| Excessive tortuosity of the coronary arteries(CT)is a somewhat common finding in patients referred for coronary angiography,reported in 14–40% of patients referred for angiography.The presence of CT has been associated with chest pain and myocardial perfusion abnormalities during stress in the absence of obstructive coronary artery disease.Fluid dynamic modeling suggests that stress-induced ischemia may be attributable to a reduction in distal coronary artery perfusion pressure from viscous and turbulence energy losses.The physiologic reasons for CT are unclear.Pre-clinical studies where elastases and collagenases were used to alter arterial morphology together with genetic and pathologic analysis of rare clinical disorders such as arterial tortuosity syndrome have indicated that arterial tortuosity arises from abnormalities in arterial elastin fibers and extracellular matrix.Apart from inherited disorders,some but not all studies have linked CT with hypertension and female sex,and with increased left ventricular(LV)mass from pressure but not volume overload and smaller heart size.Hypertrophic cardiomyopathy(HCM)is associated with an increased left ventricular(LV)wall thickness.HCM is the most common genetic heart disease,characterized by marked clinical and morphologic heterogeneity.Diagnosis is usually based on the echocardiographic finding of unexplained left ventricular(LV)hypertrophy,defined by increased wall thickness in 1 or more LV segments.LV mass is generally assumed to be increased in patients with phenotypically expressed HCM,based largely on early pathological studies.CT among HCM patients has not been studied.Disruption of the ordered arrangement of myofibers alters normal cardiac mechanical function,resulting in temporal and spatial heterogeneity in regional myocardial contractility.Although global LV function is generally unaltered,asynchrony and asynergy in regional function lead to delayed diastolic relaxation and impaired diastolic filling.18-21 Whilst LV ejection fraction is frequently normal in both,LV strain assessment could differentiate,compared to a normal person.Cardiovascular magnetic resonance(CMR),by virtue of its high-resolution volumetric reconstruction of the LV chamber,currently affords a highly accurate and reproducible quantitative assessment of mass.We sought to establish if cardiovascular magnetic resonance myocardial feature tracking(CMR-FT),an emerging method allowing accurate assessment of myocardial deformation,differentiates between HCM with or without CT.Additionally,CMR assessment of fibrosis and LV hypertrophy allowed association analyses and comparison of diagnostic capacities.Part 1:Analysis of coronary tortuosity and prognosis among HCMpatients Objective:Aim to discover whether changes in coronary artery morphology exist among HCM patients and the change is valuable for prognosis Methods:1.Retrospectively,choose HCM and non-HCM patients hospitalized in Fuwai central cardiovascular hospital from1 st Dec 2017 to 10 th June 2021 according to inclusion and exclusion criteria,two groups were matched according to age,sex and hypertension,and divided into HCM group and control group.2.Collect the patient admission baseline data(general information,vital signs,blood test results,ultrasound results)in Fuwai central cardiovascular hospital;46patients were selected and the coronary angiography results were independently interpreted by two independent interpreters using the film reading system of inpatient interventional surgery,and consistency analysis was conducted.Finally,one interpreter was selected to analyze the coronary angiography results of all patients.3.Telephone follow-up was performed,ending on July 10,2021,and the time of all-cause death,ICD implantation,arrhythmia,ischemic stroke,and rehospitalization were recorded.4.The differences in baseline data and coronary angiography results between the HCM group and control group were analyzed.Logistic regression analysis was conducted to explore the influencing factors of CT,and Cox proportional risk model was used to analyze the influence of CT and other factors on the outcome events.Results:1.HCM group had 156 patients with septal hypertrophic cardiomyopathy,24 patients with apical hypertrophic cardiomyopathy,15 patients with symmetric hypertrophic cardiomyopathy,121 patients with SAM sign+,HCM group had a higher history of atrial fibrillation than control group.The average LVOTG of the HCM group was 49.5mm Hg,and the highest LVOTG was 167 mm Hg.The anterior and posterior diameter of left atrium,LVEF and left ventricular thickness in HCM group were significantly higher than those in control group,and the average left ventricular thickness was 20.9mm Hg,while LVEDD,LVESD and SV in HCM group were significantly lower than those in control group.2.The proportion of CT in HCM group was higher than that in control group(124 cases vs.74 cases,P < 0.05).The total score of CT in