Microvascular Resistance Reserve Research Articles

Microvascular resistance reserve in relation to total and vessel-specific atherosclerotic burden.

The relationship between coronary artery atherosclerosis and microvascular resistance remains unclear. This study aims to clarify the relationship between total atherosclerotic and vessel-specific atherosclerotic burden and microvascular resistance reserve (MRR). In this post-hoc analysis of the PACIFIC 1 trial, symptomatic patients without prior coronary artery disease (CAD) underwent [15O]H2O positron emission tomography, coronary computed tomography angiography (CCTA) and invasive fractional flow reserve (FFR). MRR was assessed across all three coronary branches, utilizing PET-derived coronary flow reserve and invasive FFR measurements. CCTA was used to assess patient and vessel-specific plaque volumes. Percentage atheroma volume (PAV) was defined as total plaque volume divided by vessel volume. The study included 142 patients (55% male, 57.5±8.6 years) with 426 vessels with a mean MRR of 3.77±1.64. While a significantly higher PAV was observed in the left anterior descending artery territory, MRR was similar across the three coronary branches. Generalized Estimating Equations without correction for cardiovascular risk factors identified that patient-specific PAV tertiles but not vessel-specific PAV tertiles were related to vessel-specific MRR. After correction for cardiovascular risk factors, compared to the first tertile of patient-specific PAV, the second tertile showed a vessel-specific MRR decrease of β=-0.362, p=0.018, and the third tertile showed a decrease of β=-0.347, p=0.024. In patients without prior CAD, patient-specific plaque burden was negatively associated to vessel-specific MRR; however, vessel-specific plaque burden was not related to vessel-specific MRR. Our findings suggest that the relation between atherosclerotic burden and an impaired microcirculatory function is of systemic origin.

Advancing prognostic insights in STEMI patients through microvascular resistance reserve evaluation

Abstract Background Coronary microvascular dysfunction (CMD) after ST-Elevation Myocardial Infarction (STEMI) is associated with persistent symptoms and poor outcomes. Microvascular Resistance Reserve (MRR) is an innovative metric for evaluating coronary microvasculature that is unaffected by epicardial stenoses or the hemodynamic impact of vasodilators. While MRR's prognostic ability is recognized in chronic coronary syndrome, its application in ACS remains unestablished. Purpose We sought to investigate the prognostic value of MRR in STEMI patients. Methods This is a prospective study of 210 STEMI patients with multivessel disease who had undergone successful primary percutaneous coronary intervention (PCI). At 3 months follow-up, they returned for complete revascularization and coronary physiology evaluations, including coronary flow reserve (CFR), fractional flow reserve (FFR), and index of microcirculatory resistance (IMR), using bolus thermodilution. MRR was calculated using the formula: MRR = (CFR/FFR) × (Pa rest/Pa hyper), where Pa rest and Pa hyper represent resting and hyperemic aortic pressure, respectively1. We utilized an MRR cutoff of 3.0 based on Boerhour et al. The association between MRR and major adverse cerebrocardiovascular events (MACCE) at 12-month follow-up, defined as the composite of stroke, revascularization, myocardial infarction (MI), heart failure hospitalization, and death, was investigated. Results The median age was 65 years, and 40.48% were female. At a 3-month follow-up, 27% (56 patients) exhibited MRR <3.0, who were predominantly female (62.50% vs 32.47%, p<0.001) with a higher incidence of diabetes (39.29% vs 18.83%, p = 0.004). No significant differences were observed in age, body mass index, or STEMI location (anterior or inferior) when comparing between MRR groups. The MACCE-free survival at 12 months was significantly lower in patients with an MRR < 3.0 (48.2%) compared to those with an MRR ≥ 3.0 (11.0%; log-rank p < 0.001, Fig1A). The MRR < 3.0 group showed higher rates of ischemic stroke (8.93% vs. 1.30%, p = 0.022) and hospitalization for heart failure (21.43% vs. 2.60%, p < 0.001), while the incidence of nonfatal myocardial infarction (MI) and cardiovascular death were similar between the two MRR groups (Figu1B). In multivariable Cox regression analysis, MRR was an independent predictor for 12-month MACCE (Hazard Ratio 0.45 per unit increase, 95% Confidence Interval 0.31-0.67, p<0.001). The areas under the receiver operating characteristic curves for predicting 12-month MACCE using FFR, CFR, IMR, and MRR yielded values of 0.609, 0.762, 0.781, and 0.743, respectively (Fig2). The prognostic performances of CFR, IMR, and MRR were similar and superior to that of FFR. Conclusion This study establishes the novel parameter MRR as a superior prognostic indicator in STEMI patients compared to FFR, and on par with CFR and IMR. MRR is a reliable predictor of MACCE, and various clinical incidents post-STEMI.

