capture sex-related differences in myocardial function. Prospective studies across different imaging platforms are warranted to validate sex-adapted thresholds and to determine whether sex-specific management strategies can translate into improved clinical outcomes.

Acknowledgments

The authors extend their sincere appreciation to their colleagues in the Department of Nuclear Medicine for their invaluable assistance in data collection and curation.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0323/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0323/dss

Funding: This work was supported by grants from the National Natural Science Foundation of China (Nos. U22A6008 and 82027804), the Shanxi Province Higher Education “Billion Project” Science and Technology Guidance Project, and the Research Project Supported by Shanxi Scholarship Council of China (No. 2024-147).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0323/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of the First Hospital of Shanxi Medical University (No. 2022-K-128). All participants were informed of the study objectives and provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J 2024;45:3415-537. [Crossref] [PubMed]
2. Kerneis M, Cosentino F, Ferrari R, Georges JL, Kosmachova E, Laroche C, Maggioni AP, Rittger H, Steg PG, Maczynska J, Tavazzi L, Valgimigli M, Gale CP, Komajda MCICD investigators group. Impact of chronic coronary syndromes on cardiovascular hospitalization and mortality: the ESC-EORP CICD-LT registry. Eur J Prev Cardiol 2022;29:1945-54. [Crossref] [PubMed]
3. Gebhard C, Maredziak M, Messerli M, Buechel RR, Lin F, Gransar H, et al. Increased long-term mortality in women with high left ventricular ejection fraction: data from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) long-term registry. Eur Heart J Cardiovasc Imaging 2020;21:363-74. [Crossref] [PubMed]
4. Shi Y, Ma J, Li S, Liu C, Liu Y, Chen J, Liu N, Liu S, Huang H. Sex difference in human diseases: mechanistic insights and clinical implications. Signal Transduct Target Ther 2024;9:238. [Crossref] [PubMed]
5. Shi K, Zhang G, Fu H, Li XM, Jiang L, Gao Y, Qian WL, Shen LT, Xu HY, Li Y, Guo YK, Yang ZG. Sex differences in clinical profile, left ventricular remodeling and cardiovascular outcomes among diabetic patients with heart failure and reduced ejection fraction: a cardiac-MRI-based study. Cardiovasc Diabetol 2024;23:266. [Crossref] [PubMed]
6. Norris CM, Yip CYY, Nerenberg KA, Clavel MA, Pacheco C, Foulds HJA, et al. State of the Science in Women’s Cardiovascular Disease: A Canadian Perspective on the Influence of Sex and Gender. J Am Heart Assoc 2020;9:e015634. [Crossref] [PubMed]
7. Litwin SE, Zile MR. Should We Test for Diastolic Dysfunction? How and How Often? JACC Cardiovasc Imaging 2020;13:297-309.
8. Kosmala W, Marwick TH. Asymptomatic Left Ventricular Diastolic Dysfunction: Predicting Progression to Symptomatic Heart Failure. JACC Cardiovasc Imaging 2020;13:215-27. [Crossref] [PubMed]
9. Garcia EV, Slomka P, Moody JB, Germano G, Ficaro EP. Quantitative Clinical Nuclear Cardiology, Part 1: Established Applications. J Nucl Med 2019;60:1507-16. [Crossref] [PubMed]
10. Pieske B, Tschöpe C, de Boer RA, Fraser AG, Anker SD, Donal E, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J 2019;40:3297-317. [Crossref] [PubMed]
11. Shaw LJ, Merz CN, Pepine CJ, Reis SE, Bittner V, Kip KE, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Sopko G. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women’s Ischemia Syndrome Evaluation. Circulation 2006;114:894-904. [Crossref] [PubMed]
12. Patel N, Greene N, Guynn N, Sharma A, Toleva O, Mehta PK. Ischemia but no obstructive coronary artery disease: more than meets the eye. Climacteric 2024;27:22-31. [Crossref] [PubMed]
13. Sušić L, Maričić L, Vincelj J, Vadoci M, Sušić T. Understanding the association between endothelial dysfunction and left ventricle diastolic dysfunction in development of coronary artery disease and heart failure. Acta Biomed 2021;92:e2021204. [Crossref] [PubMed]
14. Takahashi T, Wei J, Iribarren AC, Gulati M, Cook-Wiens G, Nelson MD, Sharif B, Handberg EM, Anderson RD, Petersen J, Berman DS, Pepine CJ, Merz CNB. Rationale and design of the women’s ischemia syndrome evaluation mechanisms of coronary microvascular dysfunction leading to preheart failure with preserved ejection fraction (WISE Pre-HFPEF). Am Heart J 2025;284:47-56. [Crossref] [PubMed]
