The outcomes of acute myocardial infarction patients comorbidity with hypertension and hyperhomocysteinemia

This study investigated the outcomes and major adverse cardiovascular events (MACEs) incurred by acute myocardial infarction (AMI) patients comorbiding with hypertension and hyperhomocysteinemia (HHcy) during hospitalization and 1-year follow-up. 648 consecutive AMI patients were divided into four categories: (1) hypertension with Hcy ≥ 15 µmol/L; (2) hypertension with Hcy < 15 µmol/L; (3) no-hypertension with Hcy ≥ 15 µmol/L; (4) no-hypertension with Hcy < 15 µmol/L. Information taken from these case files included gender, past medical history, vital signs, laboratory examination, electrocardiogram, coronary angiography, cardiac ultrasound, and medicine treatment. The primary endpoints were duration of coronary care units (CCU) stay, duration of in-hospital stay, and MACEs during follow-up. Our data show that hypertension and HHcy have a synergistic effect in AMI patients, AMI comorbiding with hypertension and HHcy patients had more severe multi-coronary artery disease and more frequent non-culprit coronary lesions complete clogging, had a higher prevalence of pro-brain natriuretic peptide, and significant decreases in the left ventricular ejection fraction. These patients had significant increases in the duration of CCU stay and in-hospital stay, had significant increase in the rate of MACEs, had significant decreases in the survival rate during follow-up.

The primary endpoints and its components. First, the primary endpoints and its components during hospitalization were analysed. For hypertension patients, there were significant increase in the duration of coronary care units (CCU) stay (4.31 ± 2.61 vs. 3.32 ± 2.05, P < 0.001) and the duration of hospital stay (13.11 ± 4.95 vs. 11.94 ± 4.43, P = 0.020) in the HHcy patients; the rate of MACEs (defined as cardiovascular death, acute heart failure, and arrhythmia complications) (23.8% vs. 14.0%, P = 0.021) were also increase in the HHcy patients. When the components of MACEs were further investigated, we found that the cardiac death rate (7.9% vs. 3.8%, P = 0.108) and arrhythmia complications rate (11.9% vs. 6.4%, P = 0.077) increased in the HHcy patients (Table 3). For no-hypertension patients, there were a trend of increased such as the MACEs rate, the cardiovascular death rate, duration of CCU stay, and duration of hospital stay in the HHcy patients, but these did not reach a significant value (Table 3). Then the primary endpoints and its components during 1-year follow-up were analysed. For hypertension patients, there were significant increase in the rate of MACEs (defined as cardiovascular death, repeat MI, and repeat PCI/CABG) (17.2% vs. 8.6%, P = 0.026) in the HHcy patients. When the componensts of MACEs were further investigated, we found that the cardiovascular death rate (5.7% vs. 2.9%, P = 0.222) increased in the HHcy patients, but there were only a trend of increased the incidence of repeat MI, and repeat revascularization, these did not reach a significant value (Table 3). For no-hypertension patients, there were a trend of increased the incidence of MACEs and cardiovascular death rate, but these did not reach a significant value (Table 3). Kaplan Meier analysis of cumulative survival at 1-year follow-up demonstrated that the significant survival down-regulated in hypertension comorbidity with HHcy group comparing with other three groups (Fig. 1).

