Prognostic Impact Of Coronary Microvascular Dysfunction Assessed By CaIMR In HFpEF&MINOCA Patients

BackgroundDuring the last few decades,cardiovascular disease,particularly ischemic heart disease,has represented a major burden and has accounted for the leading cause of disease-related deaths.Consistent data shows that coronary microvascular dysfunction(CMD)is frequently observed and ranges between 25～75%in individuals with multiple cardiovascular risk factors without obstructive coronary artery disease.CMD is the result of marked abnormalities of myocardial blood flow,either by impaired dilation and/or increased vascular resistance of the microvessels caused by cardiomyocyte injury may perhaps be responsible for symptoms and deranged hemodynamics in patients with persistent myocardial ischemia.CMD is also proposed to be an important predictor of adverse prognosis in a substantial group of patients,including in patients with heart failure(HF)with preserved ejection fraction(HFpEF)and myocardial infarction with nonobstructive coronary arteries(MINOCA),while no treatment options in these patient groups have proven convincingly effective,the outcomes have not improved in recent decades.Prompt identification of optimal management therapy of patients also requires accurate diagnosis and classification of patients with underlying pathology,which may pave the way for novel therapies to improve hemodynamic and exercise capacity,and overall outcomes.Therefore,accurate diagnosis and classification of patients with CMD are essential.The index of microvascular resistance(IMR)is established as the gold standard and widely used measure of coronary physiology to assess minimal coronary microvascular resistance,and the invasively measured IMR is a marker of CMD.However,the microvascular function measurement is not typically assessed in all patients and remains undetected due to multiple reasons and has become an unmet therapeutic need.AimHere,this work aims to evaluate the emerging prognostic impact of CMD assessed via coronary angiography derived-index of microvascular resistance(caIMR)in a specific population that includes HFpEF and MINOCA and to provide clinical insights on coronary microcirculation in these groups of patients as a potential target for new intervention strategies which go beyond conventional methods to provide prognostic benefits and risk stratification for the patients.Part one:Prognostic role of CMD assessed by caIMR in heart failure with preserved ejection fractionAimWe sought to demonstrate the prognostic value of the coronary angiographyderived Index of microvascular resistance(caIMR)in HFpEF patients.MethodsParticipants in the study were consecutive patients who were undergoing evaluation using coronary angiography,serum NTproBNP levels,and transthoracic 2dimensional echocardiography during hospitalization at Shanghai Tenth People’s Hospital from 2018 to 2020.We enrolled HFpEF patients(N=172,72.1±10.4 years,male:68.0%)with heart failure symptoms and without flow-limiting CAD.The most common objective for evaluation was to evaluate chest pain,dyspnea,or a combination of the two.Patients’ clinical characteristics,medical history,laboratory,and medication data were ascertained during hospitalization.A comprehensive evaluation of coronary microvascular function was performed by caIMR.caIMR was estimated from computational pressure-flow dynamics simulations,which were then applied to CAG.The primary outcome was a composite of all-cause death,acute myocardial infarction,and HF readmission.CMD was defined as caIMR>25.ResultsCMD was found in 59.3%of the total cohort.HFpEF patients were stratified into two groups;CMD(caIMR>25)and non-CMD(caIMR<25).The mean age was 72.1 ± 10.4 years,and 68.0%were males.No significant differences were found between the two groups in terms of baseline characteristics,including sex,BMI,and prevalence of comorbidities(hypertension,diabetes,atrial fibrillation,COPD,and CKD)as well as discharge medication.Laboratory and blood investigations(such as NTproBNP,troponin T,HBA1C,Fasting blood glucose,triglycerides,LDL cholesterol,HDL cholesterol,creatinine,uric acid,and eGFR)between the two groups were similar.In contrast,CMD patients showed a trend toward lower mean total cholesterol compared to patients without CMD(3.5±0.9 vs.3.8±0.9,P=0.054).The cardiac structure and function evaluated by conventional echocardiography and