15. Elboudwarej O, Wei J, Darouian N, Cook-Wiens G, Li Q, Thomson LEJ, Petersen JW, Anderson RD, Mehta P, Shufelt C, Berman D, Azarbal B, Samuels B, Handberg E, Sopko G, Pepine CJ, Bairey Merz CN. Maladaptive left ventricular remodeling in women: An analysis from the Women’s Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study. Int J Cardiol 2018;268:230-5. [Crossref] [PubMed]
16. Brendel JM, Mayrhofer T, Karády J, Kolossváry M, Kerkovits NM, Langenbach IL, Jung M, Kelsey MD, Langenbach MC, Pagidipati N, Shah SH, Lu MT, Ferencik M, Douglas PS, Foldyna B. Risk in Women Emerges at Lower Coronary Plaque Burden Than in Men: PROMISE Trial. Circ Cardiovasc Imaging 2026;19:e019011. [Crossref] [PubMed]
17. Hahn VS, Knutsdottir H, Luo X, Bedi K, Margulies KB, Haldar SM, Stolina M, Yin J, Khakoo AY, Vaishnav J, Bader JS, Kass DA, Sharma K. Myocardial Gene Expression Signatures in Human Heart Failure With Preserved Ejection Fraction. Circulation 2021;143:120-34. [Crossref] [PubMed]
18. Mehta PK, Huang J, Levit RD, Malas W, Waheed N, Bairey Merz CN. Ischemia and no obstructive coronary arteries (INOCA): A narrative review. Atherosclerosis 2022;363:8-21. [Crossref] [PubMed]
19. Sorop O, Heinonen I, van Kranenburg M, van de Wouw J, de Beer VJ, Nguyen ITN, et al. Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. Cardiovasc Res 2018;114:954-64. [Crossref] [PubMed]
20. Haider A, Bengs S, Portmann A, Gebert P, Rossi A, Mikail N, et al. Sex-specific cardiac ageing and sympathetic compensation: a translational study. Eur Heart J 2025;ehaf922.
21. Brown K, Xu K, Hahn RT, Pibarot P, Leipsic JA, Ma Y, Clavel MA, Elmariah S, Weissman NJ, Asch FM, Khalique OK, Leon MB, Cremer PC, Lindman BR, Alu MC, Douglas PS, Daubert MA. Impact of Coronary Artery Disease on Cardiovascular Outcomes Differs Between Men and Women With Severe Aortic Stenosis. Circ Cardiovasc Interv 2025;18:e014999. [Crossref] [PubMed]
22. Nelson MD, Gomez-Arnold JM, Wei J, Lauzon M, Zamani SK, Maughan J, Obrutu O, Shufelt C, Handberg E, Pepine C, Bairey Merz CN. Contributors to high left ventricular ejection fraction in women with ischemia and no obstructive coronary artery disease: Results from the Women’s Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) Study. Am Heart J 2024;278:41-7. [Crossref] [PubMed]
23. Izzo R, Losi MA, Stabile E, Lönnebakken MT, Canciello G, Esposito G, Barbato E, De Luca N, Trimarco B, de Simone G. Development of Left Ventricular Hypertrophy in Treated Hypertensive Outpatients: The Campania Salute Network. Hypertension 2017;69:136-42. [Crossref] [PubMed]
24. Lønnebakken MT, Izzo R, Mancusi C, Gerdts E, Losi MA, Canciello G, Giugliano G, De Luca N, Trimarco B, de Simone G. Left Ventricular Hypertrophy Regression During Antihypertensive Treatment in an Outpatient Clinic (the Campania Salute Network). J Am Heart Assoc 2017;6:e004152. [Crossref] [PubMed]
25. Omar M, Jensen J, Ali M, Frederiksen PH, Kistorp C, Videbæk L, Poulsen MK, Tuxen CD, Möller S, Gustafsson F, Køber L, Schou M, Møller JE. Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial. JAMA Cardiol 2021;6:836-40. [Crossref] [PubMed]
26. Salah HM, Fudim M, Al’Aref SJ, Khan MS, Almarzooq ZI, Devabhaktuni SR, Mentz RJ, Butler J, Greene SJ. Meta-Analysis of Efficacy of Sacubitril/Valsartan in Heart Failure With Preserved Ejection Fraction. Am J Cardiol 2021;145:165-8. [Crossref] [PubMed]
27. Stolfo D, Uijl A, Vedin O, Strömberg A, Faxén UL, Rosano GMC, Sinagra G, Dahlström U, Savarese G. Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum: Phenotyping, and Prognostic and Therapeutic Implications. JACC Heart Fail 2019;7:505-15. [Crossref] [PubMed]
28. Reynolds HR, Cyr DD, Merz CNB, Shaw LJ, Chaitman BR, Boden WE, et al. Sex Differences in Revascularization, Treatment Goals, and Outcomes of Patients With Chronic Coronary Disease: Insights From the ISCHEMIA Trial. J Am Heart Assoc 2024;13:e029850. [Crossref] [PubMed]
29. Gaudino M, Di Franco A, Cao D, Giustino G, Bairey Merz CN, Fremes SE, Kirtane AJ, Kunadian V, Lawton JS, Masterson Creber RM, Sandner S, Vogel B, Zwischenberger BA, Dangas GD, Mehran R. Sex-Related Outcomes of Medical, Percutaneous, and Surgical Interventions for Coronary Artery Disease: JACC Focus Seminar 3/7. J Am Coll Cardiol 2022;79:1407-25. [Crossref] [PubMed]
30. Grodzinsky A, Cho YJ, Jones PG, Shaw L, Merz CNB, Boden W, Stone G, Mark DB, Spertus JA, Maron DJ, Hochman JS, Reynolds HR. Sex Differences in Coronary Disease Health Status Outcomes: the ISCHEMIA Trial. Eur Heart J Qual Care Clin Outcomes 2026;qcag052.