Discussion
To the best of our knowledge, the present study is the first to report the baseline characteristics and outcomes of AMI patients comorbidity with hypertension and HHcy. Our novel major findings are summarized as follows: (1) AMI patients with hypertension and HHcy have more severe multi-coronary artery disease and more frequent NCCLs chronic total occlusion; (2) AMI patients with hypertension and HHcy have a higher prevalence  Hcy is a type of amino acid that contains sulfur and is produced by methionine metabolism. HHcy was believed to promote atherogenesis and atherothrombosis through several mechanisms 2 . Hcy metabolism generated reactive oxygen species that could directly injure the endothelium. Hcy had been shown to inhibit nitric oxide synthase, leading to endothelial dysfunction. 10% of general population coronary artery disease (CAD) risk was attributed to Hcy 8 . The elevated Hcy concentration was closely related to the mortality and morbidity of CAD 9 . The risk of coronary artery disease would be increased by 60% for men and 80% for women with an elevation of 5 µmol/L in plasma Hcy 8 . HHcy was not only associated with CAD but also with AMI. In AMI patients, elevated Hcy level was associated with a higher risk of coronary events and death, independently of other risk factors 10 . An elevated plasma Hcy level was an independent predictor of the incidences of heart failure, cardiac rupture, death, and the total 30-day cardiovascular events in AMI patients 11 . Plasma Hcy concentration was an independent predictor for long-term mortality and MACE in ACS octogenarians after controlling conventional cardiovascular risk factors 12 . Culprit lesions, the treatment of which was the primary goal of PCI, had been found to be responsible for AMI, while NCCLs were considered to be innocent 13 . Hcy was an independent risk factor for NCCLs progression after 12 months of follow-up in elderly patients with ACS who had undergone PCI 14 . In the present study, we found that for hypertension patients, coronary artery atherosclerosis was more severe that presented with multi-vessel disease (61.4% vs. 47.8%, P = 0.010), more frequent in non-culprit vessels chronic total occlusion (14.9% vs. 7.6%, P = 0.035), and significant decreases in LVEF (48.78 ± 9.18% vs. 53.20 ± 6.96%, P = 0.021) in the HHcy patients. Because of these disease feature, there were significant increase in the CCU stay (4.31 ± 2.61 vs. 3.32 ± 2.05, P < 0.001) and hospitalization stay (13.11 ± 4.95 vs. 11.94 ± 4.43, P = 0.020), the rates of MACEs during hospitalization or during 1-year follow-up also increased in the HHcy patients. Among the no-hypertension patients, we also found that coronary artery disease was more severe that presented with multi-vessel disease (50.3% vs. 39.7%, P = 0.005) in the HHcy patients. Our data was similar with previous study, which suggested the HHcy could predict the risk and outcomes of patients with AMI.
Hypertension was one of the main risk factors for atherosclerosis development. Some pathophysiologic mechanisms involved in the genesis of hypertension (such as endothelial dysfunction, insulin resistance, and diabetes) were also the risk factors for CAD 15 . Hypertension was shown to be associated with an increased rate of adverse outcomes after AMI such as heart failure and cardiovascular death 16 . HHcy had been linked to hypertension for the past years, elevated Hcy levels had been consistently reported in hypertensive patients. Previous studies found that hypertension and HHcy had shown a multiplicative effect, increased the risk of stroke 17 and recurrent ischemic stroke 18 . Hypertension and HHcy should be the major intervention measures to decrease the incidence of carotid atherosclerotic plaques as well as the stroke 19 . Prevalence of events increased with increasing plasma Hcy levels suggesting a contribution of Hcy to cerebro-cardiovascular diseases in hypertensive patients 20 . HHcy were associated with impaired endothelial dependent vasodilatation in hypertension, Hcy and endothelium dysfunction might promote thrombogenesis and atherogenesis, leading to adverse cardiovascular events 21,22 . It had been well known that pathophysiologic mechanism of cerebro-cardiovascular atherosclerosis was identical. Then we supposed that hypertension comorbidity with HHcy might have multiplicative effect in the outcomes of AMI patients. In the present study, our data were similar with previous study. We found that for HHcy patients, coronary artery disease was more severe that presented with multi-vessel disease (61.4% vs. 50.3%), more frequent non-culprit vessels chronic total occlusion (14.9% vs. 9.8%), and significant increases in Pro-BNP (628 (1311, 2125) vs. 265 (680, 1324) pg/mL) in the hypertension patients. We also found that the rates of MACEs during hospitalization or during 1-year follow-up also increased in the hypertension patients when In conclusion, the results of this study could have some relevant implications for identification the outcomes and management of AMI patients comorbidity with hypertension and HHcy. Comparing to AMI patients with hypertension or HHcy alone, AMI patients comorbidity with hypertension and HHcy significantly increased the risk of MACEs at in-hospital and1-year follow-up, and decreased the survival rate at 1-year follow-up.