tissue Doppler parameters(such as LVPWD,LVEF,LAVI,E’,E/e’,LVEDD,LVESD)did not vary in both groups.No echocardiographic parameter could identify the presence or absence of CMD.caIMR in HFpEF patients with CMD was significantly higher than in those without CMD(30.3±5.0 vs.20.6±3.1,P<0.001).Sixty-two patients experienced an incidence of composite events during the median follow-up period of 15 months.Kaplan-Meier analysis illustrated an increased risk of composite events in patients with high caIMR(log-rank P<0.001).In multivariate-adjusted analysis,caIMR≥25 was an independent predictor of clinical outcomes(HR,3.98;95%CI:2.01-7.89,P<0.001).The ROC curve analysis showed an AUC of 0.792(95%CI 0.715 to 0.869,P<0.001)for caIMR to predict adverse outcomes.ConclusionCMD,as assessed by caIMR,frequently coexists in HFpEF patients.caIMR is a significantly strong predictor of composite events and adverse clinical outcomes in HFpEF patients.These findings indicate that CMD may play a role in worsening symptoms and causing decompensation in people with HFpEF.As a result,CMDtargeted therapy may enhance HFpEF patients’ quality of life and prognosis.Part two:Prognostic role of CMD assessed by caIMR in Myocardial infarction with non-obstructive coronary arteriesAimThis study aimed to evaluate the prognostic role of CMD as assessed by caIMR in MINOCA patients.MethodsParticipants in the study were consecutive patients with no previous history of myocardial infarction who were undergoing evaluation for acute myocardial infarction(AMI)using electrocardiography,serum troponin levels,and coronary angiography during hospitalization at Shanghai Tenth People’s Hospital between 2015 to 2019.This study included 262 MINOCA patients.Patients’ clinical characteristics,medical history,laboratory,and medication data were ascertained during hospitalization.A comprehensive evaluation of coronary microvascular function was performed by caIMR.caIMR was estimated from computational pressure-flow dynamics simulations,which were then applied to CAG.The primary endpoint of the study was major adverse cardiovascular events(MACE),defined as cardiovascular death,non-fatal MI,heart failure,stroke,and angina readmission.CMD was defined as caIMR≥40.ResultsMINOCA patients were stratified into two groups;CMD(caIMR≥40)and nonCMD(caIMR<40).CMD was found in 54.5%of total MINOCA patients.The mean age was 62.9± 13.1 years,and 51.1%were females.No significant differences were found between the two groups in terms of baseline characteristics,including sex,BMI,Tobacco use,and prevalence of cardiovascular risk factors(hypertension,hyperlipidemia,atrial fibrillation,diabetes,history of stroke and heart failure,and presenting ECG with S TEMI/N S TEMI,as well as LVEF evaluated by echocardiography.The laboratory investigations with cardiac biomarkers(troponin T,CKMB,myoglobin,NTproBNP)revealed no significant differences between CMD and without CMD group(all P>0.05),as well as other biochemistry parameters(i.e.,CRP,fasting blood glucose,HbAlc,triglycerides,total cholesterol,LDL cholesterol HDL cholesterol,creatinine,and uric acid)did not differ between the groups.The commonly prescribed secondary prevention medications such as dual antiplatelet therapy(DAT)with aspirin and clopidogrel,statins,beta-blockers,CCB,and ACE-I or ARB on discharge were similar between the CMD and non-CMD groups.caIMR in MINOCA patients with CMD was significantly higher than in those without CMD(52.8±11.1 vs.32.3±4.5,P<0.001).Overall,54 MACE were experienced during a 28 months median of follow-up.On comparisons in patients without CMD,the incidence of MACE was significantly high in the CMD group(13.4%vs.26.5%,P=0.008).In patients with high caIMR,Kaplan-Meier survival analysis curves demonstrated a significantly increased risk of MACE incidence(log-rank P=0.009).In multivariate-adjusted analysis,caIMR>40 was an independent predictor of MACE(HR,1.83;95%CI,1.01-3.32;P=0.047).The ROC curve analysis showed an AUC of 0.635(95%CI 0.547to 0.723,P<0.002)for caIMR to predict adverse outcomes.ConclusionsCMD,as assessed by caIMR,frequently coexists in MINOCA patients.caIMR was an independent predictive factor of clinical outcomes in MINOCA patients.These findings indicate that CMD may play a role in exacerbating and provoking adverse prognosis in MINOCA patients.As a result,CMD-targeted therapy may enhance MINOCA patients’ quality of life and outcomes.