31. Ikeda K, Munhoz D, Brouwers S, Sonck J, Matsuo H, Shinke T, et al. Sex Differences in Atherosclerotic Coronary Artery Disease Patterns. J Am Heart Assoc 2025;14:e039496. [Crossref] [PubMed]
32. Akincioglu C, Berman DS, Nishina H, Kavanagh PB, Slomka PJ, Abidov A, Hayes S, Friedman JD, Germano G. Assessment of diastolic function using 16-frame 99mTc-sestamibi gated myocardial perfusion SPECT: normal values. J Nucl Med 2005;46:1102-8.
33. Malek H, Samiei N, Yaghoobi N, Bavaghar N, Firoozabadi H, Rastgou F, Bakhshande H, Rajabi AB, Hedayati R. Assessment of LV diastolic dysfunction in myocardial perfusion imaging: a correlative study with transthoracic echocardiography. Nucl Med Commun 2021;42:979-83. [Crossref] [PubMed]
34. Mazinani M, Tajik-Mansoury MA, Sabour M, Jadidi M. A comparison of 8 and 16 frames gated SPECT imaging for determination of left ventricular volumes and ejection fraction: effects of gender and myocardial counts. Int J Cardiovasc Imaging 2021;37:2079-84. [Crossref] [PubMed]
35. Ansari M, Hashemi H, Soltanshahi M, Qutbi M, Azizmohammadi Z, Tabeie F, Javadi H, Jafari E, Barekat M, Assadi M. Factors That Impact Evaluation of Left Ventricular Systolic Parameters in Myocardial Perfusion Gated SPECT with 16 Frame and 8 Frame Acquisition Models. Mol Imaging Radionucl Ther 2018;27:55-60. [Crossref] [PubMed]
36. Xu B, Liu L, Abdu FA, Yin G, Mohammed AQ, Xu S, Lv X, Fan R, Feng C, Shi T, Zhang W, Xu Y, Cai H, Yu F, Che W. Prognostic Value of Diastolic Dysfunction Derived From D-SPECT in Coronary Artery Disease Patients With Normal Ejection Fraction. Front Cardiovasc Med 2021;8:700027. [Crossref] [PubMed]
37. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277-314. [Crossref] [PubMed]
38. Alexanderson-Rosas E, Espinola-Zavaleta N, Garcia EV, Peix A, Massardo T, Pabon LM, Antonio-Villa NE, Carvajal-Juarez I, Mesquita CT, Jimenez-Heffernan A, Patel C, Karthikeyan G, Kumar A, Butt S, Kalaivani M, Marin V, Morozova O, Paez D. Diastolic dyssynchrony assessment by gated myocardial perfusion-SPECT in subjects who underwent cardiac resynchronization therapy. J Nucl Cardiol 2021;28:1413-21. [Crossref] [PubMed]
39. Zhu JY, Wang XC, Huang N, Li XQ, Cheng Y, Wu ZF, Li YY, Wu P, Li L, Wei H, Li SJ, Cao JM. Prognostic value of summed motion score assessed by gated SPECT myocardial perfusion imaging in patients with dilated cardiomyopathy. Front Cardiovasc Med 2023;10:1144333. [Crossref] [PubMed]
40. Zhao C, Shi S, He Z, Malhotra S, Wang C, Zhao Z, Li X, Wen H, Tang S, Zhou Y, Zhou W. Spatial-temporal V-Net for automatic segmentation and quantification of right ventricle on gated myocardial perfusion SPECT images. Med Phys 2023;50:7415-26. [Crossref] [PubMed]
41. Gimelli A, Liga R, Bottai M, Pasanisi EM, Giorgetti A, Fucci S, Marzullo P. Diastolic dysfunction assessed by ultra-fast cadmium-zinc-telluride cardiac imaging: impact on the evaluation of ischaemia. Eur Heart J Cardiovasc Imaging 2015;16:68-73. [Crossref] [PubMed]
42. Nitta K, Kurisu S, Sumimoto Y, Ikenaga H, Ishibashi K, Fukuda Y, Kihara Y. Diagnostic value of peak filling rate derived from ECG-gated myocardial perfusion SPECT for detecting myocardial ischaemia in patients with non-obstructive coronary artery disease. Acta Cardiol 2020;75:37-41. [Crossref] [PubMed]