Coronary Flow Velocity Reserve Research Articles

CONTRAST STRESS ECHOCARDIOGRAPHY FINDINGS IN MYOCARDIAL BRIDGING COMPARED TO NORMAL CORONARY COURSE, WITH AND WITHOUT CORONARY ARTERY DISEASE

Abstract Background Myocardial bridging (MB) correlation with ischemia remains a diagnostic challenge. There is a lack of studies that have assessed MB using contrast stress echo and compared the findings with those in patients demonstrating a normal coronary course, with or without obstructive coronary artery disease (CAD). Methods We evaluated all consecutive patients who underwent contrast stress echocardiography and coronary computed tomography angiography (CCTA) due to suspected symptoms of CAD within 3 months in Parma Hospital. Coronary computed tomography angiography served as the reference standard for detecting MB and obstructive CAD. The patients were divided into 3 groups: (1) MB and no evidence of obstructive CAD (MB group, N = 64), (2) no evidence of obstructive CAD or MB (NoCAD group, N = 135), (3) obstructive CAD without MB (CAD group, N = 68). Results The coronary flow velocity reserve in the LAD (CFVR–LAD) was reduced in the MB and CAD groups, measuring 1.91 ± 0.21 and 1.82 ± 0.28, respectively, whereas it was 2.27 ± 0.34 in the NoCAD group (P < .001). The MB and CAD groups exhibited a higher prevalence of reversible myocardial perfusion defects (rMPDs) compared to the NoCAD group (57.8% vs 64.7% vs 3.7%, P < .001). Reversible wall motion abnormalities were frequently observed in the CAD group and rarely found in the MB and NoCAD groups (47.1% vs 18.8% vs 4.4%, P < .001). In multivariable analyses, the presence of MB was independently associated with reduced CFVR–LAD (odds ratio = 14.55; 95% CI, 6.84–30.93; P < .001) and the presence of rMPD (odds ratio = 37.96; 95% CI, 13.49–106.84; P < .001). Patients with deep MB (>2 mm depth) and very deep MB (≥5 mm depth) exhibited significantly greater CFVR–LAD reduction and rMPD than those with superficial MB. Conclusions Myocardial bridging is capable of inducing rMPD and reducing CFVR–LAD similar to obstructive CAD. The depth of the MB correlates with the abnormalities found in the stress echo evaluation. Contrast stress echo may serve as a valuable noninvasive tool for evaluating patients with MB.

Female mice with menopause exhibit coronary microvascular disease

Menopause is a natural process as women age, and women with menopause are at higher risk of having cardiovascular diseases than men at the same age. Coronary microvascular disease (CMD) is one of the causes of angina, and the prevalence of CMD is higher in women than in men, and more postmenopausal women have CMD than premenopausal women. However, the causes of CMD in postmenopausal women are not clear. In this study, we investigate whether and how menopause leads to coronary microvascular disease in female mice. Menopausal mice were generated by administering a 20-day injection of 4-Vinylcyclohexene diepoxide (VCD, 160 mg/kg/day in sesame oil, i.p.). VCD gradually destroys primordial and primary follicles in ovaries and leads to ovary failure while keeping the ovary tissues intact; this model is close to the natural progression of human menopause. The vehicle, sesame oil, was administered in control mice. Coronary flow velocity reserve (CFVR) was measured to assess coronary microvascular function. Isometric tension was conducted in third-order coronary arteries (CAs). Capillary density was measured and compared in the left ventricle. Experiments were performed at 6 weeks (perimenopause period) and 8 weeks (post-menopause period) after the injection of VCD or vehicle in female mice. There was no significant difference in CFVR between VCD-injected mice and vehicle-injected mice 6 weeks after the injection. However, at 8 weeks after the injection, VCD-injected mice exhibited a significant decline in CFVR compared to the control mice. Coronary microvascular dysfunction can be driven by attenuated vascular relaxation in small coronary arteries and/or capillary rarefaction. We first conducted isometric tension and found that endothelium-dependent relaxation was significantly attenuated in VCD-injected mice at 8 weeks after the injection, but not at 6 weeks, compared to the controls. There was no significant difference in EC-independent relaxation between the two groups at any age. Interestingly, there was no significant difference in capillary density between VCD-injected mice and vehicle-injected mice at 6 weeks and 8 weeks after the injection. Postmenopausal mice, but not perimenopausal mice, develop CMD due to attenuated endothelium-dependent relaxation. This suggests that improving endothelium-dependent relaxation is the potential mechanism to treat CMD in postmenopausal women. Supported by NIH R01HL142214 and DOD W81XWH2110472. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Coronary Microvascular Dysfunction in Acute Cholestasis-Induced Liver Injury.