Impact of microvascular resistance reserve on post-STEMI cardiac remodelling and diastolic function

Abstract Background Coronary microvascular dysfunction (CMD) is a common sequelae of ST-segment elevation myocardial infarction (STEMI), preventing adequate recovery of left ventricular (LV) perfusion. The interferences of con-commitment epicardial stenosis or hyperemic hemodynamic alterations limit traditional physiologic metrics. The microvascular resistance reserve (MRR) was developed to overcome these shortcomings. Purpose We aim to investigate the association between post-STEMI MRR, and the ensuing left ventricle (LV) diastolic dysfunction, and functional remodeling. Methods In this prospective, observational study, we enrolled STEMI patients with multivessel disease who successfully underwent primary percutaneous coronary intervention (PCI). At three months post-PCI, all patients received complete revascularization followed by coronary physiology assessment using the bolus thermodilution method to measure the fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR). MRR was calculated using the formula: MRR = (CFR/FFR) × (Pa rest/Pa hyper), where Pa rest and Pa hyper represent resting and hyperemic aortic pressure, respectively(1). CMD was defined as an MRR < 3.0 based on Boerhout et al(2). Diastolic dysfunction was defined according to the ASE 2016 guidelines. Functional LV remodelling (FLVR) was categorized according to Chimed et al(3). The relationship between CMD and the stages of FLVR and diastolic dysfunction was scrutinized over a 12-month follow-up period. Results We enrolled 210 patients, of whom 125 (59.5%) were men with a median age of 65 (IQR: 58–76). At the 3-month follow-up, the MRR was 3.46 (IQR 3.00, 3.92), with 56 (26.7%) patients having CMD (MRR<3.0). MRR is significantly correlated with the change of LVEF between primary PCI and 12 months (r=0.48, p<0.001, Fig1A). CMD patients have lower LVEF at 12 months (50.00% vs. 40.00%; p < 0.001) and demonstrated significantly less recovery in LV systolic function (-10.00% vs. 8.00%; p < 0.001, Fig 1B, 1C). CMD patients had a higher prevalence of grade 2 or 3 LV diastolic dysfunction (65.38% vs. 3.95%; p < 0.001, Fig 2A) and a higher incidence of advanced FLVR (Groups 3 and 4) compared to those without CMD (30.77% vs. vs. 10.53%; p < 0.001, Fig 2B). In multivariable logistic regression analysis, MRR was independently associated with LV diastolic dysfunction (0.17, 95%CI 0.08-0.33, p<0.001). Conclusions The novel parameter MRR is significantly related to LVEF recovery in STEMI patients and is an independent predictor for advanced LV diastolic dysfunction and FLVR. CMD patients, as diagnosed with MRR, showed a higher prevalence of advanced FLVR and diastolic dysfunction. These results suggest that MRR is a useful parameter for the identification and management of CMD in STEMI patients.

Prognostic implications of microvascular resistance reserve in symptomatic patients with intermediate coronary stenosis

Abstract Background Microvascular resistance reserve (MRR) is a novel index reflecting coronary microcirculatory function, irrespective of epicardial coronary artery stenosis. There is limited evidence regarding whether MRR can be an independent prognostic tool in patients with stable ischemic heart disease (IHD). Objective To evaluate clinical outcomes according to MRR in patients with stable IHD accompanied with or without significant epicardial coronary artery stenosis. Methods The current study included 547 consecutive patients undergoing systematic echocardiographic and invasive physiologic assessment for suspected stable IHD. Significant epicardial coronary artery stenosis was defined as fractional flow reserve (FFR)≤0.80. Coronary microvascular dysfunction (CMD) was defined as MRR≤3.0. Primary outcome was major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure. Results Among the total patients, 172 patients (31.4%) had FFR≤0.80 and 200 patients (36.6%) had CMD defined by MRR≤3.0. MRR showed no significant correlation with FFR (R=-0.031, P=0.469), however, it was significantly correlated with index of microcirculatory resistance (R=-0.353, P<0.001), NT-proBNP (R=-0.296, P<0.001), left ventricular filling pressure (E/e’) (R=-0.224, P<0.001), and diastolic dysfunction grade (P<0.001). During median follow-up of 3.3 years (interquartile range from 2.0 to 4.5 years), MRR was significantly associated with MACE risk (HR 1.23 per-1 decrease, 95% CI 1.12-1.36, P<0.001). CMD defined by MRR≤3.0 was associated with an increased MACE risk in both FFR>0.80 (41.0% vs. 26.0%; HRadj 1.59, 95% CI 1.07-2.35, P=0.021) and FFR≤0.80 (34.7% vs. 14.8%; HRadj 2.32, 95% CI 1.12-4.82, P=0.024) groups. Conclusion Decreased MRR was associated with the presence of cardiac diastolic dysfunction as well as with increased left ventricular filling pressure. The presence of CMD defined by MRR was independently associated with the risk of a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure in patients with stable IHD, irrespective of significant epicardial coronary artery stenosis.

Microvascular functional assessment using microvascular resistance reserve in patients undergoing elective fractional flow reserve-guided percutaneous coronary intervention

Abstract Background Microvascular resistance reserve (MRR) has been proposed as an index for coronary microvascular function. However, the determinants of MRR and the prevalence of coexistent coronary microvascular dysfunction (CMD) in patients with obstructive coronary disease remains elusive. We sought to assess the prevalence of CMD and determinants for MRR. Methods We retrospectively investigated 703 physiologically significant (FFR≤0.80) chronic lesions in our institutional physiological registry. All patients underwent pre-PCI physiological assessment including FFR, CFR and MRR. CMD was defined with MRR<2.1. The characteristics and physiological findings were compared between CMD and non-CMD. The predicting factors for CMD were investigated. Results In a total cohort, FFR, CFR and MRR were 0.70(0.6-0.75), 1.82 (1.27-2.80) and 3.20 (2.22-4.30), respectively. CMD was observed in 142 (20.2%) vessels. Older age (71[65-77] vs 69[62-75], p=0.007), female patients (24.6% vs 14.4%, p=0.005) and non-LAD culprit lesions (42.3% vs 32.4%, p=0.014) were significantly more frequent in CMD. Furthermore, CMD group was significantly associated with the history of hemodialysis and heart failure (10.6% vs 3.6%, p=0.001, 38.0% vs 31.0%, p=0.015 respectively). FFR and CFR were lower in CMD than non-CMD (0.67[0.60-0.73] vs 0.70[0.61-0.76], p<0.001, 1.03[0.82-1.21] vs 2.16[1.56-3.00], p<0.001, respectively). In multiple linear regression analysis, low FFR, non-LAD lesion, older age, female and history of hemodialysis were significant predictors for the presence of CMD. Conclusion The prevalence of coexistent CMD in patients undergoing PCI was 20.2%, when defined as MRR≤2.1. Non-LAD lesion location, older age, women, history of hemodialysis, and FFR were significantly associated with the presence of CMD.

