Implications and Associations of Elevated Resting Coronary Microvascular Resistances – Results from the SNAPE International Database

O. Velollari (Mainz)¹, S. Miner (Toronto)², H. M. Renteria (Madrid)³, A. M. Leone (Rome)⁴, R. Sykes (Glasgow)⁵, S. Biscaglia (Cona (FE))⁶, L. Di Serafino (Napoli)⁷, G. Esposito (Milan)⁸, D. Galante (Rom)⁹, J. Oreglia (Milan)¹⁰, D. Ang (Clydebank)¹¹, M. Weferling (Bad Nauheim)¹², C. Berry (Glasgow)¹³, J. Escaned (Madrid)³, F. Crea (Rome)⁴, G. Campo (Ferrara)¹⁴, T. Gori (Mainz)^1
1Universitätsmedizin der Johannes Gutenberg-Universität Mainz Zentrum für Kardiologie Mainz, Deutschland; ²Southlake Regional Health Centre Cardiology Toronto, Kanada; ³Hospital Clinico San Carlos Madrid, Spanien; ⁴Catholic University of the Sacred Heart Agostino Gemelli Hospital Rome, Italien; ⁵University of Glasgow Institute of Cardiovascular & Medical Sciences Glasgow, Großbritannien; ⁶Azienda Ospedaliero-Universitaria S. Anna Cardiovascular Institute Cona (FE), Italien; ⁷Department of Advanced Biomedical Sciences, University of Naples Federico II Napoli, Italien; ⁸Division of Interventional Cardiology, De Gasperis Cardio Center ASST Grande Ospedale Metropolitano Niguarda Milan, Italien; ⁹Center of Excellence in Cardiovascular Rom, Italien; ¹⁰De Gasperis Cardio Center ASST Grande Ospedale Metropolitano Niguarda Division of Interventional Cardiology Milan, Italien; ¹¹School of Cardiovascular and Metabolic Health, University of Glasgow Clydebank, Großbritannien; ¹²Kerckhoff Klinik GmbH Abteilung für Kardiologie Bad Nauheim, Deutschland; ¹³Golden Jubilee National Hospital, University of Glasgow School of Cardiovascular and Metabolic Health Glasgow, Großbritannien; ¹⁴Cardiovascular Institute Dipartimento di Medicina Traslazionale U.O. Cardiologia Ferrara, Italien

Background:  
Coronary microvascular dysfunction is defined as reduced coronary flow reserve and/or increased hyperemic microvascular resistances. The significance of elevated resting resistance remains unclear. This study aims to investigate the clinical relevance of elevated resting IMR in patients with angina and non-obstructive coronary arteries (ANOCA). 
Methods:  
1001 ANOCA patients (62±11 years old, 56% female) underwent invasive assessment of coronary flow, pressure, resistance and spasm provocation using a standardized protocol (NCT06125392) across nine international centers. The upper reference limit for resting coronary resistances was defined as the 95th percentile of the values measured in a subgroup with normal hemodynamic responses to adenosine and acetylcholine and no history of stenting, myocardial infarction or heart failure. An independent ANOCA cohort (N=154) served as external validation.  
Results: 
Overall, 130 (13%, 64±11 years old) patients had an elevated resting microvascular resistance (>112 U). When compared with patients with normal resting IMR, these had a higher prevalence of hypertension [78% vs. 60%; p<0.001] and were more often male [59% vs. 42%; p<0.001].  
Patients with elevated resting resistances had lower heart rate at rest (68±13 vs. 74±13, p<0.001) accompanied by a lower rate-pressure product (6829±1728mmHg*b/min vs. 7353±1678; p<0.001). Resting (1.5±0.4s vs. 0.7±0.3s, p<0.001) and hyperemic coronary flow (0.4±0.2s vs. 0.2±0.15s, p<0.001) were reduced, while coronary flow reserve was higher (4.7±2.2 vs. 3.3±1.7, p<0.001). Similarly, microvascular resistance was higher during adenosine (33±18U vs. 19±11U) and acetylcholine infusion (52±32U vs.  30±19U; both p<0.001). The assessment of resting resistances showed high repeatability (Pearson correlation coefficient = 0.728; Cronbach’s alpha = 0.841). 
In univariate analysis, hypertension (2.39 [1.54-3.72]; p<0.001), use of Angiotensin receptor blockers (ARB) (1.58 [1.05-2.37]; p=0.029),  hyperlipidaemia (1.52 [1.02-2.26]; p=0.041), a history of rest symptoms (1.59 [1.04-2.43]; p=0.031) were associated with elevated resting IMR, while female sex showed a negative association with elevated resting IMR (OR=0.49 [0.34-0.71]; p<0.001).  
These findings were confirmed in the external validation cohort. Elevated resting resistances was associated with larger left atrial area (ß* = 0.19; p=0.03) and impaired left atrial function (ß* = -0.28; p=0.002), higher pulmonary arterial pressure (ß* = 0.23; p=0.03), smaller end-diastolic left ventricular volume (ß* = -0.19; p=0.03), left ventricular hypertrophy (ß* = 0.41; p<0.001), and reduced global longitudinal strain (ß* = 0.20; p=0.03). 
Conclusion: 
Assessment of coronary resistances at rest is repeatable. Elevated resting microvascular resistance is associated with younger age, hypertension, abnormalities in cardiac structure and function, and reduced external cardiac work while coronary flow reserve (and therefore vascular responsiveness) is preserved.