Systemic Arterial Hypertension

ACE2 (angiotensin-converting enzyme 2) has been recognized as the binding receptor for SARS-CoV-2 at the onset of the infectious process in a host cell. This binding is achieved through the recognition of the RBD domain belonging to the S1 subunit of the viral S protein. The distribution and presence of ACE2 in human body tissues could act as potential viral targets and, therefore, be susceptible to infection. This receptor has been highly identied in type II alveolar epithelial cells of the lung, brain, and enterocytes of the small intestine⁷.

ACE2 (angiotensin-converting enzyme 2) is a secreted and membrane-associated aminopeptidase expressed in various tissues⁸. Discovered in 2000 as a homolog of the angiotensin-converting enzyme (ACE)⁹, it has a potent negative regulatory action on the reninangiotensin system (RAS), which plays a signicant role in cardiovascular physiology and homeostasis through the regulation of electrolyte balance, blood pressure and vascular tone^10,11. Dysfunction of the RAS results in elevated levels of angiotensin II, a vasoactive peptide with vasoconstrictive and inflammatory properties, increasing the number of macrophages and their infiltration into the vascular wall, thereby raising immune cell numbers and inammation, contributing to increased oxidative stress¹⁰.

In various animal models and human studies, it has been demonstrated that chronic administration of renin-angiotensin system (RAS) inhibitors increases the expression of ACE2. This suggests the possibility of higher susceptibility to SARS-CoV-2 infection and a more severe disease course with the use of RAS inhibitors¹².

The endothelium, lining the inner wall of vessels and being the primary regulator of vascular homeostasis, modulates the balance between vasoconstriction/vasodilation, inhibits the proliferation/migration of vascular wall muscle cells, and also modulates hemostasis. Endothelial dysfunction is an event that precedes the morphological changes characteristic of atherogenesis and contributes to the development of complications of atherosclerotic plaque¹³.

This common denominator is most prevalent among COVID-19 comorbidities. In hypertension, sustaine delevation of systemic pressure in the microvasculature leads to premature aging and increased turnover of endothelial cells, affecting the endothelium's ability to release endothelium-derived relaxing factors, causing vasoconstriction¹⁴. Endothelial dysfunction is suggested to be involved in COVID-19 progression due to atypical manifestations among patients, such as cardiac injury and hypercoagulability, indicated by increased levels of D-dimer and Von Willebrand factor. Common inammator y markers obser ved in endothelial dysfunction, including C-reactive protein, IL-6, and TNF-alpha, are also elevated in COVID-19 patients⁽¹⁵⁾. The mechanical stress caused by high intraluminal pressure in the vascular wall activates NADPH oxidase (NOX), the main enzyme producing reactive oxygen species, triggering oxidative stress leading to endothelial dysfunction. This oxidative stress incites a destructive cascade in the arterial wall followed by chronic inammation resulting in changes in the arterial wall, such as remodeling, increased intimamedia thickness, and functional remodeling¹⁶.

Obesity

Overweight and obesity are major health issues in Mexico⁽¹⁷⁾. According to the latest "National Health and Nutrition Survey 2020," the combined prevalence of overweight-obesity in adults over 20 years was 76.8% in women and 73.0% in men¹⁸.

Obesity, along with other diseases like diabetes mellitus or hypertension, are risk factors and increase mortality due to COVID-19. These conditions are associated with hypertrophy and hyperplasia of adipocytes, which disrupt the balance in the production of adipokines, inducing the secretion of pro-inammatory adipokines such as leptin, interleukins (IL-1β, IL-6, and IL-8), TNF-α, MCP-1, and decreasing the production of anti-inammatory adipokines like adiponectin^18,19. These cytokines cause low-grade inammation and a dysfunction of innate immunity, predisposing to the development of infections.

Leptin acts on pulmonary broblasts and contributes to lung inammation by inducing pro-inammatory cytokines and chemokines, with high leptin levels associated with more severe lung inammation in COVID-19 patients. There is a positive correlation between the duration of SARS-CoV-2 infection and the degree of interstitial brosis; pulmonary brosis due to an excess of extracellular matrix components produced by activated myobroblasts poses a barrier to gas exchange²⁰.

The cellular receptor for SARS-CoV-2, besides being expressed in the heart, vessels, lungs, kidneys, testicles, and brain, is also present in adipose and lung tissues in obese patients²¹.

Elevated expression of angiotensinconverting enzyme by adipose tissue promotes greater viral replication, and adipose tissue can act as a reservoir and storage for the virus. These patients are more susceptible to thromboembolic episodes due to hypercoagulability²².

Obesity also leads to a procoagulant state, which can be exacerbated by SARSCoV-2 infection, thus leading to worse clinical outcomes²³.

