European Journal of Cardiovascular Medicine

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions worldwide, leading not only to acute illness but also to a range of persistent symptoms and long-term complications, collectively termed post-acute sequelae of SARS-CoV-2 infection (PASC) or long COVID [1,2]. While the acute phase of infection typically resolves within weeks, a subset of patients experience ongoing symptoms such as fatigue, breathlessness, cognitive disturbances, and cardiovascular dysfunction that may persist for months [3,4].

Patients with underlying comorbidities have shown a higher predisposition to both severe COVID-19 and its long-term consequences. Among these, metabolic syndrome (MetS)—a cluster of conditions including central obesity, dyslipidemia, hypertension, and impaired glucose tolerance—has emerged as a significant risk factor [5,6]. MetS is associated with chronic systemic inflammation, endothelial dysfunction, and impaired immune response, all of which may contribute to an exaggerated response to SARS-CoV-2 and hinder recovery [7,8].

Several studies have reported increased hospitalization rates, intensive care admissions, and mortality among COVID-19 patients with pre-existing MetS [9,10]. However, the long-term impact of COVID-19 in this population remains underexplored. Early evidence suggests that these individuals may face a heightened risk of developing chronic respiratory issues such as pulmonary fibrosis, worsening glycemic control, new-onset diabetes, cardiovascular complications, and neuropsychiatric symptoms including depression and cognitive impairment [11-13].

The interplay between post-COVID pathophysiology and the metabolic and inflammatory milieu in MetS warrants comprehensive evaluation. Prospective cohort studies can offer valuable insight into the natural history of post-COVID complications, particularly in high-risk groups [14,15]. Therefore, this study aims to assess the long-term post-COVID complications in patients with pre-existing metabolic syndrome, with a focus on cardiometabolic, pulmonary, and neurocognitive outcomes over a one-year follow-up period.

Study Design and Setting: This prospective cohort study was conducted across three tertiary care hospitals in India. Written informed consent was obtained from all participants prior to enrolment.

Study Population: The study included adult patients aged 30–65 years who had recovered from laboratory-confirmed SARS-CoV-2 infection (RT-PCR positive) and had a prior diagnosis of metabolic syndrome (MetS), as defined by the International Diabetes Federation (IDF) criteria. MetS was diagnosed based on the presence of central obesity (waist circumference ≥90 cm in men or ≥80 cm in women) along with at least two of the following: elevated triglycerides (≥150 mg/dL), low HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women), hypertension (SBP ≥130 mmHg or DBP ≥85 mmHg), or fasting plasma glucose ≥100 mg/dL.

A control group of age- and sex-matched patients who had also recovered from COVID-19 but did not have pre-existing MetS was included for comparative analysis. Exclusion criteria for both groups were: (1) patients with chronic respiratory diseases unrelated to COVID-19, (2) pre-existing neurodegenerative or psychiatric disorders, and (3) those lost to follow-up.

Data Collection and Follow-Up: Baseline demographic data, comorbidities, and severity of COVID-19 illness (mild, moderate, or severe based on national guidelines) were recorded at the time of enrolment. All participants were followed at three specific time points: 3 months, 6 months, and 12 months post-COVID recovery. During each follow-up visit, patients underwent clinical evaluation and laboratory testing to assess the development of new health issues or progression of pre-existing conditions.

Outcome Measures: The primary outcomes assessed were:

• Incidence of new-onset type 2 diabetes mellitus (based on ADA criteria)
• Worsening of existing hypertension (increased medication requirement or uncontrolled BP)
• Respiratory complications (e.g., persistent dyspnoea, reduced pulmonary function tests, or imaging findings suggestive of fibrosis)
• Neuropsychiatric symptoms (evaluated using Montreal Cognitive Assessment and General Anxiety Disorder-7 scale)
• Chronic fatigue (assessed using the Fatigue Severity Scale)

Statistical Analysis: Descriptive statistics were used to summarize baseline characteristics. Continuous variables were presented as mean ± standard deviation (SD), and categorical variables as frequencies and percentages. Chi-square test or Fisher’s exact test was applied for comparison of categorical variables between MetS and non-MetS groups. For continuous variables, independent t-tests or Mann–Whitney U tests were used, as appropriate. A p-value of <0.05 was considered statistically significant. Data were analyzed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).

A total of 500 participants were enrolled in the study, of which 300 had pre-existing metabolic syndrome (MetS group), and 200 were without metabolic syndrome (control group). The mean age of participants was 52.1 ± 8.7 years, with males comprising 58% of the study population. Baseline characteristics such as age, gender distribution, and severity of COVID-19 illness were comparable between the two groups.