Previous studies have shown cardiac abnormalities in acute liver injury, suggesting a potential role in the associated high mortality. We designed an experimental study exploring the short-term effects of acute cholestasis-induced liver injury on cardiac function and structure in a rodent bile duct ligation (BDL) model to elucidate the potential interplay. Thirty-seven male Sprague-Dawley rats were subjected to BDL surgery (n = 28) or served as sham-operated (n = 9) controls. Transthoracic echocardiography, Doppler evaluation of the left anterior descending coronary artery, and myocardial contrast echocardiography were performed at rest and during adenosine and dobutamine stress 5 days after BDL. Immunohistochemical staining of myocardial tissue samples for hypoxia and inflammation as well as serum analysis were performed. BDL animals exhibited acute liver injury with elevated transaminases, bilirubin, and total circulating bile acids (TBA) 5 days after BDL (TBA control: 0.81 ± 2.54 µmol/L vs. BDL: 127.52 ± 57.03 µmol/L; p < 0.001). Concurrently, cardiac function was significantly impaired, characterized by reduced cardiac output (CO) and global longitudinal strain (GLS) in the echocardiography at rest and under pharmacological stress (CO rest control: 120.6 ± 24.3 mL/min vs. BDL 102.5 ± 16.6 mL/min, p = 0.041; GLS rest control: -24.05 ± 3.8% vs. BDL: -18.5 ± 5.1%, p = 0.01). Myocardial perfusion analysis revealed a reduced myocardial blood flow at rest and a decreased coronary flow velocity reserve (CFVR) under dobutamine stress in the BDL animals (CFVR control: 2.1 ± 0.6 vs. BDL: 1.7 ± 0.5 p = 0.047). Immunofluorescence staining indicated myocardial hypoxia and increased neutrophil infiltration. In summary, acute cholestasis-induced liver injury can lead to impaired cardiac function mediated by coronary microvascular dysfunction, suggesting that major adverse cardiac events may contribute to the mortality of acute liver failure. This may be due to endothelial dysfunction and direct bile acid signaling.

Concomitant amyloidosis is the primary cause of endothelial and coronary microvascular dysfunction in carpal tunnel syndrome

Study objectivesPatients with carpal tunnel syndrome (CTS) show manifestations of arterial abnormalities, including carotid intimal thickening and increased vascular stiffness. As carpal tunnel syndrome is associated with amyloidosis, we hypothesized that previously observed abnormalities can largely be related with concomitant amyloidosis rather than CTS itself. DesignProspective observational study. SettingMedeniyet University Goztepe Hospital Participants61 patients with CTS (of whom 32 had biopsy-proven amyloidosis) and 36 healthy controls. InterventionsSubjects underwent ultrasound examinations for the measurement of coronary flow velocity reserve (CFVR), flow-mediated vasodilatation (FMD) and carotid intimal-media thickness (CIMT). Main outcome measuresComparison of CFVR, FMD and CIMT in CTS patients with or without amyloidosis. ResultsPatients with either CTS or CTS with concomitant amyloidosis (CTS-A) had significantly lower FMD (9.7 % ± 4.0 % in CTS and 10.3 % ± 4.6 % in CTS-A groups, p < 0.05 for both) and CFVR (2.4 (2.1–2.8) in CTS and 1.8 (1.6–2.1) in CTS-A groups, p < 0.001 for both) as compared to controls, while CIMT was only increased in CTS-A group (0.70 (0.60–0.80), p < 0.001). The reduction in CFVR was solely related to an increased basal flow velocity in CTS patients while there was also a reduced hyperemic flow velocity in patients with CTS-A. ConclusionMost arterial phenomena in CTS patients could be attributable to concomitant amyloidosis, although endothelial dysfunction was present even in patients with CTS without amyloidosis.

Coronary myocardial bridge imaging by stress-echocardiography and coronary adipose tissue attenuation on computed tomography angiography

Myocardial bridging is a congenital defect characterized by the course of a segment of the coronary arteries within the heart muscle most frequently affecting the left anterior descending coronary artery (LAD). Patients with myocardial bridging may present with episodes of exertional anginal chest pain. The gold standard for non-invasive diagnosis of myocardial bridge is coronary computed tomography angiography (CCTA), which allows anatomical characterization. Coronary flow velocity reserve (CFVR) of the LAD on stress echocardiography (SE) can play an important role in the diagnosis of myocardial bridging of the LAD; a relationship between CVFR-LAD and coronary inflammation by estimating the attenuation of peri-coronary adipose tissue at CCTA has been demonstrated in patients without obstructive ischaemic heart disease. Therefore, coronary inflammation localized to the LAD has been assessed in patients diagnosed with myocardial bridging of the LAD and previous SE with CFVR-LAD in a case series.

Feasibility of coronary flow velocity reserve during semi-supine exercise echocardiography: a single center study of 3,014 patients

Aim: There is a lack of studies that analyzed factors influencing on feasibility of coronary flow velocity reserve (CFVR) during exercise stress echocardiography (SE). The aim of the study was to define the feasibility of assessment of CFVR during exercise through SE depending on experience, techniques, and clinical factors. Methods: This is a single-center study. SE was performed using three generations of echo systems in five consecutive cohorts of patients by experienced and novice specialists. All patients performed a supine bicycle testing. CFVR was calculated in the middle/middle-distal parts of the left anterior descending artery (LAD). Three different adjustment settings were used for LAD visualization. Results: The study included 3,014 patients (59 years old ± 11 years old, 54% males). Age [odds ratio (OR) 0.98, 95% confidence interval (CI) 0.96–0.99, P &lt; 0.01], body mass index (BMI; OR 0.95, 95% CI 0.91–0.98, P &lt; 0.003), rest heart rate (OR 0.98, 95% CI 0.97–0.99, P &lt; 0.0005) and doctor’s experience (OR 2.7, 95% CI 1.57–4.53, P &lt; 0.0003) were independent factors that influence on feasibility. The feasibility of CFVR assessment during exercise SE in the whole population by experienced doctors was 89.4%. The feasibility of CFVR assessment of LAD in obese patients performed by experienced doctors using modern echo machines and new techniques was high (86.0%). Conclusions: Coronary artery velocity reserve during supine exercise SE is a feasible, non-invasive available tool. The new generation echo machine and the new techniques provide a good feasibility of CFVR assessment, even in novice doctors. Despite a lower level of possibility to assess CFVR in obese patients or with a higher resting heart rate, this method is feasible in a great majority of such patients.