Assessment of structural and functional microvascular dysfunction using microvascular resistance reserve versus invasive exercise stress testing

Abstract Background Coronary microvascular dysfunction is an heterogenous entity with structural dysfunction present in about 60% of cases. Although Coronary Flow Reserve (CFR) is commonly used for diagnosis, this index is nonspecific to the microvasculature. The effectiveness of the recently introduced Microvascular Resistance Reserve (MRR) and absolute microvascular resistance (Rµ) in identifying microvascular dysfunction endotypes remains uncertain. Objective To evaluate whether MRR and hyperemic Rµ assessment are effective in dichotomizing functional and structural microvascular dysfunction as compared with Rµ and coronary blood flow (Q) monitoring during exercise. Methods Rµ and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery of consecutive patients with Angina and Non-Obstructive Coronary Arteries. An MRR<2.3 was considered the cutoff for coronary microvascular dysfunction. Q and Rµ were assessed during subsequent stress testing with an incremental workload of 30 watts every two minutes, using a dedicated supine cycling ergometer. Results Coronary microvascular dysfunction was observed in 36.6% of the participants with suspected Angina with Non-Obstructive Coronary Artery disease (11 out of 30). Median hyperemic Rµ was 561 [381; 684] Wood Unit (WU) among patients with microvascular dysfunction. Participants with structural dysfunction (MRR<2.3 and hyperemic Rµ>561WU), had a resting Rµ similar to participants without CMD (1286±410 versus 1231±291 WU) but exhibited both impaired reduction of Rµ (139 [64; 288] versus 191 [74; 317] WU per 30 watts) and increase of Q during exercise (20 [1; 37.5] versus 52 [15.5; 92.0] mL/min per 30 watts). Patients with functional dysfunction (MRR<2.3 and hyperemic Rµ<561WU) had lower resting Rµ (672±219 WU) and higher resting Q (152±39 versus 84±24 mL/min) with a similar increase of Q during exercise (55 [30.5; 103.0] than participants without CMD. Mean N-terminal pro B-type natriuretic peptide level was higher in the structural group (425±563 ng/L) as compared to the functional and normal groups (86±10 ng/L and 50±80 ng/L respectively). Conclusion The use of MRR combined to hyperemic Rµ, derived from continuous intracoronary thermodilution, enables the assessment of coronary microvascular dysfunction with an accurate distinction between functional and structural endotypes.Microvascular hemodynamic adaptationNTpBNP level

The influence of epicardial resistance on Microvascular Resistance Reserve (MRR)

Abstract Background The optimal index of microvascular function should be specific for the microvascular compartment. Yet, coronary flow reserve (CFR), despite being widely used to diagnose coronary microvascular dysfunction (CMD), is influenced by both epicardial and microvascular resistance. Conversely, microvascular resistance reserve (MRR) adjusts for fractional flow reserve (FFR), and thus is theoretically independent of epicardial resistance. Purpose We tested the hypothesis that MRR, unlike CFR, is not influenced by increasing epicardial resistance, and thus is a more specific index of microvascular function. Methods In a cohort of 16 patients that had undergone proximal left anterior descending artery stenting, we created four grades of artificial stenosis (no stenosis, mild, moderate, and severe) using a coronary angioplasty balloon inflated to different degrees within the stent. For each stenosis grade, we calculated CFR and MRR using continuous thermodilution (64 measurements of each) in order to assess their response to changing epicardial resistance. Results Graded balloon inflation resulted in a significant sequential decrease in mean FFR (no stenosis: 0.82 ±0.05; mild: 0.72 ±0.04; moderate: 0.61 ±0.05; severe: 0.48 ±0.09, p<0.001). This translated into a linear decrease in mean hyperaemic coronary flow (no stenosis: 170.5 ±66.8 ml/min; mild: 149.8 ±58.8 ml/min; moderate: 124.4 ±53.0 ml/min; severe: 94.0 ±45.2 ml/min, p<0.001) (Figure 1). CFR exhibited a marked linear decrease with increasing stenosis (no stenosis: 2.5 ±0.9; mild: 2.2 ±0.8; moderate: 1.8 ±0.7; severe: 1.4 ±0.6), corresponding to a decrease of 0.3 for a decrease in FFR of 0.1 (p<0.001). Conversely, MRR exhibited a minimal decrease across all stenosis grades (no stenosis: 3.0 ±1.0; mild: 3.0 ±1.0; moderate: 2.9 ±1.0; severe: 2.8 ±1.0), corresponding to a decrease of just 0.05 for a decrease in FFR of 0.1 (p<0.001) (Figure 1). Conclusion MRR, unlike CFR, is minimally influenced by epicardial resistance, and thus should be considered the most specific index of microvascular function.Figure 1.Absolute blood flow (Q) vs FFRFigure 2.MRR/CFR vs FFR

Functinal assessment in Angina and Non-Obstructive Coronary Arteries (ANOCA) patients: from Microvascular Resistance Reserve (MRR) to different subtypes of Coronary Microvascular Dysfunction (CMD)

