Sudden Cardiac Death and Sudden Cardiac Arrest in Patients with Human Immunodeficiency Virus: A Systematic Review

The importance of this review lies in its study of the risk of sudden cardiac death (SCD) and sudden cardiac arrest (SCA) in people living with the human immunodeficiency virus (PLWH). To the best of our knowledge, this is the first review investigating the effect of the human immunodeficiency virus (HIV) on SCD and SCA. The review's objective was to determine the risk of SCD and SCA in PLWH. To do this, the electronic databases Ovid MEDLINE, EMBASE, Cochrane Central, Scopus, and Google Scholar were systematically searched to identify eligible studies published before January 31, 2021. Reference lists of the included studies were searched for further identification of relevant studies. The search terms included: "Sudden Cardiac Death," "Sudden Cardiac Arrest," "Human Immunodeficiency virus," "HIV," "Acquired immunodeficiency syndrome," and "AIDS." Only observational studies that assessed the association between SCD and SCA in PWLH were selected. Data were extracted by two independent authors who screened titles, abstracts, and articles to meet the inclusion criterion. Quality assessment was done by using modified Downs and Black checklist. A total of seven studies were included in this review. Five studies revealed a higher incidence of SCD in PLWH, two of which focused on patients with HIV and low left ventricular ejection fraction (LVEF). The other two studies were about the association of HIV and SCA. Studies reported that PLWH had a three- to five-fold higher incidence of SCD as compared to non-HIV patients. HIV patients with low LVEF had a higher incidence of SCD than HIV patients with normal LVEF. PLWH had a higher incidence of SCA and less successful cardiopulmonary resuscitation (CPR) as compared to patients without HIV. After adjusting for various confounders in multiple studies, all the studies reported a higher incidence of SCD in PLWH. To conclude, PLWH is at an increased risk of SCD and SCA. Some risk factors for this include LVEF, viral load (VL), and the cluster of differentiation 4 (CD4) count. There is a paucity of data on the mechanisms involved, although a higher prevalence of cardiac fibrosis and interstitial fibrosis in PLWH may play a role. Because of the general suboptimal quality of the heterogeneous nature of the current evidence, further, rigorous studies are needed to determine the association of increased risk of SCD and SCA in PLWH.


Introduction And Background
Human immunodeficiency virus (HIV) infection was defined by the World Health Organization (WHO, 2007) as positive HIV antibody testing using rapid or laboratory-based enzyme immunoassay and/or positive HIVribonucleic acid (RNA) or HIV-deoxyribonucleic acid (DNA) or HIV p24 antigen. The result should be confirmed by a second test [1]. In 2019, 38 million people were living with HIV (PLWH), with around 690,000 deaths from acquired immunodeficiency syndrome (AIDS)-related illnesses worldwide. In 2019, around 2.2 million people were living with HIV in western and central Europe, and North America, with 12,000 HIVrelated deaths [2].
Sudden cardiac death (SCD) is a sudden unexpected cessation of cardiac function with hemodynamic collapse, which results in death within one hour of onset. If the patient survived, that event was called sudden cardiac arrest (SCA). In general, most studies reported that the incidence of SCD is 1 or 2 per 100,000 persons per year; however, Couper et al. reported that the incidence is between 0.75 and 11.9 cases per 100,000 persons per year [3]. The underlying etiology and pathogenesis of SCD vary; ventricular fibrillation is the most common cause of SCD. Structural heart disease, including ischemic heart disease, nonischemic cardiomyopathy, and noncardiac conditions like pulmonary embolism, aortic rupture, and other arrhythmias, are also associated with SCD [4]. Few studies reported an association between SCD and HIV. Therefore, in the present study, we performed a systemic review of whether HIV is associated with SCD and SCA, focusing on patients with heart failure.

Review Methods
This systematic review was conducted according to Preferred Reporting for Systematic Review and Meta-Analysis (PRISMA) as recommended by Cochrane Collaboration [5]. A systematic literature review using MEDLINE, EMBASE, Cochrane Central, Scopus, and Google Scholar was performed using the terms "HIV," "AIDS," "Sudden Cardiac Death," and "Sudden Cardiac Arrest" for literature published till January 31, 2021. We included additional articles found in the review of bibliographies or suggested by co-authors based on their relevance to the selected search terms.

Study Selection and Eligibility Criteria
Search results were saved in EndNote files and transferred into Covidence. Two reviewers (BA and NB) independently performed the title and abstract screening to include the articles regarding PLWH, SCD, and SCA. Conflicts were resolved through a third author (KG). Next, we reviewed the selected articles using the following inclusion criteria: randomized controlled trial (RCT); observational study; study population involving adults with HIV; primary outcome SCD, SCA; assessment of incidence and prevalence between HIV and SCD or SCA; English written text; Full text. We excluded case reports and case series with five or fewer cases, studies population children, non-full text articles. Conflicts were resolved through the third author (KG).

Data Extraction
Data from included studies were extracted independently by two reviewers (BA, KG) from Covidence. The consensus was reached in case of any inconsistency with a third author (NB). The data extracted for qualitative synthesis included location, year of study, study design, sample size, population age (in years), and incidence or prevalence of SCD or SCA. The data were entered in Microsoft Office Excel 2016 (Microsoft Corporation, Redmond, WA) by BA and checked by a second author (KG). Any discrepancy was resolved by a discussion between the authors.

Assessment of the Methodological Quality of Included Reviews
We assessed the methodical rigor of the included studies using the modified Downs and Black checklist for RCTs and non-randomized studies [6]. The checklist has 27 items with a total possible score of 28. Papers were rated excellent if they scored above 25, good if they scored between 20 and 25, fair if they scored between 15 and 19, and poor if they scored <15. Each study was assessed by two independent investigators (NB and RR), and discrepancies in scoring were resolved by a third author (BA).