HCM group was significantly higher than that in control group(P < 0.001).The scores of each coronary vessel in HCM group were all significantly higher than those in control group(P < 0.05).The proportion of vascular tortuosity sign in HCM group was significantly higher than that in control group(80 cases: 28 cases,P < 0.0001),17 cases of Corkscrew sign with 360° change of vascular direction in HCM group,accounting for 8.7%,while no Corkscrew syndrome was found in control group.3.CT was more common in HCM group than in control group(OR=1.68,95%CI:1.26-2.24,P <0.0001).In HCM group,LAD tortuosity,LCX tortuosity,RCA tortuosity and CT were 1.8,1.88,2.43,2.11 times of control group,statistically significant.There was a negative correlation between Wrap-LAD and the occurrence of CT,and the incidence of coronary pedantry in patients with WRAP-LAD was 1/5of that in patients without WRAP-LAD(OR=0.2,95%CI: 0.06-0.66,P =0.008).4.Years of follow-up was 1.4 in HCM group and 1.8 in control group,and Incidence density of the primary endpoint was significantly higher in HCM group than control group(6.0/100 person-years: 2.2/100 person-years,RR 2.67,95%CI:1.15-6.22,P =0.019),and the composite endpoint in the HCM group was significantly higher than control group(23.6/100 person-years: 11.1/ person-year,RR 2.09,95%CI: 1.31-3.33,P= 0.002),Cox proportional risk model analysis showed coronary tortuosity score(HR=1.41,95%CI: 1.14-1.75,P=0.001)and age(HR=1.04,95%CI:1.0-1.08,P =0.048)were risk factors for primary endpoint events.HCM was an independent risk factor for all-cause hospitalization and composite endpoint(HR=2.14,95%CI: 1.28-3.59,P =0.004,HR=1.99,95%CI: 1.26-3.14,P =0.03).Conclusions:1.HCM patients are prone to coronary tortuosity;In addition,Se HCM is prone to LAD,LCX and RCA coronary tortuosity,while AHCM is only prone to LCX and RCA tortuosity,and Sy HCM is prone to RCA tortuosity.2.Coronary tortuosity increases the risk of adverse events(all-cause death,ischemic stroke,ICD implantation,and arrhythmia)by 41% in HCM patients and is expected to be a new prognostic factor for HCM.Part 2:Correlation analysis of myocardial deformation and coronary tortuosity in HCM patientsObjective:The main objectives of this study are: 1.Is there any difference in myocardial strain in HCM patients with different types? 2.To explore the mechanism of coronary tortuosity in HCM patients using CMR myocardial strain analysis.Methods:1.Select HCM patients of the first part who underwent CMR,divided into HCM+CT group and HCM+non-CT group,according to the position of hypertrophy,HCM patients were divided into Se HCM,AHCM and Sy HCM;2.Myocardial strain by CMR-FT analysis was performed.CMR results of 10 patients were randomly selected and analyzed by two independent observers respectively,and inter-observer and intra-observer consistency tests were performed.3.Compare the baseline data and myocardial strain analysis of Se HCM,SyHCM and AHCM groups,and compare the baseline data and myocardial strain analysis of HCM+CT group and HCM+non-CT group.4.Logistic regression analysis was performed to explore the measurement results of myocardial strain affecting coronary tortuosity in all HCM patients and Se HCM patients,respectively.Cox proportional risk model was used to analyze the influence of CT,LAD tortuosity,LCX tortuosity and RCA tortuosity on the endpoint events in all HCM patients and Se HCM patientsResults:1.There were 31 persons in HCM+CT group and 31 persons in HCM+non-CT group,10 persons with AHCM,45 persons with Se HCM,and 7 persons with Sy HCM.There were no significant differences in baseline characteristics and coronary angiography between HCM+CT group and HCM+non-CT group.There were no significant differences in baseline characteristics and coronary angiography results among AHCM,Se HCM,Sy HCM.2.The heart of HCM+CT group was larger and heavier,but there was no statistical difference compared with HCM+non-CT group.The strain,strain rate and displacement of HCM patients were all lower than reported normal value.GRD-basal and GLD-basal in HCM+CT group were significantly lower than HCM+non-CT group.There were also consistent results among Se HCM patients.There were significant differences in left ventricular mass index among AHCM,Se HCM and Sy HCM groups,and the sequence from mild to severe was AHCM,Se HCM and Sy HCM.There were no significant differences in global strain,strain rate and displacement among the three groups(except GLD).Compared with Se HCM,apical strain,strain rate and displacement of AHCM were significantly reduced,while basal strain,strain rate and displacement of Se HCM were significantly reduced,and the myocardial movement at the hypertrophic site was significantly further weakened,while Sy HCM was not further weakened.3.GLD-basal was negatively correlated with CT(OR=0.69,95%CI: 0.49-0.97,P=0.032).There was also a significant negative correlation between GRD-basal and LCX tortuosity(OR=0.50,95%CI: 