Association of cardiac injury with hypertension in hospitalized patients with COVID-19 in China

Outbreak of global pandemic Coronavirus disease 2019 (COVID-19) has so far caused countless morbidity and mortality. However, a detailed report on the impact of COVID-19 on hypertension (HTN) and ensuing cardiac injury is unknown. Herein, we have evaluated the association between HTN and cardiac injury in 388 COVID-19 (47.5 ± 15.2 years) including 75 HTN and 313 normotension. Demographic data, cardiac injury markers, other laboratory findings, and comorbidity details were collected and analyzed. Compared to patients without HTN, hypertensive-COVID-19 patients were older, exhibited higher C-reactive protein (CRP), erythrocyte sedimentation rate, and comorbidities such as diabetes, coronary heart disease, cerebrovascular disease and chronic kidney disease. Further, these hypertensive-COVID-19 patients presented more severe disease with longer hospitalization time, and a concomitant higher rate of bilateral pneumonia, electrolyte disorder, hypoproteinemia and acute respiratory distress syndrome. In addition, cardiac injury markers such as creatine kinase (CK), myoglobin, lactic dehydrogenase (LDH), and N-terminal pro brain natriuretic peptide were significantly increased in these patients. Correlation analysis revealed that systolic blood pressure correlated significantly with the levels of CK, and LDH. Further, HTN was associated with increased LDH and CK-MB in COVID- 19 after adjusting essential variables. We also noticed that patients with elevated either high sensitivity-CRP or CRP demonstrated a significant high level of LDH along with a moderate increase in CK (p = 0.07) and CK-MB (p = 0.09). Our investigation suggested that hypertensive patients presented higher risk of cardiac injury and severe disease phenotype in COVID-19, effectively control blood pressure in HTN patients might improve the prognosis of COVID-19 patients.

www.nature.com/scientificreports/ large proportion of patients who incur severe COVID-19 disease symptoms and disproportionately experience worse outcome than one without HTN 13-15 . Cardiac injury occurs at an early stage of COVID-19, such that rate of incidence noticed during admission at 16.44% rose up to 25.53% with those non-survivors 16 . Similarly, another study with a big cohort of 416 patients reported a 19.7% incidence of cardiac injury in COVID-19 patients. These reports suggest that concurrent myocardial damage could be an independent risk factor in hospital mortality 12 . Although a precise underlying mechanism driving cardiac injury in COVID-19 remains obscure, plausible reasons could be viral infection or a preexisting cardiovascular disease or the combination of both and this is worsened in the patients, who have an exaggerated cytokine storm 4 . However, two recent independent postmortem examinations demonstrated the absence of viral particles in cardiac tissues irrespective of a pronounced local tissue inflammation 17,18 which suggests that deteriorating pre-existing cardiovascular disease could be the primary cause of cardiac injury in COVID-19 patients. Since ACE2 is extensively expressed in the heart tissue and plays a role in cardiovascular homeostasis, we decided to investigate the role of HTN in SARS-CoV-2 mediated myocardial damage in COVID-19 patients. As determined, this study examined in depth on the potential association between HTN and cardiac injury in patients with COVID-19.

Methods
Study design and participants. In this multicenter retrospective study, 388 laboratory-confirmed COVID-19 patients admitted in the designated hospitals between January 16 th and March 14 th , 2020 were randomly enrolled. Patients, who were 18 years or older were included in this investigation. The diagnosis for COVID-19 was strictly followed in accordance with World Health Organization interim guidance 19 and the principles outlined in the Declaration of Helsinki. This study protocol was approved by the Ethics Committee of Xiangya Hospital, Central South University, Hunan and the informed written consent was obtained from all study participants.