Coronary Flow Velocity Reserve Declines After Anthracycline Therapy in Breast Cancer Patients

Anthracycline therapy (ANT) is associated with cancer therapy-related cardiac dysfunction. Coronary flow velocity reserve (CFVR) has shown prognostic utility in non-cancer cohorts, but no data have been obtained in a cardio-oncology setting. We investigated the acute effect of ANT on CFVR in breast cancer patients. A total of 12 female breast cancer patients undergoing ANT had pre- and post-ANT CFVR assessment. A significant decline in CFVR occurred (baseline: 2.66 ± 0.41 vs post-ANT: 2.47 ± 0.37, P = 0.016). This prospective study is the first to identify ANT-related coronary physiology changes in humans. Further studies are required to determine their clinical significance.

Noninvasive transthoracic doppler flow velocity and invasive thermodilution to assess coronary flow reserve.

Coronary flow reserve (CFR) provides prognostication and coronary physiological information, including epicardial coronary stenosis and microvascular function. The relationship between stress transthoracic Doppler echocardiography (TDE)-derived coronary flow velocity reserve (CFRS-TDE) and thermodilution-derived coronary flow reserve (CFRthermo) before and after elective percutaneous coronary intervention (PCI) remains unclear. This single-center prospective registry study evaluated patients who underwent fractional flow reserve (FFR)-guided elective PCI for left anterior descending artery (LAD) lesions with wire-based invasive physiological measurements and pre- and post-PCI stress TDE examinations. A total of 174 LAD lesions from 174 patients were included in the final analysis. A modest correlation was detected between the pre-PCI CFRS-TDE and the pre-PCI CFRthermo (r=0.383, P<0.001). The frequently used CFRS-TDE threshold of 2.0 corresponded to a pre-PCI CFRthermo of 2.18. Pre-PCI CFRS-TDE underestimated pre-PCI CFRthermo [1.89 (1.44-2.31) vs. 2.05 (1.38-2.93), P<0.001]. Both CFRS-TDE and CFRthermo increased significantly post-PCI [pre-PCI CFRS-TDE 1.89 vs. post-PCI CFRS-TDE 2.33, P<0.001; pre-PCI CFRthermo 2.05 (1.38-2.93) vs. post-PCI CFRthermo 2.59 (1.63-3.55), P<0.001]. In contrast, there was no significant relationship between changes in CFRS-TDE and changes in CFRthermo after PCI (r=0.008, P=0.915) or between post-PCI CFRS-TDE and post-PCI CFRthermo (r=0.054, P=0.482). Pre-PCI CFRS-TDE and CFRthermo are modestly correlated, but post-PCI CFRS-TDE and CFRthermo have no correlation. CFRS-TDE and CFRthermo are not interchangeable, particularly post-PCI, suggesting that the two metrics represent different coronary physiologies after PCI.

Sex differences of sequential changes in coronary blood flow and microvascular function in patients with suspected angina.

This study evaluated the sex differences of sequential changes in coronary blood flows and microvascular function in patients with suspected angina but with no obstructed coronary arteries. A total of 202 consecutive patients who experienced chest pain but had no significant coronary artery stenosis and who underwent adenosine stress echocardiography were included in the study. Coronary blood flow (CBF) velocities were measured at 1, 2, and 3min after adenosine infusion. The mean age was 61years, and 138 (68%) were women. Approximately 40% of patients had coronary microvascular dysfunction (CMD, coronary flow velocity reserve < 2.3), with women exhibiting higher CMD prevalence. The left ventricular (LV) mass index was similar between men and women, while women exhibited higher baseline rate pressure products (RPP). At baseline, coronary blood flow velocities were similar between the sexes. However, CBF velocities in women gradually increased during the examination; and in men, the increase was abrupt and steep during the early stages of examination (p = 0.015 for interaction between time and sex), even with similar RPP in stress. Coronary flow velocity reserve was steadily lower in women compared to men (1min, 2.09 ± 0.86 vs 2.44 ± 0.87; 2min, 2.39 ± 0.72 vs 2.63 ± 0.85; 3min, 2.45 ± 0.70 vs 2.68 ± 0.73). In patients with suspected angina but with no obstructed coronary arteries, CMD was especially prevalent among women. Women exhibited higher oxygen consumption, while exhibiting slower and gradual increases in CBF velocities. Conversely, men exhibited faster and steeper increases in CBF velocities even with similar RPP in stress.