Abstract Background Coronary microvascular dysfunction (CMD) is a heterogeneous condition defined by a reduced coronary flow reserve (CFR) and low/high values of index of microvascular resistance (IMR). A new index, the microvascular resistance reserve (MRR) has been developed, but its clinical significance is unclear. Purpose We aimed to investigate the relationships between functional indices in ANOCA (Angina and No Obstructive Coronary Arteries) patients and to assess the hemodynamic and clinical characteristics of different CMD subtypes. Materials and methods We prospectively enrolled consecutive ANOCA patients who underwent a comprehensive functional assessment of microvascular domain by thermodilution technique. CFR, IMR and MRR were estimated and correlated each other. Patients were divided in two groups according to the presence of CMD (defined by a CFR<2.5). Subsequently High Hyperaemic Resistance (HHR) and Low Hyperaemic Resistance (LHR) CMD subtypes were defined according to low or high IMR values respectively (cut-off 25). Microvascular flow and resistance were estimated both at rest and during hyperaemia with Tmnrest /IMRrest and Tmnhyp/IMR respectively. All functional indices were compared between groups. Results one hundred and eight patients were available for the analysis. 66 patients in the Normal Group (CFR≥2.5), 20 patients in HHR CMD (CFR<2.5 and IMR≥25), 22 patients in LHR CMD (CFR<2.5 and IMR<25). MRR showed a strong correlation (r 0.966, p <0.01) with CFR, while a mild and negatively correlation was found between CFR and IMR (r -0.242, p=0.01) and MMR and IMR (r -0.261, p<0.01). MRR showed a good discriminatory power (AUC 0.97, 95% CI 0.94 – 0.99) and accuracy (85%) in detecting CMD when compared to CFR. LHR CMD patients showed reduced microvascular resistance (IMRrest 34.3±15.1 vs 90.1±54.5 Normal Group vs 75.8±28.9 HHR CMD, p<0.01) and increased flow at rest (Tmnrest 0.37±0.17 vs 0.96±0.62 Normal Group vs 0.81±0.43 HR CMD, p<0.01), while HHR CMD patients had impaired flow during hyperemia (Tmnhyp 0.45±0.24 vs 0.26±0.18 Normal Group vs 0.21±0.07 LR CMD p<0.01). MRR was reduced in CMD patients (Normal 4.70±1.78 vs CMD 2.20±0.59, p<0.01), with no differences between CMD subtypes (HHR 2.17±0.47 vs LHR CMD 2.24±0.70, p=0.66). Conclusions In INOCA patients, MRR and CFR are strongly correlated and could be considered as functionally interchangeable tools. LHR CMD subtype is characterized by a pathological low resistance and high flow at rest while HHR CMD presented an impaired flow during hyperaemia.

Cycling coupled to intra-coronary thermodilution to evaluate angina with non-obstructive coronary artery disease

Abstract BACKGOUND Patients with Angina and Non-Obstructive Coronary Artery disease (ANOCA) face misdiagnosis and inadequate treatment. A new continuous thermodilution method enables assessment of absolute coronary blood flow (Q) and microvascular resistance (Rµ). The effectiveness of saline-induced hyperemia in capturing exercise-induced coronary flow regulation remains unknown. OBJECTIVE To describe Q and Rµ adaptation during exercise and to explore the correlation between Coronary Flow Reserve (CFR) derived from saline and exercise-induced hyperemia, as well as Microvascular Resistance Reserve (MRR). Methods Q, Rµ, CFR and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery, followed by subsequent stress testing using a dedicated supine cycling ergometer. The microvascular parameters were assessed during incremental workload of 30 watts every two minutes. CFRsaline<2.5 was considered the cutoff for coronary microvascular dysfunction. A minimal sample size of 29 participants was required to detect a hypothesized Spearman coefficient correlation r=0.5 between CFRsaline and CFRexercise using a 80% power and 5% significance level test. Results Coronary microvascular dysfunction was observed in 53.3% of the participants with suspected ANOCA (16 out of 30). During cycling, participants with coronary microvascular dysfunction had a lower reduction in Rµ (-109 [32; 286] versus -202 [102; 379] WU per 30 watts, p<0.01) and a lower ability to increase coronary flow (7 [30.5; 103.0] versus 21 [5.8; 45.0] mL/min per 30 watts, p=0.01) compared with those without coronary microvascular dysfunction. In the overall population, average CFRsaline and CFRexercise were 2.70±0.90 and 2.85±1.54, respectively (p=0.46) with an agreement classification of 83.3%. A good correlation between the two techniques was observed for both CFR (Spearman coefficient r=0.73, p<0.0001) and MRR (r=0.76, p<0.0001). Monitoring of CFR and Rµ during exercise unmasked functional coronary microvascular dysfunction priorly labeled as normal by saline induced hyperemia in 13.3% of the study population. These individuals had a moderate and late decrease of Rµ during the early stages of exercise, with a plateau up to 75% of their theoretical workload. Conclusion Participants with coronary microvascular dysfunction demonstrated compromised CFR due to impaired reduction of Rµ during physical workload. Saline-induced hyperemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate hemodynamic adaptation among participants with functional dysfunction.