Data collection.
The medical records of 388 COVID-19 patients were retrospectively reviewed and analysed. Epidemiological (age and sex) as well as clinical information (symptoms, chronic medical histories, laboratory findings and other complications) along with the radiological results, documented during hospitalization were collected and verified independently by two physicians. Based on the seventh edition of the Chinese National Health Commission (https:// www. scirp. org/ refer ence/ refer ences papers. aspx? refer enceid= 28515 16), patients were categorized into severe disease status, if they meet any of the following criteria: 1) shortness of breath, respiratory rate ≥ 30 beats per min; 2) oxygen saturation ≤ 93% at rest; 3) arterial oxygen partial pressure/ oxygen concentration ≤ 300 mmHg (1 mmHg = 0.133 kPa); 4) lung images showing obvious progress of lesion size > 50% within 24 − 48 h. and patients were classified into mild disease status, if they presented mild clinical symptoms or mild/no lesions on imaging findings.
Cardiac injury biomarker data such as creatine kinase (CK), creatine kinase-MB (CK-MB), myoglobin, lactate dehydrogenase (LDH), and N-terminal pro brain natriuretic peptide (NT-proBNP) were assessed immediately after hospitalization. Cardiac troponin I (cTnI) was not accounted in this study, since most of the patients presented within the normal range of cTnI and that was indicated as < 0.01 ng/mL. Criteria of acute respiratory distress syndrome (ARDS) was followed as mentioned in the Berlin definition 18 . All patients were carefully reviewed for their chronic medical history (coronary heart disease, arrhythmia, hyperlipidaemia, HTN diabetes, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, and cerebrovascular disease) and divided into two groups based on their pre-existing HTN. All clinical features and study outcomes were compared between hypertensive-and normotensive-COVID-19 patients.
Subgroup analysis on the correlation between inflammation and cardiac injury was conducted in COVID-19 patients concurrent with HTN. Specifically, hypertensive COVID-19 patients were divided into two groups based on their elevated level of either C-reactive protein (CRP) or high sensitivity-CRP (hs-CRP), and cardiac injury markers were compared. Statistical analysis. Statistical analyses were performed using SPSS version 20.0 statistical software (SPSS Inc., Chicago, IL, USA). Descriptive statistics was obtained for all study variables. Continuous variables were presented as mean ± standard deviation (SD), if they were normally distributed; otherwise, they were presented as median ± range interquartile (IQR), and categorical variables as frequencies. All categorical variables between the patients with and without HTN were analyzed using Fisher exact test or χ2 test and continuous variables were compared using t-test or Mann-Whitney U test, as appropriate. The Spearman correlation coefficient was calculated to disclose relationship of inflammatory or cardiac injury markers with blood pressure. Further, binary logistic regression model was performed to determine the association between blood pressure and cardiac injury in these patients after adjusting essential variables. Statistical charts were generated using Prism 7 (GraphPad Software Inc., San Diego, CA, USA). A two-sided p < 0.05 was considered statistically significant for the entire data set.
Laboratory and radiographic findings. We next sought to investigate the metrics of laboratory and radiography assessments. As expected, hypertensive-COVID-19 patients demonstrated a significant higher level of CRP ( 12. HTN and cardiac injury. Next, we sought to investigate the association between blood pressure and cardiac injury. As seen in the Fig. 1, patients with HTN demonstrated a significant increase in the level of cardiac injury markers -CK, myoglobin, LDH, and NT-pro BNP, while change in CK-MB was subtle. Correlation analysis revealed that systolic blood pressure in patients with COVID-19 correlated significantly with the levels of CK (R = 0.124, p = 0.01), and LDH (R = 0.103, p = 0.05); while diastolic blood pressure showed a trend to correlate with the level of myoglobin (R = 0.113, p = 0.06) and LDH (R = 0.089, p = 0.09) (Fig. 2). Further logistic regression analysis showed that HTN was associated with increased LDH (p = 0.001) and CK-MB (p = 0.05) in COVID-19 patients after adjusting age, gender, and comorbidity of diabetes, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, and chronic kidney disease (Table 4).
Previous studies have demonstrated that inflammatory cells such as macrophage and T cells in HTN infiltrate into the heart and results in cardiac and other end-organ damage 20 . A significant correlation between cardiac injury (levels of CK, myoglobin, LDH, and CK-MB) and inflammation (CRP, hs-CRP) has been observed in the present study (Fig. 3). We next compared cardiac injury markers in hypertensive-COVID-19 patients with and without CRP/hsCRP incensement and found that patients who presented an elevated inflammatory status also demonstrated a significant increase in LDH and a moderate increase in CK (p = 0.07) and CK-MB (p = 0.09) (Fig. 4). Further correlation analysis suggested a significant correlation between hs-CRP and systolic blood pressure in patients with COVID-19 (Fig. 5). Those results suggested that HTN was associated with increased cardiac injury, and inflammation might participate in hypertensive mediated cardiac injury.