Analysis of Outcome
The primary outcome of interest was the association between SCD and HIV patients with and without heart failure (HF). The secondary outcome was the association between HIV and SCA.

Study Identification and Selection
We identified 272 relevant citations. After removing the duplicates, 140 citations were selected as potentially relevant. The titles and abstracts were screened, and then 10 full-text articles were chosen for further review. Three articles were excluded, one of them was an editorial review and the other two were irrelevant intervention and outcome. Finally, seven articles were included in this systematic review ( Figure 1).

Characteristics of Included Studies
The patient's baseline characteristics and summary of the included studies are outlined ( Table 1 and Table  2). The patients' baseline characteristics included age, gender, body mass index (BMI), HIV parameters, risk factors, and co-morbidities.

Assessments of Bias, Study Quality, and Heterogeneity
The assessment of the methodological quality of the studies ranged from fair to low. Most of the studies included in this systematic review were observational and provided fair quality evidence ( Table 3). These studies had a high heterogeneity level due to variability in the participants, interventions, and outcomes reported.

Secondary Outcome
Our secondary outcome was the risk of SCD or SCA in PWLH and having low LVEF and the success rate of CPR in PLWH.

Discussion
SCA leading to SCD is the most common cause of death worldwide, representing more than 50% of all cardiovascular disease deaths [14]. Myocardial fibrosis, primary electrophysiological conditions, and coronary artery disease predispose to SCD. Possible precipitating factors include ischemia, hypoxia, toxins, and electrolyte abnormalities. Combination of susceptible myocardium and precipitating factors lead to ventricular arrhythmias and SCA, followed by SCD if the CPR was unsuccessful in retrieving the patient.
In this systematic review, we included seven studies that reported the effect of HIV on SCD; five studies analyzed the association between SCD and HIV; Yen et al. [8] reported a higher incidence rate of SCD in PLWH than non-HIV patients, 68.31 and 9.31 per 100,000 persons per year, respectively. Lai et al. [9] reported that compared with the general population, PLWH had a higher risk of incident coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, SCD, heart failure, and chronic kidney disease but had a lower risk of atrial fibrillation. Tseng et al. [12] reported that SCD account for most cardiac and many non-AIDS natural deaths in PLWH. Alvi et al. [7] and Moyers et al. [11] were mainly on Heart Failure (HF) patients and determined the impact of LV dysfunction on SCD in PLWH. Alvi et al. [7] reported that PLWH had a 3-fold increase in SCD [(21 vs. 6.4%), adjusted OR=3.0, CI (1.78-4.24)]. Moyers et al. [11] reported that the incidence of SCD for EF<30% as compared to EF>40% was significantly higher (HR of 22.0, 95% CI 6.0-80.9, p<0.001).
Tseng et al. [12]  All three articles agreed that the PLWH has a higher incidence of SCD than the general population, and it was statistically significant.
Both Alvi et al. [7] and Moyers et al. [11] were interested in the HIV patient who had HF or LV dysfunction. Alvie et al. [7]  . They also reported that low LVEF, low CD4, and higher viral load were predictors of SCD. Moyer et al. [11] determined the impact of LVEF on SCD in PLWH. They included 423 patients who had at least one transthoracic echocardiogram, and the results revealed that the lower the EF, the higher the risk of SCD. The risk of SCD for EF<30% was higher compared to EF>40% (HR of 22.0, 95% CI 6.0-80.9, p<0.001). Both studies showed that HIV patients with HF have a higher rate of SCD than HIV patients without HF, and the lower the EF, the higher the SCD events.
Two studies analyzed the association between SCA and HIV, Mongaeden et al. [10]  This study has many limitations. First, the quality of included studies was limited to fair, with one poor article. Variation in study quality contributed to the heterogeneity of findings noted. Other sources of heterogeneity are likely to include population differences, including age as a factor contributing to SCD or SCA. Second, all of the included studies were observational studies (prospective or retrospective) affecting the extracted data. Some medical history details can be missed, which leads to selection and information biases. Third, all of the articles lacked the autopsy findings for the SCD cases, so all cases of SCD were presumed not confirmed. Usually, a histopathological exam of the heart is essential to know the underlying etiology [15]. Fourth, Sudden death in PLWH with CD4+ T cell count < 50/cm has been termed as HIV death rather than SCD. The cause of death in such circumstances is severe immunodeficiency rather than SCD. Alvi et al. [7], Mongarden et al. [10], Moyers et al. [11], and Tseng et al. [12] reported that their patients had a CD4+ T cell count of more than 50/cm. But Yen et al. [8], Lai et al. [9], and Raviglione et al. [13] didn't report CD4+ T cell count for their patients. Fifth, external validation was questionable in all of these studies, as these studies were in a specific location and lacked randomization.
To the best of our knowledge, this is the first review investigating the effect of HIV on SCD and SCA.

Conclusions
This systematic review revealed a higher rate of SCD and SCA in a patient with HIV than in the general population. The risk is even higher in HIV patients with low LVEF. After adjusting for various confounders like age, sex, and race, the risk factors for cardiovascular disease, persistently low CD4 counts, and high viral loads are also associated with increased risk of SCA and SCD in PLWH. There is a paucity of data on the mechanisms involved, although the prevalence of cardiac fibrosis and interstitial fibrosis in PLWH may play a role. Because of the general suboptimal quality of the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of increased risk of SCD and SCA in PLWH.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.