Coronary microvascular dysfunction in heart failure: observations from the MICRO registry

Abstract Background Heart failure (HF) is one of the leading causes of hospitalization in the elderly. Coronary microvascular dysfunction (CMD), among other risk factors, is linked to the pathogenesis and clinical manifestations of HF. Purpose This abstract aims to summarize key findings from a comprehensive analysis of CMD in subgroups of HF, shedding light on its association with hemodynamic parameters. Methods Patients experiencing recurrent angina (CCS II-IV) and no relevant epicardial stenosis were enrolled in a prospective registry (MICRO). Epicardial and microvascular responses (pressure, resistance and flow) were assessed at rest and during adenosine and acetylcholine testing. The impact of an elevated left ventricular end-diastolic pressure (LVEDP) in the absence of clinical signs of HF was also investigated. Results Overall, 188 patients (63% (118) women, mean age 65±11 years) with angina and no epicardial stenosis were enrolled. Patients with HF (n=26) displayed lower hyperemic flow in response to endothelium-independent adenosine (5.2±3.1 vs. 7.3±4.4; P=0.004), lower coronary flow reserve (2.9±1.5 vs. 4.4±1.1; P<0.001) and microvascular resistance reserve (3.3±2.1 vs. 5.2±2.7; P<0.001), and increased microvascular resistance during adenosine-induced hyperemia (25±21 vs. 17±11; P=0.045). An increased LVEDP without clinical signs of HF was not associated with a lower coronary flow reserve (4.3±1.9 vs. 2.6±1.2; P=0.006) or microvascular resistance reserve (4.9±2.1 vs. 2.8±1.7; P=0.004). Microvascular resistance during acetylcholine (endothelium-dependent)-induced hyperemia was lower in HF patients (36.2±23.5 vs. 57.4±37.8; P=0.018). Conclusion(s) Patients with heart failure displayed signs of impaired microvascular endothelium-independent responses while endothelium-dependent reactivity appears to be maintained. An elevated LVEDP without clinical HF was not associated with impaired coronary microvascular function.

Absolute coronary flow and microvascular resistance before and after TAVR

Abstract Purpose This study aims to investigate microcirculatory changes, both at rest and during hyperemia, using continuous intracoronary thermodilution, before TAVR, immediately post-TAVR, and at 6-month follow-up. Methods We included consecutive patients with high-gradient AS undergoing TAVR with non-obstructive coronary artery disease in the left anterior descending artery (LAD). Absolute coronary flow (Q) and microvascular resistance (R) were measured in the LAD using continuous intracoronary thermodilution at rest (Qrest) and during hyperemia (Qhyper) before and after TAVR, as well as at 6-month follow-up. Echocardiography and cardiac computed tomography (CCT) were used to quantify total myocardial mass and LAD-specific mass. Regional myocardial perfusion (QN) was calculated by dividing absolute coronary flow by the subtended myocardial mass. Results In 51 patients, absolute flow and microvascular resistance were assessed at rest and during hyperemia before and after TAVR. The mean age was 84.1 ± 5.0 years, and 35 participants were male (68.6%). Measurements were also obtained 6 months after TAVR in 20 (39%) patients. Overall, there were no significant changes in resting and hyperemic flow and resistance before and after TAVR (Qrest 68 [55-88] mL/min vs 69 [54 – 92] mL/min, p=0.776; Qhyper 158 [129 – 200] mL/min vs 172 [132, 216] mL/min, p=0.449, before and after TAVR, respectively). Consequently, coronary flow reserve (CFR) and microvascular resistance reserve (MRR) remained unchanged. At 6 months, there were no significant changes in flow and resistance both at rest and during hyperemia compared to baseline (Qrest: 72 [63-84] vs 83 [59-108] mL/min, p=0.658; Qhyper: 181 [158-200] vs 194 [167-222] mL/min, p=0.492; pre-TAVR and at 6 months follow-up, respectively), resulting in unchanged CFR and MRR. However, at follow-up, there was a noteworthy reduction in left ventricular mass of approximately 13% (from 201.9 ± 37.9g to 175.1 ± 46.6 g, p<0.001), leading to an increase in hyperemic perfusion (QN,hyper: 0.86 [0.69-1.06] vs 1.20 [0.99-1.32] mL/min/g, p=0.008; pre-TAVR and follow-up, respectively), but not in resting perfusion (QN, rest: 0.34 [0.30-0.48] vs 0.47 [0.36-0.67] mL/min/g, p=0.06). Conclusion Immediately after TAVR, there are no changes in absolute coronary flow and coronary flow reserve. Over time, LV remodeling is associated with increased hyperemic perfusion, indicating that, in the context of the observed pathophysiological changes in coronary microcirculation in AS patients after TAVR, the reverse LV remodeling has a more significant impact than the acute LV unloading achieved by valve replacement itself.

Predictors of microvascular spasm by spasm provocation testing in patients having angina with no obstructive coronary arteries

Abstract Background Microvascular dysfunction in patients having angina with no obstructive coronary arteries (ANOCA) has been recognized to be associated with poor prognosis, while microvascular spasm (MVS) has not been fully studied due to its diagnostic challenge. Purpose We aimed to explore clinical and coronary physiological characteristics of MVS. Methods We retrospectively studied patients with ANOCA who underwent spasm provocation test (SPT) with intracoronary acetylcholine administration followed by coronary physiological assessment. Epicardial spasm and MVS were diagnosed in accordance with the latest guideline. Physiological indices such as coronary flow reserve (CFR), index of microcirculatory resistance (IMR) and microvascular resistance reserve (MRR) were assessed by bolus thermodilution method using pressure temperature wire in LAD and RCA. Results In a total of 141 patients, 40 (28.4%) patients were diagnosed as epicardial spasm and 22 (15.6%) were diagnosed as MVS according to the diagnostic criteria of the latest guideline. Women was more frequent (63.9% vs 27.3%, P=0.002) and IMR of LAD was significantly higher (34.80 vs 22.95, P=0.005) in patients with versus without MVS. In addition, hypertension tended to be frequent (81.8% vs 60.5%, P=0.089) in patients with MVS. In a multivariable logistic regression analysis, women (odds ratio 5.64 [OR], 95% CI 1.90 – 16.7, P=0.0018) and IMR of LAD (OR 1.02, 95% CI 1.00 – 1.05, P=0.029) were independently associated with the diagnosis of MVS. On the other hand, no clinical characteristics and physiological parameter were significantly associated with epicardial spasm. In a comparison between microvascular and epicardial spasm, women (OR 8.30, 95%CI 2.23 – 30.9, P=0.0016) and IMR of LAD (OR 1.04, 95%CI 1.00 – 1.08, P=0.0462) were still significantly more frequent in MVS patients in multivariable analysis. Conclusion Women and higher IMR of LAD were significantly frequent in patients with versus without MVS, and hypertension tended to be frequent in MVS patients.