Discussion
To the best of our knowledge, this is the first report providing comprehensive information on epidemiological, demographic, clinical, laboratory and radiological characteristics of hospitalized COVID-19 patients in the context of HTN and ensuing myocardial damage. Our results specifically highlighted a significant association between HTN and cardiac injury in COVID-19 patients. In addition, our subgroup analysis demonstrated that inflammation could be a potential factor driving HTN induced cardiac injury in COVID-19. The case-fatality rate for overall COVID-19 ranges from 0.0 to 28.9% across different geographical locations, while it rises up to 40% in patients admitted to intensive care unit 21 . Most importantly, cardiac injury has been reported as an independent risk factor of mortality in patients with COVID-19 12,22 . A recent meta-analysis showed that 24.4% of the hospitalized COVID-19 patients developed cardiac injury and 72.6% of them did not survive 23 . Studies also showed that hospitalized, COVID-19 patients with preexisting cardiovascular disease, such as HTN have been more susceptible to COVID-19 related cardiac injury 23,24 . Consistently, our study also demonstrated that HTN was the most common comorbidity (almost 19.3%) observed in hospitalized COVID-19 patients and also, these patients displayed an increase of cardiac injury markers, such as LDH, CK, and myoglobin.  www.nature.com/scientificreports/ As one of the most common cardiovascular comorbidities, HTN is a risk factor for increased intensive care unit admission 14 , utilization of mechanical ventilation 25 , and mortality 26 . A blood pressure control with a target of < 130/80 mmHg during hospitalization is associated with fewer adverse clinical events in patients with COVID-19 27 . High blood pressure is one of the most critical risk factors for developing cardiovascular complications 28,29 . In this study, we have demonstrated that systolic blood pressure in patients with COVID-19 correlated significantly with the levels of CK, LDH; and hypertension was associated with increased LDH and CK-MB in COVID-19 patients after adjusting age, gender, and comorbidity of diabetes, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, and chronic kidney disease. Thus, our study provided direct evidence in establishing a strong association between HTN and cardiac injury in COVID-19.
COVID-19 infection activates an excess production of inflammatory cytokines (interleukin-6 and tumour necrosis factor-α)-a cytokine storm which results in systemic inflammation, multi organ dysfunction and acutely, affecting the cardiovascular system 30,31 . An uncontrolled and dysfunctional immune response characterized by continuous activation and proliferation of lymphocytes and macrophages are the hallmark of this cytokine   18,33,34 .
In this study, we found inflammatory markers such as CRP, hs-CRP were significantly increased in hypertensive-COVID-19. Further, in the hypertensive group, COVID-19 patients with increased CRP or hs-CRP presented an increased level of cardia injury markers, LDH (p < 0.001), CK (p = 0.07) and CK-MB (p = 0.09). Incidentally, chronic inflammation associated with HTN synergizes cytokine storm and worsens host immune surveillance in SARS-CoV-2 infection 35,36 . It has been established that macrophages and T cells infiltrate into the heart in response to HTN, which ultimately results in end-organ damage 20 . Further, the deficiency of CD8 + cytotoxic T cells effectively protect against hypertension-induced cardiac damage in COVID-19 37,38 . A significant linear correlation between hs-CRP and systolic blood pressure has been observed in the present study, suggesting HTN associated pro-inflammatory state might drives cardiac injury that worsens the prognosis of patients with COVID-19.   www.nature.com/scientificreports/ We acknowledge that number of confirmed COVID-19 patients enrolled in this study is a limitation and further validation of our findings on a larger, multiple centered cohorts is warranted. Moreover, constrains such as space, time and the hospitals designated warded us off from utilizing conventional techniques such as echocardiography and electrocardiography.

Conclusion
Our investigation suggested that HTN is associated with a higher risk of cardiac injury and severe disease phenotype in COVID-19, effectively control blood pressure in HTN patients might improve the prognosis of COVID-19 patients. This study also suggested HTN associated pro-inflammatory state might drive cardiac injury that worsens the prognosis of patients with COVID-19, thus provided a cue in understanding the mechanism of cardiac injury in COVID-19.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.