Methods
Study population and inclusion criteria. This study was a single center retrospective study based on the medical records of enrolled patients, which comprised 736 consecutive AMI patients, second-generation drugeluting stent implantation in all patients, which were defined as NSTEMI or STEMI 23 , and who were admitted to our hospital from June 2018 to December 2020. Among them, 41 patients who were missing Hcy values were excluded. 47 patients with incomplete clinical data, hypothyroidism, and those who took medicine that could potentially affected the Hcy metabolism (such as folic acid, vitamins, and carbamazepine) were excluded. 648 patients were finally enrolled in this research. Information taken from these case files included gender, age, discharge diagnosis, history of smoking, hypertension, diabetes mellitus, dyslipidemia, Hcy, vital signs, laboratory examination, electrocardiogram, coronary arteriography, cardiac ultrasound, complications, and medicine treatment. The primary endpoints of this study were duration of CCU stay, duration of hospital stay, and MACEs defined as cardiovascular death, acute heart failure, arrhythmia, myocardial infarction (MI), and repeat revascularization (repeat percutaneous coronary intervention or coronary artery bypass grafting). Follow-up was obtained in every patient that survived to discharge by reviewing the medical records and / or by telephone interview with the patient or family members at 1-year after admission.
The study complied with the declaration of Helsinki for investigation in human beings and was approved by the Ethical Committee of The First Affiliated Hospital of Nanchang University. As the study obtained relevant information from the previous medical records, the Ethical Committee agreed that the researchers did not need to obtain the written consent of the relevant patients.
Definitions. Hypertension was defined as blood pressureure ≥ 140/90 mmHg or the use of antihypertensive medications. Diabetes mellitus was defined as fasting plasma glucose ≥ 6.1 mmol/L and postprandial glucose ≥ 7.8 mmol/L, and/or diagnosed diabetes mellitus receiving treatment. Dyslipidemia was defined as current treatment with cholesterol-lowering medications or TC value of > 5.72 mmol/L and/or TG value of > 1.7 mmol/L and/or LDL-C value of > 3.12 mmol/L and/or HDL-C value of < 1.0 mmol/L. HHcy was defined as Hcy ≥ 15 mmol/L. Serum samples were measured in the first 48 h after admission from peripheral venous blood samples. Patients that had smoked during the previous 6 months were classified as smokers and were selfreported. Arrhythmia included atrial fibrillation, ventricular premature beat, ventricular tachycardia, and atrioventricular block. AMI was diagnosed if the patient fulfilled 2 of the following 3 standards: chest pain continuing for > 30 min; dynamic alteration of ST-T appears in the electrocardiogram (ECG); and dynamic increases in troponin I or creatine kinase MB greater than three times the upper limit of normal value. Coronary artery stenosis was diagnosed based on the presence of > 50% lumen obstruction of at least one of three major coronary arteries. Statistical analysis. All analyses were conducted using the statistical software SPSS statistics 20 (IBM Corp, Armonk, NY, USA), and P < 0.05 was considered to be statistically significant. Continuous variables were expressed as mean ± standard deviation or median (with inter-quartile range), and categorical variables as numbers and percentages. Comparisons between quartiles were made by analysis of variance test for continuous variables and the Pearson chi-square test for categorical variables. Survival analysis was performed by applying the Kaplan-Meier method and log-rank test. Multivariate COX regression was used to determine the main risk factors for MACEs in follow-up. Multivariate COX regression analysis adopted the entry method, and P < 0.05 (two-sided) was considered as the difference was statistically significant.