Microvascular resistance reserve: impact on health status and myocardial perfusion after revascularization in chronic coronary syndrome.

The microvascular resistance reserve (MRR) is a novel invasive index of the microcirculation, which is independent of epicardial stenoses, and MRR has both diagnostic and prognostic implications. This study investigates whether MRR is associated with health status outcomes by revascularization in patients with moderate coronary stenoses. Consecutive patients with stable chest pain and moderate (30-90% diameter) stenoses on invasive coronary angiography (n=222) underwent invasive physiology assessment. Revascularization was performed by guideline recommendations. At baseline and follow-up, health status and myocardial perfusion were assessed by Seattle Angina Questionnaire (SAQ) and positron emission tomography. The primary endpoint was freedom from angina at follow-up with secondary endpoints including changes in health status by SAQ domains and myocardial perfusion by MRR and revascularization status. Low MRR was defined as ≤3.0. Freedom from angina occurred in 38/173 patients. In multivariate analyses, MRR was associated with freedom from angina at follow-up (odds ratio 0.860, 95% confidence interval 0.740-0.987). By MRR and revascularization groups, patients with normal MRR who did not undergo revascularization, and patients with abnormal MRR who underwent revascularization, improved health status of angina frequency (mean difference SAQ angina frequency score 8.5 [3.07-13.11] and 13.5 [2.82-23.16], respectively). For both groups, health status of physical limitation (mean difference in SAQ physical limitation score 9.7 [4.79-11.93] and 8.7 [0.53-13.88], respectively) and general health status (mean difference in SAQ summary score 9.3 [5.18-12.50] and 10.8 [2.51-17.28], respectively) also improved. Only patients with abnormal MRR who underwent revascularization improved myocardial perfusion. In patients with moderate coronary stenoses, MRR seems to predict symptomatic and perfusion benefit of revascularization.

Development and validation of a novel angiography-derived index of absolute coronary blood flow and resistance.

Intracoronary continuous thermodilution has been recently proposed as an invasive method to quantify absolute coronary flow (Qabs) and resistance (Rabs) in vivo. The aim of the present study is to develop and validate of a novel pressure-wire- and microcatheter-free surrogate of coronary flow and resistance derived from a standard coronary angiogram. Angiography derived coronary flow (Qangio) and resistance (Rangio) was prospectively validated in a two-center cohort of patients from Oxford Heart Centre and the Essex Cardiothoracic Centre. Qabs and Rabs were measured during resting and hyperemic conditions with continuous thermodilution using the Rayflow microcatheter. Qangio and Rangio were computed from the diagnostic coronary angiogram in a blinded fashion in resting and hyperemic conditions. A total of 62 patients and 115 vessels were included in the present analysis. The median Qabs at rest was 75ml/min (53-95) and 151ml/min (105-203) during hyperemia; Qangio at rest was 84ml/min (66-108) and 154ml/min (115-195) during hyperemia. There was a strong correlation between Qabs and Qangio (R = 0,72; p < 0.001, R = 0,86; p < 0.001 respectively) with satisfactory interclass correlation (0.841, 95% CI 0.509-0.957; p = 0.0003). The median Rabs was 1111 mmHg/(L/min) (830-1581.4) at rest and 454 mmHg/(L/min) (348-610) during hyperemia; angiographic resistance (Rangio) was 937.4 mmHg/(L/min) (695.4-1261.9) at rest and 492.4 mmHg/(L/min) (406-697) during hyperemia. There was a strong correlation between Rabs and Rangio in both conditions (R = 0,81; p < 0.001 and R = 0,78; p < 0.001 respectively). The was a good correlation between absolute coronary flow reserve (CFR) and angiography-derived CFR (R = 0,61; p < 0.001) and between absolute microvascular resistance reserve (MRR) and angiography-derived MRR (R = 0,49; p < 0.001).

Changes in absolute coronary flow and microvascular resistance during exercise in patients with ANOCA.