At the 12-month follow-up, significant differences were observed in post-COVID complications between the MetS and control groups. Table 1 summarizes the prevalence of cardiometabolic complications. New-onset type 2 diabetes was reported in 80 individuals (26.7%) in the MetS group compared to 16 individuals (8.0%) in the control group (p < 0.001). Additionally, worsening hypertension requiring therapeutic intensification was observed in 96 participants (32%) with MetS, whereas only 20 participants (10%) in the control group experienced similar progression (p = 0.002) (Table 1).

Table 1. Cardiometabolic Complications at 12-Month Follow-Up

Pulmonary outcomes showed that 99 participants (33.1%) in the MetS group developed fibrotic lung changes or reduced diffusion capacity, compared to 29 individuals (14.5%) in the control group (p < 0.01). Dyspnoea on exertion was also significantly more common among MetS patients (41.0%) than controls (20.5%) (Table 2).

Table 2. Pulmonary and Respiratory Sequelae

Neuropsychiatric complications were also more prominent in the MetS group. Memory disturbances were reported by 85 participants (28.3%) in the MetS group compared to 32 (16.0%) in the control group (p = 0.01). Anxiety symptoms based on the GAD-7 scale were present in 30.2% of MetS participants and 15.5% of controls (p = 0.008) (Table 3).

Table 3. Neuropsychiatric Symptoms Post-COVID

These findings suggest that individuals with pre-existing metabolic syndrome were significantly more likely to develop long-term post-COVID complications across multiple systems, including cardiometabolic, respiratory, and neurocognitive domains (Tables 1–3).

This prospective cohort study highlights a significant burden of long-term post-COVID complications in individuals with pre-existing metabolic syndrome (MetS), compared to those without MetS. The findings demonstrate increased incidences of cardiometabolic dysfunction, persistent respiratory impairment, and neuropsychiatric disturbances in the MetS group over a 12-month follow-up period. These results emphasize the importance of targeted surveillance and rehabilitation strategies for this high-risk population.

The increased prevalence of new-onset type 2 diabetes and worsening hypertension among post-COVID MetS patients aligns with previous findings that suggest SARS-CoV-2 infection may exacerbate pre-existing metabolic imbalances or precipitate new metabolic conditions [1,2]. The virus has been reported to impair pancreatic beta-cell function and modulate insulin signalling through inflammatory and immune-mediated pathways [3]. In addition, the use of corticosteroids during acute COVID-19 management may further contribute to glucose dysregulation [4].

Hypertension aggravation in MetS patients following COVID-19 could be attributed to the dysregulation of the renin-angiotensin-aldosterone system (RAAS), endothelial dysfunction, and heightened sympathetic activity observed in post-infectious states [5,6]. Chronic inflammation and oxidative stress, which are already elevated in individuals with MetS, may persist or worsen post-infection, thereby increasing vascular resistance and blood pressure [7].

Our study also observed a significantly higher frequency of pulmonary complications, including reduced diffusing capacity and fibrotic lung changes, in the MetS cohort. These findings are in agreement with studies reporting long-term pulmonary sequelae, particularly in patients with metabolic comorbidities who experienced moderate-to-severe COVID-19 [8,9]. Impaired pulmonary repair mechanisms, increased pro-fibrotic cytokines, and persistent alveolar damage have been implicated in the development of post-COVID interstitial lung abnormalities [10].

Neuropsychiatric manifestations such as memory impairment, anxiety, and chronic fatigue were markedly more common in MetS patients. This is consistent with previous studies that have suggested a higher vulnerability to cognitive decline and mood disorders in individuals with metabolic disturbances [11,12]. The bidirectional interaction between systemic inflammation and neuroinflammation, along with potential blood-brain barrier disruption by SARS-CoV-2, may contribute to these outcomes [13]. Furthermore, the prolonged hospitalization, social isolation, and psychological stress experienced during illness and recovery may exacerbate these symptoms, particularly in patients with pre-existing health concerns [14].

The chronic low-grade inflammation characteristic of MetS appears to potentiate the multi-systemic impact of SARS-CoV-2, leading to prolonged and more severe post-COVID symptoms. This underscores the necessity for personalized post-COVID care models that incorporate metabolic monitoring, pulmonary rehabilitation, and neuropsychological support.

Despite its strengths, this study has certain limitations. First, the reliance on clinical and imaging findings without histopathological confirmation may limit the accuracy of some pulmonary diagnoses. Second, although the sample size was adequate, it may not fully capture all regional and genetic variations that influence disease outcomes. Lastly, the possibility of residual confounding cannot be ruled out, despite attempts to match and adjust for baseline characteristics.

In conclusion, the results of this study reinforce the emerging understanding that metabolic syndrome significantly increases the risk of long-term complications following COVID-19. Future research should focus on interventional strategies that can mitigate these risks and improve long-term health outcomes in this vulnerable population.

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