Combined Assessment of Fractional Flow Reserve and Coronary Flow Velocity Reserve after Drug-Eluting Stent Implantation

Coronary flow velocity reserve (CFVR) can be measured noninvasively using stress transthoracic Doppler echocardiography (S-TDE). The prognostic significance of S-TDE-derived CFVR after percutaneous coronary intervention (PCI) remains unknown. The aim of this study was to investigate the prognostic value of post-PCI CFVR and its additional efficacy to fractional flow reserve (FFR) in patients undergoing elective PCI. A retrospective study was conducted involving 187 consecutive patients with chronic coronary syndrome who underwent elective PCI guided by FFR for the left anterior descending coronary artery. Pre- and post-PCI wire-based FFR and CFVR assessments of the left anterior descending coronary artery using S-TDE were performed in all patients. The association between post-PCI clinical and physiologic parameters and major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, heart failure, and unplanned remote target vessel revascularization, was evaluated. Three-quarters of patients exhibited CFVR increase after PCI, while all patients showed FFR improvement. During a median follow-up period of 1.5years, MACE occurred in 21 patients (11.2%). Among clinical demographics, patients with MACE had higher levels of N-terminal pro-brain natriuretic peptide compared with those without MACE (median, 615pg/mL [interquartile range, 245-1,500pg/mL] vs 180pg/mL [interquartile range, 70-559pg/mL]; P=.010). Post-PCI S-TDE-derived CFVR was lower in patients with MACE, while post-PCI FFR showed a nonsignificant tendency to be lower in patients with MACE. In a multivariable analysis, higher NT-proBNP (adjusted hazard ratio, 1.33; 95% CI, 1.02-1.74; P=.038), post-PCI CFVR ≤ 2.0 (adjusted hazard ratio, 2.93; 95% CI, 1.16-7.40; P=.023), and post-PCI FFR ≤ 0.82 (adjusted hazard ratio, 3.93; 95% CI, 1.52-10.18; P=.005) were independently associated with MACE. In patients with chronic coronary syndrome who underwent successful elective PCI for left anterior descending coronary artery, the combined assessment of S-TDE-derived post-PCI CFVR and post-PCI FFR provided a significant association with the occurrence of MACE.

Multiple Phenotypes of Chronic Coronary Syndromes Identified by ABCDE Stress Echocardiography

Regional wall motion abnormality is considered a sensitive and specific marker of ischemia during stress echocardiography (SE). However, ischemia is a multifaceted entity associated with either coronary artery disease (CAD) or angina with normal coronary arteries, a distinction difficult to make using a single sign. The aim of this study was to evaluate the diagnostic potential of the five-step ABCDE SE protocol for CAD detection. From the 2016-2022 Stress Echo 2030 study data bank, 3,229 patients were selected (mean age, 66±12years; 2,089 men [65%]) with known CAD (n=1,792) or angina with normal coronary arteries (n=1,437). All patients were studied using both the ABCDE SE protocol and coronary angiography, within 3months. In step A, regional wall motion abnormality is assessed; in step B, B-lines and diastolic function; in step C, left ventricular contractile reserve; in step D, coronary flow velocity reserve in the left anterior descending coronary artery; and in step E, heart rate reserve. SE response ranged from a score of 0 (all steps normal) to a score of 5 (all steps abnormal). For CAD, rates of abnormal results were 347 for step A (19.4%), 547 (30.5%) for step B, 720 (40.2%) for step C, 615 (34.3%) for step D, and 633 (35.3%) for step E. For angina with normal coronary arteries, rates of abnormal results were 81 (5.6%) for step A, 429 (29.9%) for step B, 432 (30.1%) for step C, 354 (24.6%) for step D, and 445 (31.0%) for step E. The dominant "solitary phenotype" was step B in 109 patients (9.1%). Stress-induced ischemia presents with a wide range of diagnostic phenotypes, highlighting its complex nature. Using a comprehensive approach such as the advanced ABCDE score, which combines multiple markers, proves to be more valuable than relying on a single marker in isolation.

Echocardiographic functional determinants of survival in heart failure with abnormal ejection fraction