0.27-0.92,P=0.026).Results were similar in Se HCM;4.Patients in the HCM+CT group were followed up for an average of 1.2 years,during which 8 patients were followed up for end point(including 1 death,1 ICD implantation,1 new ischemic stroke and 5 arrhythmia).Patients in the HCM+non-CT group were followed up for average 1.3 years,only 2 patients were followed up for endpoint(both were new onset of atrial fibrillation).HCM patients with CT,LAD tortuosity and LCX tortuosity had higher risk of endpoint events than those without tortuosity.However,whether RCA tortuosity had no significant effect on endpoint events in HCM patients.In Se HCM,there were 6 endpoint events(1 death,5 arrhythmia)in the mean follow-up of 1.4 years,and 2 endpoint events(both were new onset of atrial fibrillation)in the non-CT group.Se HCM patients with LAD tortuosity alone had a significantly higher risk of end-point events than patients without LAD tortuosity(P=0.009).Conclusions:1.The myocardial strain,strain rate and displacement of HCM patients were all weaker than those of normal subjects,which in hypertrophic region were further significantly weakened.2.CT is correlated with the weakened longitudinal movement of LV basal segment,LCX is correlated with the weakened radial movement of LV basal segment.CT and weakened myocardial displacement suggest the serious state and poor prognosis of HCM patients.Part 3:Genetic analysis of coronary tortuosity in HCM patientsObjective:The main purpose of this study was to investigate the genetic mechanism of CT in HCM patientsMethods:1.Telephone follow-up was conducted for HCM patients and ask them to return to the hospital for blood sampling.Ten non-HCM patients with CT in the hospital were screened for blood samples.2.After signing the testing contract,the blood samples shall be sent to Shanghai Yunxu Biotechnology Co.,LTD for WES;3.HCM patients were divided into HCM+MYH7 group and HCM group according to the presence of MYH7 gene mutation,and the baseline characteristics and coronary angiography results of the two groups were analyzed.4.According to the established screening steps,the mutation sites unique to HCM+CT group that may be related to CT were screened out,and the degree of CT was analyzed in patients with or without the mutation genes.Results:1.A total of 23 HCM patients(13 with CT and 10 without CT)and 10 control+ CT groups were enrolled.5 HCM patients with MYH7 gene mutation were all missense mutations,three of which were new mutations and predicted amino acid changes(E317Q,E1902 Q,D778E).2.HCM patients with or without MYH7 mutation were divided into two groups: HCM group and HCM+MYH7 group.There was no significant difference in baseline data between two groups,but PRO-BNP level was higher in MYH7 mutation group and LVOGT tended to be higher than non-MYH7 mutation group,but there was no significant difference.There was also no significant difference in coronary angiography between the two groups.3.The Q30 value of WES for 13 HCM+CT patients was 93% on average,and the data quality was good.The genes considered to be related to CT were screened out: 7 mutated genes and 8 mutated loci: ADAMT5,EGFL7,PPP2R1 B,COL22A1,CD36,PLOD1,FLNA.PLOD1 genes are associated with Ehrlers-Danlos syndrome.p.r205 h changes have also been reported.FLNA gene mutations are associated with X-linked dominant periventricular heterotopia.The change of p.v6333 a is firstly found.The above-found mutations in the genes involved in angiosis,cardiovascular development and maintenance of vascular stability,vascular smooth muscle cells,endothelial cells and other processes for oxidative stress response,mainly involved in Aortic dissection,expansion of tumor,aortic aneurysm,intracranial aneurysm and atherosclerosis.However relationship between these mutations and CT has yet not been reported.The 7 SNP mutations predicted by software are all conserved,and the protein structure is easy to change after mutation.4.The degree of CT was more severe in HCM+CT+mutation group than HCM+CT+non-mutation group,with chi-square value of 3.75,P=0.053,but the difference was not statistically significant.Conclusions:1.At present,there is no correlation between MYH7 gene mutation and CT in HCM patients.2.WES results showed that ADAMT5,EGFL7,PPP2R1 B,COL22A1,CD36,PLOD1,FLNA and PLOD1 gene mutations occurred in HCM+CT patients,with a total of 8 mutation sites.In addition,the degree of CT in HCM patients with the above-mentioned mutated genes tends to be more severe.Full Conclusion:Patients with HCM are more likely to suffer coronary tortuosity and more severe tortuosity.Coronary tortuosity increases the risk of adverse events in HCM patients by 41% and is expected to be a new prognostic predictor of HCM;reduced myocardial motion in different segments of HCM patients and altered genetic factors are possible mechanisms of coronary tortuosity. |
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