Bidirectionality between Cardiometabolic Diseases and COVID-19: Role of Humoral Immunity

Abstract

Cardiometabolic diseases and abnormalities have recently emerged as independent risk factors of coronavirus disease 2019 (COVID-19) severity, including hospitalizations, invasive mechanical ventilation, and mortality. Determining whether and how this observation translates to more effective long-term pandemic mitigation strategies remains a challenge due to key research gaps. Specific pathways by which cardiometabolic pathophysiology affects humoral immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vice versa, remain unclear. This review summarizes current evidence of the bidirectional influences between cardiometabolic diseases (diabetes, adiposity, hypertension, CVDs) and SARS-CoV-2 antibodies induced from infection and vaccination based on human studies. Ninety-two studies among >408,000 participants in 37 countries on 5 continents (Europe, Asia, Africa, and North and South America) were included in this review. Obesity was associated with higher neutralizing antibody titers following SARS-CoV-2 infection. Most studies conducted prior to vaccinations found positive or null associations between binding antibodies (levels, seropositivity) and diabetes; after vaccinations, antibody responses did not differ by diabetes. Hypertension and CVDs were not associated with SARS-CoV-2 antibodies. Findings underscore the importance of elucidating the extent that tailored recommendations for COVID-19 prevention, vaccination effectiveness, screening, and diagnoses among people with obesity could reduce disease burden caused by SARS-CoV-2.

Keywords: SARS-CoV-2; antibodies; cardiovascular diseases; diabetes; obesity.

FIGURE 1

Underlying biological rationale for potential impacts of adiposity on humoral immune response against SARS-CoV-2. Elevated body mass index is associated with adipose tissue dysregulation [31], increased adipocyte size [32], as well as the increased infiltration and proinflammatory polarization of macrophages [33, 34]. Obesity induces toll-like-receptor signaling pathways, which subsequently upregulate Type I interferon (IFN) signaling and other proinflammatory responses. Obesity-associated chronic low-grade inflammation has been shown to reprogram adipocytes and immune cells, including by altered gene expression [33], resulting in higher proinflammatory cytokine production. Since Type I IFN is a key innate immune response against SARS-CoV-2 [36], it is hypothesized that underlying obesity triggers an excessive proinflammation response during SARS-CoV-2 infection, which results in greater local tissue damage, COVID-19 severity, and elevated neutralizing antibodies. BMI, body mass index; COVID-19, coronavirus disease 2019; IFN, interferon; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

FIGURE 2

Putative biological rationale explaining bidirectional effects of glucose–insulin metabolism dysregulation and humoral immune response against SARS-CoV-2. Among individuals with uncontrolled diabetes, hyperglycemia and dysregulated glucose–insulin metabolism can lead to elevated proinflammatory mediators. Based on aging and geriatric studies, chronic proinflammation could accelerate physiologic aging of B cells, resulting in reduced functional capacity to produce high-affinity protective antibodies. Following SARS-CoV-2, a strong proinflammatory response could lead to hyperinflammation. ACE2, angiotensin converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

FIGURE 3

Key temporally dependent factors affecting links between cardiometabolic health and COVID-19 outcomes. Comparing prior findings regarding humoral immunity and cardiometabolic health is challenging due to the temporal dependence of related extrinsic and intrinsic factors at the population and individual level. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

FIGURE 4

Comparison of geography and study design across studies in review. Among 92 studies included in this review, geographic distribution is visually illustrated by a heatmap (A) and the total number of participants in studies, stratified by country (B). Blue dots are proportionally scaled to represent the number of participants (B). The percentage of studies with differing study designs (cohort, cross-sectional, intervention) are illustrated (C). ^a 88 studies are included in this map. Four studies were excluded from this visualization as they included data from participants in multiple countries, including Austria, Peru, Ireland, Netherlands, Portugal, Romania, Serbia, and Norway. Created with Datawrapper. ^b 90 studies were included. Two multi-site studies were excluded because the number of participants was reported in aggregate and not stratified by geographic location [77,101].

FIGURE 5

Overview of key knowledge gaps, challenges, and opportunities. Despite growing evidence of cardiometabolic diseases as independent risk factors of COVID-19 severity, including mortality, intubations, and hospitalizations (A), the etiology (B) as well as the impact on transmissibility (C) of SARS-CoV-2 vaccines remain unclear (D). Several large cohort studies have shown that postacute sequelae of COVID-19 include metabolic abnormalities in some individuals, although implications have yet to be determined given key remaining research gaps. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.