Background and AimsPatients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF) have a heterogeneous prognosis, and assessment of coronary physiology with coronary flow velocity (CFV) and coronary flow velocity reserve (CFVR) may complement established predictors based on wall motion and EF.Methods and resultsIn a prospective multicenter study design, we enrolled 1,408 HF patients (age 66 ± 12 years, 1,035 men), with EF &amp;lt;50%, 743 (53%) with coronary artery disease, and 665 (47%) with normal coronary arteries. Recruitment (years 2004–2022) involved 8 accredited laboratories, with inter-observer variability &amp;lt;10% for CFV measurement. Baseline CFV (abnormal value &amp;gt;31 cm/s) was obtained by pulsed-wave Doppler in mid-distal LAD. CFVR (abnormal value ≤2.0) was assessed with exercise (n = 99), dobutamine (n = 100), and vasodilator stress (dipyridamole in 1,149, adenosine in 60). Inducible myocardial ischemia was identified with wall motion score index (WMSI) stress &amp;gt; rest (cut-off Δ ≥ 0.12). LV contractile reserve (CR) was identified with WMSI stress &amp;lt; rest (cutoff Δ ≥ 0.25). Test response ranged from score 0 (EF &amp;gt; 30%, CFV ≥ 32 cm/s, CFVR &amp;gt; 2.0, LVCR present, ischemia absent) to score 5 (all steps abnormal). All-cause death was the only endpoint. Results. During a median follow-up of 990 days, 253 patients died. Independent predictors of death were EF (HR: 0.956, 95% CI: 0.943–0.968, p &amp;lt; 0.0001), CFV (HR: 2.407, 95% CI: 1.871–3.096, p &amp;lt; 0.001), CFVR (HR: 3.908, 95% CI: 2.903–5.260, p &amp;lt; 0.001), stress-induced ischemia (HR: 2.223, 95% CI: 1.642–3.009, p &amp;lt; 0.001), and LVCR (HR: 0.524, 95% CI: 0.324–.647, p = 0.008). The annual mortality rate was lowest (1.2%) in patients with a score of 0 (n = 61) and highest (31.9%) in patients with a score of 5 (n = 15, p &amp;lt; 0.001).ConclusionHigh resting CFV is associated with worse survival in ischemic and nonischemic HF with reduced EF. The value is independent and additive to resting EF, CFVR, LVCR, and inducible ischemia.

The importance of vasodilator stress echocardiography in predicting all-cause mortality and acute heart failure in hypertrophic cardiomyopathy

Abstract Background Reduced coronary flow velocity reserve (CFVR) in the left anterior descending coronary artery (LAD) during vasodilator stress echocardiography (VSE) is a marker of poor outcome and is associated with higher baseline coronary flow velocity (CFV) in hypertrophic cardiomyopathy (HCM). However, whether resting CFV has additive predictive value to CFVR during VSE in HCM is unknown. Aim To assess the prognostic value of baseline CFV and CFVR during VSE in HCM. Methods 325 adult HCM patients (age=52+15 years, 147 [45%] females) with preserved left ventricular function and no known coronary artery disease who underwent VSE in 6 certified centers between 1999 and 2021 were prospectively analyzed. VSE modality was adenosine (0.14 mg/kg/min in 2', n=232) or dipyridamole (0.84 mg/kg in 6', n=93). CFVR in the LAD was assessed by transthoracic (n=306) or transoesophageal (n=19) echocardiography. Patients were followed for a median of 67 months (IQ range 31-103 months), the primary endpoint was a composite of all-cause mortality and acute heart failure (HF). Results Receiver operating characteristic analysis was used to determine the best cut-off value of CFV (&amp;gt;31 cm/s, elevated) and CFVR (≤2.0, reduced) to predict the primary endpoint. Patients with reduced CFVR had more frequently elevated baseline CFV (75% vs 49%, p&amp;lt;0.001). Elevated resting CFV was a predictor of composite endpoint at univariable (HR 2.04, 95% CI 11.05-3.97, p=0.035) but not at multivariable analysis. A reduced CFVR was an independent predictor of all-cause mortality (HR 5.50, 95% CI 1.94-15.59, p=0.001), acute HF (HR 5.80, 95% CI 1.60-21.00, p=0.007), and the composite end-point (HR 4.95, 95% CI 2.39-10.25, p&amp;lt;0.001). The 5-year event rate was 6-fold higher in patients with reduced CFVR compared to patients with preserved CFVR (19% vs 3%, p&amp;lt;0.001), with no additional impact of resting CFV (see Figure). Conclusion LAD CFVR ≤2.0 during VSE is a strong and independent predictor of all-cause mortality and acute HF in HCM. Elevated resting CFV is more frequent in patients with reduced CFVR, but has no independent prognostic value when CFVR is considered.Kaplan-Meier event-free survival curves

Independent prognostic value of ejection fraction, resting coronary flow, coronary flow reserve, myocardial viability, and inducible ischemia in heart failure with a reduced ejection fraction

Abstract Background and Aims Patients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF) have a heterogeneous prognosis, and assessment of coronary physiology with coronary flow velocity (CFV) and coronary flow velocity reserve (CFVR) may complement established predictors based on wall motion. Methods and results In a prospective multicenter study design, we enrolled 1,408 HF patients (age 66±12 years, 1,035 men), with EF &amp;lt;50%, 743 (53%) with coronary artery disease, and 665 (47%) with normal coronary arteries. Recruitment (years 2004-2022) involved 8 accredited laboratories, with inter-observer variability &amp;lt;10% for CFV measurement. Baseline CFV (abnormal value &amp;gt;31 cm/s) was obtained by pulsed-wave Doppler in mid-distal LAD. Coronary flow velocity reserve (CFVR, abnormal value ≤2.0) was assessed with exercise (n=99), dobutamine (n=100), and vasodilator stress (dipyridamole in 1,149, adenosine in 60). Inducible myocardial ischemia was identified with wall motion score index (WMSI) stress&amp;gt; rest (cut-off ∆≥0.12). LV contractile reserve (CR) was identified with WMSI stress&amp;lt; rest (cutoff ∆≥0.25). Test response ranged from score 0 (EF&amp;gt;30%, CFV ≤31 cm/s, CFVR &amp;gt;2.0, LVCR present, ischemia absent) to score 5 (all steps abnormal). All-cause death was the only end-point. Results During a median follow-up of 990 days, 253 patients died. Independent predictors of death were EF (HR: 0.956, 95% CI: 0.943-0.968, p&amp;lt;0.0001), CFV (HR: 2.407, 95% CI: 1.871-3.096, p&amp;lt;0.001), CFVR (HR: 3.908, 95% CI: 2.903-5.260, p&amp;lt;0.001), stress-induced ischemia (HR: 2.223, 95% CI: 1.642-3.009, p&amp;lt;0.001), and LVCR (HR: 0.524, 95% CI: 0.324-.647, p=0.008). The annual mortality rate was lowest (1.2%) in patients with a score of 0 (n=61) and highest (31.9%) in patients with a score of 5 (n=15, p&amp;lt;0.001). Conclusion High resting CFV predicts worse survival in ischemic and nonischemic HF with reduced EF. The value is independent and additive to resting EF, CFVR, LVCR, and inducible ischemia.