Whether saline-induced hyperaemia captures exercise-induced coronary flow regulation remains unknown. Through this study, we aimed to describe absolute coronary flow (Q) and microvascular resistance (Rμ) adaptation during exercise in participants with angina with non-obstructive coronary artery disease (ANOCA) and to explore the correlations between saline- and exercise-derived coronary flow reserve (CFR) and microvascular resistance reserve (MRR). Rμ, Q, CFR and MRR were assessed in the left anterior descending artery using continuous thermodilution with saline infusion at 10 mL/min (rest), 20 mL/min (hyperaemia) and finally at a 10 mL/min infusion rate during stress testing with a dedicated supine cycling ergometer. An incremental workload of 30 watts every two minutes was applied. A saline-derived CFR (CFRsaline) cutoff <2.5 was used to identify coronary microvascular dysfunction (CMD). CFRsaline-defined CMD was observed in 53.3% of the participants (16/30). While cycling, these patients less of an ability to increase Q (7 [interquartile range [IQR] 30.5-103.0] vs 21 [IQR 5.8-45.0] mL/min/30 watts; p=0.01) due to a smaller decrease of Rμ (109 {IQR 32-286} vs 202 [IQR 102-379] Wood units [WU]/30 watts; p<0.01) as compared with the group with normal CFRsaline. In the overall population, CFRsaline and exercise-derived CFR (CFRexercise) were 2.70±0.90 and 2.85±1.54, respectively, with an agreement classification of 83.3%. A good correlation between saline and exercise techniques for both CFR (r=0.73; p<0.0001) and MRR (r=0.76; p<0.0001) was observed. Among participants with normal CFRsaline, 28.7% (4/14) had an impaired CFRexercise <2.5 at the peak of exercise due to a moderate and late decrease of Rμ. Saline-induced hyperaemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate adaptation among participants with exercise-related CMD.

Continuous thermodilution and microvascular resistance reserve during the index procedure in acute coronary syndrome without obstructive coronary artery disease: A pilot study.

In 5%-25% of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients, coronary angiography reveals no obstructive coronary arteries (MINOCA). Coronary microvascular disease (CMD) is a potential causal pathophysiological mechanism in these patients and can be diagnosed by continuous thermodilution assessment. Recently, the microvascular resistance reserve (MRR) has been introduced as a novel index to assess the vasodilatory capacity of the microcirculation. However, continuous thermodilution and MRR have never been investigated in the acute setting in MINOCA patients and invasive assessment of the microcirculation in these patients are currently lacking. The objectives of the study were to investigate the incidence of CMD (MRR ≤ 2.7) in patients with MINOCA and to evaluate the feasibility and safety of continuous thermodilution-based assessment during index coronary angiography in the acute setting. This study was a prospective, observational, pilot study investigating coronary physiology in the acute setting in MINOCA patients. Patients admitted with a diagnosis of NSTE-ACS were eligible for inclusion. In total, 19 MINOCA patients were included in this analysis;the mean age was 70 ± 9 years, and 79% were females. CMD was present in 6 patients (32%). Qrest was significantly higher in the MRR ≤ 2.7 group compared to the MRR > 2.7 group (0.076 [0.057-0.100] vs. 0.049 [0.044-0.071] L/min, p = 0.03). Rµ,rest was significantly lower in the MRR ≤ 2.7 group compared to the MRR > 2.7 group (1083 [710-1510] vs. 1563 [1298-1970]WU,p = 0.04). No periprocedural complications or hemodynamic instability have occurred during continuous thermodilution assessment during the index coronary angiography. In patients admitted for MINOCA undergoing immediate coronary angiography, continuous thermodilution assessmentand MRR are feasible and safe in the acute setting, and evidence of functional CMD could be observed in one-third of the MINOCA patients.

The pressure-derived microvascular resistance reserve and its correlation to Doppler MRR measurement-a proof of concept study.

Microvascular resistance reserve (MRR) is a recently introduced specific index of coronary microcirculation. MRR calculation can utilize parameters deriving from coronary flow reserve (CFR) assessment, provided that intracoronary pressure data are also available. The previously proposed pressure-bounded CFR (CFRpb) defines the possible CFR interval on the basis of resting and hyperemic pressure gradients in the epicardial vessel, however, its correlation to the Doppler wire measurement was reported to be rather poor without the correction for hydrostatic pressure. We aimed to determine the pressure-bounded coronary MRR interval with hydrostatic pressure correction according to the previously established equations of CFRpb adapted for the MRR concept. Furthermore, we also aimed to design a prediction model using the actual MRR value within the pressure-bounded interval and validate the results against the gold-standard Doppler wire technique. Hydrostatic pressure between the tip of the catheter and the sensor of the pressure wire was calculated by height difference measurement from a lateral angiographic view. In the derivation cohort the pressure-bounded MRR interval (between MRRpbmin and MRRpbmax) was determined solely from hydrostatic pressure-corrected intracoronary pressure data. The actual MRR was calculated by simple hemodynamic equations incorporating the anatomical data of the three-dimensionally reconstructed coronary artery (MRRp-3D). These results were analyzed by regression analyses to find relations between the MRRpb bounds and the actual MRRp-3D. In the derivation cohort of 23 measurements, linear regression analysis showed a tight relation between MRRpbmax and MRRp-3D (r 2 = 0.74, p < 0.0001). Using this relation (MRRp-3D = 1.04 + 0.51 × MRRpbmax), the linear prediction of the MRR was tested in the validation cohort of 19 measurements against the gold standard Doppler wire technique. A significant correlation was found between the linearly predicted and the measured values (r = 0.54, p = 0.01). If the area stenosis (AS%) was included to a quadratic prediction model, the correlation was improved (r = 0.63, p = 0.004). The MRR can be predicted reliably to assess microvascular function by our simple model. After the correction for hydrostatic pressure error, the pressure data during routine FFR measurement provides a simultaneous physiological assessment of the macro- and microvasculature.

Effects of age on microvascular function in patients with normal coronary arteries.