The function of various immune cells is also altered in obese patients; obesity affects the responses of T and B cells, thus delaying the adaptive immune response to infection. The weakened immune system in obese patients can result in a higher viral load, rapid replication, and viral spread²⁴.

From a physiological perspective, obesity impairs respiratory mechanics and gas exchange, increases airway resistance, and reduces the strength of respiratory muscles and lung volumes²⁵.

Type 2 Diabetes Mellitus

Diabetes is the second underlying cause of death in Mexico, accounting for 14% of deaths^26,27. A metaanalysis including 33 studies reported a correlation between diabetes mellitus and disease severity, with more patients requiring invasive ventilation and ICU admission, leading to higher mortality in this group²⁸.

Poor glycemic control in patients with type 2 diabetes mellitus is associated with magnesium deciency and a subacute proinammatory state, including increased circulating proinammatory cytokines and altered levels of lymphocytes, neutrophils, and macrophages compared to non-diabetic subjects^29,30.

This lived experience underscores the need for prevention in the face of a future pandemic of this magnitude. Together, these observations indicate that to reduce the impact of SARS-CoV-2, a broad approach is required; interventions must address not only virus transmission but also a comprehensive assessment of a population's health status.

Therefore, the aim of this study was to determine if type 2 diabetes mellitus, hypertension, and obesity increase mortality in patients diagnosed with COVID-19 in Mexico

Search Strategy

A systematic review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines of articles published from January 2020 to December 31, 2021 in English or Spanish.

The systematic search was performed in the following databases using Boolean operators: PubMed MeSH (Medical Subject Heading) ("COVID-19"[MeSH] or "Mexico"[MeSH]) or ("diabetes mellitus" [MeSH] or "obesity" [MeSH] or "Hypertension"[MeSH] or "Mortality"[MeSH]), Scopus (Mexico and COVID-19 or CORONAVIRUS or SARS-CoV-2 or SARS) or (diabetes, obesity, and hypertension or mortality or comorbidity), Web of Science Mexico (title) and COVID-19 (all elds) and (diabetes or hypertension or obesity or mortality (all elds) and comorbidities), Lilas (Mexico and (COVID-19 or SARS-CoV-2 or Coronavirus)), Google Scholar (Mexico and (COVID-19 or SARS-CoV-2 or Coronavirus)), and Scielo (Mexico and (COVID-19 or SARS-CoV-2 or Coronavirus)). The MeSH terms used were: "review" or "literature review" or "Meta-Analysis", type of publication].

Studies without an abstract or full text were excluded. When an abstract met the inclusion criteria, which included hospitalized patients over 20 years old, with reports of the three comorbidities studied (obesity, hypertension, and diabetes mellitus) as well as mortality, the full text was reviewed. All selected articles were identied and reviewed by four authors (AP, LC, AS, SR).

Data Collection and Analysis

Data extraction and management were performed by two independent reviewers (AP, LC). To assess whether studies met the inclusion criteria, two additional reviewers were involved in analyzing the studies (AS, SR). The study selection process is presented in Figure 1. The information extracted and analyzed from the collected studies included the year of study, number of cases included, number of diabetic patients, number of hypertensive patients, number of obese patients, and number of deceased patients. Results are summarized narratively in each relevant section within the text of this review.

Figure 1.  Study selection process in the systematic review on COVID-19 mortality in Mexico. 

From the collected studies, the following information was extracted and analyzed: year of study, number of cases included, number of diabetic patients, number of hypertensive patients, number of obese patients and number of deceased patients..

The results are summarized narratively in each relevant section within the text of this review.

Characteristics of the Included Studies

The 73 included studies were conducted in Mexico, between 2020 and 2021. Most obtained information from national databases like the National Epidemiological Surveillance System with 24 studies (32.8%), and local databases like those of the National Institute of Respiratory Diseases with 20 studies (27.3%), the Ministry of Health with 19 studies (26%), and the Mexican Institute of Social Security with 10 studies (13.6%). 64% of the study population were women, with a median age of 52.9 years SD ±13.27.

The characteristics of the studies are presented in Table 1. Generally, a mortality rate of 16.76% (Min-Max 0.77-73.73%) was reported. 71% of the studies (n=52) did not report specic mortality related to comorbidities. The most prevalent pathology was obesity with a rate of 24.23% (Min-Max 11.50-71.00%), followed by hypertension 22.23% (Min-Max 2.0-53.96%), and nally diabetes mellitus with 18.10% (Min-Max 1.83-40.00%).

Table 1.  Clinical characteristics and mortality of patients hospitalized for COVID-19 in Mexico according to each reviewed study.