High resting coronary flow velocity and reduced coronary flow velocity reserve independently predict worse survival in diabetic patients without inducible ischemia and normal left ventricular function

Abstract Background High resting coronary flow velocity (CFV) in the mid-distal left anterior descending coronary artery (LAD) can be easily assessed with transthoracic echocardiography (TTE) and is a predictor of worse survival. Purpose In this study, we sought to assess the relationship between resting CFV, coronary flow velocity reserve (CFVR), and outcome in patients without inducible regional wall motion abnormality during stress echo (SE). Methods In a prospective multicenter study design, we enrolled 6,887 patients (age 65±11 years, 3,838 men, 1,963 diabetics), with left ventricular ejection fraction (LVEF) ≥50% referred for SE. Recruitment (years 2004-2022) involved 7 accredited laboratories, with inter-observer variability &amp;lt;10% for CFV measurement at study entry. Baseline peak diastolic CFV (abnormal value &amp;gt;32 cm/s) was obtained by pulsed-wave Doppler in mid-distal LAD. Coronary flow velocity reserve (CFVR, abnormal value ≤2.0) was assessed with dipyridamole. All-cause death was the only end-point. Results The mean CFV of LAD was 30±11 cm/s. The mean CFVR was 2.37±0.58. During a median follow-up of 6.0±4.2, 1,015 (15%) patients died. At Cox analysis, resting CFV &amp;gt;32 cm/s independently predicted mortality together with CFVR &amp;lt;2, age, diabetes, previous myocardial infarction, history of coronary surgery and LVEF. Resting CFV allowed effective risk stratification either in diabetics and nondiabetics although the difference in survival based on resting CFV was more marked in the former (Figure). In addition, it added significant (p&amp;lt;0.0001) prognostic information to CFVR result in the diabetic, but not in the non-diabetic population (Figure). Conclusion High resting CFV with TTE in mid-distal LAD predicts worse survival in patients without inducible ischemia. The value is independent and additive to CFVR in diabetic patients. The combination of high resting CFV-low CFVR is associated with worse survival.

Residual Microvasuclar Dysfunction (RMVD) after percutaneous coronary intervention (PCI) assessed by stress- transthoracic Doppler echocardiography (S-TDE)

Abstract Background Microvascular dysfunction (MVD) has been increasingly acknowledged as a relevant cause of myocardial ischemia and worse prognosis. Coronary flow velocity reserve (CFVR), an integrated marker of coronary circulation, can be obtained noninvasively by stress-TDE. However, limited data is available regarding residual MVD (RMVD) of the target territory after percutaneous coronary intervention (PCI) assessed by stress- transthoracic Doppler echocardiography (S-TDE). Purpose This study aimed to investigate the echocardiographic predictors for RMVD after PCI assessed by S-TDE. Methods This study prospectively included 175 patients with chronic coronary syndrome who were scheduled for elective PCI at a single tertiary-care center between April 2019 and November 2022. All patients had anginal symptoms with de novo, functionally significant, proximal left anterior descending (LAD) lesions and underwent fractional flow reserve (FFR)-guided elective single vessel PCI for LAD. Exclusion criteria were patients with reduced left ventricular (LV) systolic function (ejection fraction &amp;lt; 50%), periprocedural myocardial infarction as defined by the fourth universal definition of myocardial infarction. Eligible patients underwent pre- (1 day before) and post-procedural (3 days after) LAD coronary flow assessments by S-TDE. Coronary flow velocity reserve (CFVR) was calculated as the ratio of the hyperemic peak diastolic flow velocity to the basal peak diastolic flow velocity. We also excluded the patients with suboptimal S-TDE imaging. We defined an RMVD after PCI as a post-PCI CFVR impairment (CFVR&amp;lt;2.0). Association between RMVD and echocardiographic parameters were evaluated. Results A total of 150 patients were included in the final analysis. RMVD was observed in forty-five (30.0%) patients after successful LAD PCI. Patients with RMVD had older age (74 [67-79] versus 72 [59-76], P=0.042) and lower estimated glomerular filtration rate (eGFR) (58.4 [37.6-75.1] mL/min/1.73m2 versus 65.9 [54.3-75.5] mL/min/1.73m2, P=0.045) than those without RMVD. Univariate logistic regression analyses revealed that higher age, lower eGFR, pre-PCI higher ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e’), shorter deceleration time of diastolic coronary flow (DDT) and lower pre-PCI CFVR were associated with post-PCI RMVD. Multivariate logistic regression analyses including age and eGFR as covariates showed higher E/e’ (adjusted odds ratio [OR] 1.13, 95% confidence interval [CI] 1.02-1.25, P=0.022), shorter DDT (OR 0.999, 95% CI 0.998-1.000, P=0.045) and lower pre-PCI CFVR (OR 0.336, 95% CI 0.165-0.683, P=0.003) were independently predictive of RMVD. Conclusions In patients with preserved LV ejection fraction who underwent successful elective FFR-guided PCI for LAD, pre-PCI LV diastolic dysfunction was associated with post-PCI residual microvascular dysfunction of LAD territory.