It has been suggested that coronary microvascular function decreases with age, irrespective of the presence of epicardial atherosclerosis. Our aim is to quantitatively investigate the effects of age on microvascular function in patients with normal coronary arteries. In 314 patients with angina with no obstructive coronary artery disease (ANOCA), microcirculatory function was tested using the continuous thermodilution method. In 305 patients, the association between age and both resting and hyperaemic myocardial blood flow (Q), microvascular resistance (Rμ), absolute coronary flow reserve (CFR) and microvascular resistance reserve (MRR) was assessed. In addition, patients were divided into 3 groups to test for differences based on age quartiles (≤52 years [24.9%], 53-64 years [49.2%], ≥65 years [25.9%]). The mean age was 59±9 years with a range from 22 to 79 years. The mean resting Q (Qrest) was not different in the 3 age groups (88±34 mL/min, 82±29 mL/min, and 86±38 mL/min, R2=0.001; p=0.62). A trend towards a decreasing mean hyperaemic Q (Qmax) was observed with increasing age (223±79 mL/min, 209±84 mL/min, 200±80 mL/min, R2=0.010; p=0.083). The mean resting Rμ (Rμ,rest) were 1,204±460 Wood units (WU), 1,260±411 WU, and 1,289±455 WU (p=0.23). The mean hyperaemic Rμ (Rμ,hyp) increased significantly with advancing age (429±149 WU, 464±164 WU, 503±162 WU, R2=0.026; p=0.005). Consequently, MRR decreased with age (3.2±1.2, 3.1±1.0, 2.9±0.9; p=0.038). This trend was present in both the patients with (n=121) and without (n=184) coronary microvascular dysfunction (CMD). There is an age-dependent physiological increase in minimal microvascular resistance and decrease in microvascular function, which is represented by a decreased MRR and is independent of atherosclerosis. The age-dependent decrease in MRR was present in both patients with and without CMD and was most evident in patients with smooth coronary arteries.

The Influence of Epicardial Resistance on Microvascular Resistance Reserve

BackgroundThe optimal index of microvascular function should be specific for the microvascular compartment. Yet, coronary flow reserve (CFR), despite being widely used to diagnose coronary microvascular dysfunction (CMD), is influenced by both epicardial and microvascular resistance. Conversely, microvascular resistance reserve (MRR) adjusts for fractional flow reserve (FFR), and thus is theoretically independent of epicardial resistance. ObjectivesThe authors tested the hypothesis that MRR, unlike CFR, is not influenced by increasing epicardial resistance, and thus is a more specific index of microvascular function. MethodsIn a cohort of 16 patients who had undergone proximal left anterior descending artery stenting, we created 4 grades of artificial stenosis (no stenosis, mild, moderate, and severe) using a coronary angioplasty balloon inflated to different degrees within the stent. For each stenosis grade, we calculated CFR and MRR using continuous thermodilution (64 measurements of each) to assess their response to changing epicardial resistance. ResultsGraded balloon inflation resulted in a significant sequential decrease in mean FFR (no stenosis: 0.82 ± 0.05; mild: 0.72 ± 0.04; moderate: 0.61 ± 0.05; severe: 0.48 ± 0.09; P < 0.001). This translated into a linear decrease in mean hyperemic coronary flow (no stenosis: 170.5 ± 66.8 mL/min; mild: 149.8 ± 58.8 mL/min; moderate: 124.4 ± 53.0 mL/min; severe: 94.0 ± 45.2 mL/min; P < 0.001). CFR exhibited a marked linear decrease with increasing stenosis (no stenosis: 2.5 ± 0.9; mild: 2.2 ± 0.8; moderate: 1.8 ± 0.7; severe: 1.4 ± 0.6), corresponding to a decrease of 0.3 for a decrease in FFR of 0.1 (P < 0.001). In contrast, MRR exhibited a negligible decrease across all stenosis grades (no stenosis: 3.0 ± 1.0; mild: 3.0 ± 1.0; moderate: 2.9 ± 1.0; severe: 2.8 ± 1.0), corresponding to a decrease of just 0.05 for a decrease in FFR of 0.1 (P < 0.001). ConclusionsMRR, unlike CFR, is minimally influenced by epicardial resistance, and thus should be considered the more specific index of microvascular function. This suggests that MRR can also reliably evaluate microvascular function in patients with significant epicardial disease.

Prognostic Value of Microvascular Resistance Reserve Measured Immediately After PCI in Stable Coronary Artery Disease.

Microvascular resistance reserve (MRR) has been proposed as a specific metric to quantify coronary microvascular function. The long-term prognostic value of MRR measured in stable patients immediately after percutaneous coronary intervention (PCI) is unknown. This study sought to determine the prognostic value of MRR measured immediately after PCI in patients with stable coronary artery disease. This study included 502 patients with stable coronary artery disease who underwent elective PCI and coronary physiological measurements, including pressure and flow estimation using a bolus thermodilution method after PCI. MRR was calculated as coronary flow reserve divided by fractional flow reserve times the ratio of mean aortic pressure at rest to that at maximal hyperemia induced by hyperemic agents. An abnormal MRR was defined as ≤2.5. Major adverse cardiac events (MACEs) were defined as a composite of all-cause mortality, any myocardial infarction, and target-vessel revascularization. During a median follow-up of 3.4 years, the cumulative MACE rate was significantly higher in the abnormal MRR group (12.5 versus 8.3 per 100 patient-years; hazard ratio 1.53 [95% CI, 1.10-2.11]; P<0.001). A higher all-cause mortality rate primarily drove this difference. On multivariable analysis, a higher MRR value was independently associated with lower MACE and lower mortality. When comparing 4 subgroups according to MRR and the index of microcirculatory resistance, patients with both abnormal MRR and index of microcirculatory resistance (≥25) had the highest MACE rate. An abnormal MRR measured immediately after PCI in patients with stable coronary artery disease is an independent predictor of MACE, particularly all-cause mortality.