Resting and stress coronary flow velocity for identification of different endotypes and risk classes in ANOCA patients beyond coronary flow velocity reserve

Abstract Background Coronary microvasculature disease (CMD) affects a subset of patients with angina with no obstructive coronary arteries (ANOCA) and is diagnosed with transthoracic echocardiography (TTE) through a reduction (≤2.0) of coronary flow velocity reserve (CFVR), measured as the stress/rest coronary flow velocity (CFV) ratio. Aim To assess the dominant (functional vs structural, high-rest vs low-stress CFV) mechanism of CMD and the corresponding long-term risk. Methods In a prospective multicenter study design, we enrolled 1,033 patients (age 63±11 years, 533 women, 230 diabetics, ejection fraction 59±5%) with ANOCA. Recruitment (years 2004-2022) involved 4 accredited laboratories, with inter-observer variability &amp;lt;10% for CFV. CFV was obtained with TTE by pulsed-wave Doppler in the mid-distal left anterior descending coronary artery at rest and after dipyridamole stress. All-cause death was the only end-point. A receiver operating characteristic analysis was used to obtain the best prognostic predictor, corresponding to &amp;gt;32 cm/s for resting and ≤53 cm/s for peak stress CFV. Results 289 patients (28%) showed a reduction in CFVR. Four groups were identified: normal rest and peak CFV (Group 1, n=465), abnormal rest and normal peak CFV (Group 2, n=350), normal rest and abnormal peak CFV (Group 3, n=210), abnormal rest and peak CFV (Group 4, n=8). During a mean follow-up of 4.8±4.1 years, 82 (8%) patients died. Eight-year mortality was 4% in Group 1, 11% in Group 2, 15% in Group 3, and 58% in Group 4 (p&amp;lt;0.0001). Yearly mortality was 2.3% in patients with isolated abnormal rest CFV as well as in those with isolated abnormal peak CFV (p=0.89) (Figure). Conclusion TTE allows phenotyping of the presence of CMD in the heterogeneous garden variety of ANOCA patients. High resting with reduced peak CFV is the less frequent, and by far more malignant, endotype.

Coronary flow velocity reserve during exercise stress echocardiography in hypertrophic cardiomyopathy

Abstract Background Coronary flow velocity reserve (CFVR) can be assessed with transthoracic echocardiography (TTE) as the stress/rest ratio of coronary flow velocity (CFV). Reduced CFVR during vasodilator stress (adenosine or dipyridamole) is a powerful predictor of adverse outcomes in hypertrophic cardiomyopathy (HCM). However, the feasibility and correlates of CFVR during the more physiological - and recommended - exercise stress echocardiography (ESE) is unresolved. Aim To assess the feasibility and functional correlates of CFVR during exercise in HCM. Methods We studied 56 HCM patients (age=49±13 years, 33 [59%] males) and 44 age- and sex-matched healthy subjects with symptom-limited semi-supine ESE. ESE assessment included CFVR (stress/rest diastolic CFV) in the mid-distal left anterior descending coronary artery, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate reserve (HRR, peak/rest heart rate). Results CFVR was feasible in 46/56 HCM patients and in 41/44 controls (82% vs 93%, p=0.138). Median CFVR was significantly lower in patients with HCM compared to controls (1.72 [1.48; 2.10] vs 2.57 [2.25; 3.30], p&amp;lt;0.001), see Figure 1. In HCM patients, among resting parameters, CFVR was inversely correlated with left ventricular maximal septal thickness (r= -0.308, p=0.038), end-systolic diameter (r= -0.393, p=0.007), resting DBP (r= -0.398, p=0.006) and resting SBP (r= -0.321, p=0.030), while in controls CFVR correlated only with resting DBP (r= -0.322, p=0.040). During exercise, HCM patients with lower CFVR (&amp;lt;1.72, i.e. 1.72) showed lower peak CFV (78±20 vs 96±24 cm/s, p=0.003) and lower HRR (1.55±0.29 vs 1.76±0.25, p=0.020), see Figure 2. Exercise duration, peak stress workload or metabolic equivalents were not related to CFVR. In multivariable analysis, resting CFV (b=-0.034, 95% CI -0.037 and -0.030, p&amp;lt;0.001), resting DBP (b=-0.003, 95% CI -0.005 and -0.001, p=0.020), peak stress CFV (b=0.019, 95% CI 0.017 and 0.021, p&amp;lt;0.001) and HRR (b=0.126, 95% CI 0.005 and 0.247, p=0.041) were independently associated with CFVR. Conclusion CFVR assessment by TTE in the left anterior descending coronary artery is feasible during semi-supine exercise in most HCM patients. CFVR is markedly reduced in HCM patients on effort, particularly in the presence of high resting CFV and low HRR.Figure 1Figure 2

TDE-derived impaired post-PCI Coronary flow velocity reserve predicts MACE in patients who underwent LAD PCI

Abstract Background Coronary flow velocity reserve (CFVR) can be obtained noninvasively by stress transthoracic Doppler echocardiography (S-TDE). However, prognostic significance of S-TDE-derived CFVR after percutaneous coronary intervention (PCI) remains unknown. Purpose This study aimed to investigate the relationship between post-PCI CFVR and major adverse cardiac event (MACE). Methods This study prospectively included 200 patients with stable coronary artery disease who were scheduled for elective PCI of de novo, single, functionally significant left anterior descending (LAD) lesions at a single tertiary-care center between April 2019 and November 2022. All patients underwent fractional flow reserve (FFR)-guided elective PCI. Exclusion criteria were patients with previous coronary artery bypass graft surgery, left main coronary artery disease and periprocedural myocardial infarction as defined by the fourth universal definition of myocardial infarction. Eligible patients underwent pre- (1 day before) and post-procedural (3 days after) LAD coronary flow assessments by stress-TDE. CFVR was calculated as the ratio of the hyperemic peak diastolic flow velocity to the basal peak diastolic flow velocity. We also excluded the patients with suboptimal S-TDE imaging. Association between post-PCI physiological parameters and MACE (composite of cardiac death, myocardial infarction, heart failure and target vessel revascularization) were evaluated. Results A total of 174 patients were included in the final analysis after successful LAD PCI. MACE occurred in twenty-one (12.0%) patients during the follow-up (1.9 [0.9-2.5] years). Clinical demographics were similar in patients with versus without MACE. Post-PCI S-TDE-derived CFVR was lower in patients with versus without MACE (P = 0.023), while post-PCI FFR values tended to be lower in patients with versus without MACE, albeit not significant (P = 0.077). Receiver-operating characteristic curve analysis revealed that the optimal cut-off values of post-PCI FFR and post-PCI CFVR values to predict MACE were 0.83 and 1.70, respectively. Significant differences in the MACE were detected according to post-PCI FFR (≤ 0.83 versus &amp;gt; 0,83: 17.9 % versus 6.7 %, P = 0.035) and post-PCI CFVR (&amp;lt; 1.70 versus ≥ 1.70: 33.3% versus 8.2%, P = 0.001). On a multivariable Cox-proportional hazard analysis, patients with post-PCI CFVR &amp;lt; 1.70 had an increased risk for MACE (adjusted hazard ratio [HR] 4.75, 95% confidence interval [CI] 1.98-11.38, P &amp;lt; 0.001), along with post-PCI FFR ≤ 0.83 (adjusted HR 2.78, 95% CI 1.07-7.20, P=0.035). Conclusions In patients who underwent successful elective PCI for LAD, S-TDE-derived impaired post-PCI CFVR and post-PCI FFR were independently associated with MACE.

Stress echocardiography: application of the ABCDE protocol in patients with permanent atrial fibrillation

Abstract Objectives A new standard of practice in stress echocardiography (SE) was founded with the development of the ABCDE protocol, which added functional information to conventional ischemia diagnosis. Each step showed to provide incremental prognostic information: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in the left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. However, the utility of SE and ABCDE protocol in patients with atrial fibrillation (AF) has never been tested. Background A growing body of evidence suggests that AF patients have a significant residual risk of myocardial infarction despite anticoagulant treatment; furthermore, they have an increased risk of heart failure and all-cause death. However, ABCDE-SE has never been applied in this population. Methods Of the 3965 patients who completed clinically indicated ABCDE-SE and with available information on rhythm stored in the shared data bank and enrolled from 13 certified centers, 3891 were in sinus rhythm (SR, Group 1) and 50 in permanent AF (Group 2) at the time of the test. ABCDE-SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). The employed stress was an exercise in 1626 (41%), vasodilator in 1864 (47%), and dobutamine in 475 (12%). Results Group 2 pts were older than Group 1 patients, more frequently hypertensives and diabetics, with lower ejection fraction, and with more signs of pulmonary congestion at rest. During stress, differences were magnified, and Group 2 patients showed more peak stress B-lines and higher values of peak WMSI compared with Group 1 (see Table). In addition, patients with AF had higher ABCDE scores (Group 1= 1.5 ±1.4 vs. Group 2= 2.6±1.6, p&amp;lt;0.0001). The distribution of the score in patients in SR and AF is shown in Figure. Conclusions Patients with AF are scarcely represented among patients undergoing SE. Patients with AF showed a higher prevalence of positivity in each step and a higher ABCDE score. More specifically, AF patients are more vulnerable than patients in SR to coronary microvascular dysfunction and chronotropic incompetence during stress.TableFigure