March20, 2023

Abstract Volume: 5 Issue: 3 ISSN:

Impact  of  Long  COVID-19  on  Cardiopulmonary  Metabolic  Syndrome  : A  Systematic  Review  and  Meta-Analysis

Attapon  Cheepsattayakorn1,3*, Ruangrong  Cheepsattayakorn 2, Porntep  Siriwanarangsun 3

1. Faculty of Medicine, Western University, Pathumtani Province, Thailand.

2. Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

3. 10th Zonal Tuberculosis and Chest Disease Center, Chiang Mai, Thailand.

Corresponding Author: Attapon Cheepsattayakorn, 10th Zonal Tuberculosis and Chest Disease  Center, 143  Sridornchai  Road  Changklan  Muang  Chiang  Mai  50100 

Copy Right: © 2022 Attapon Cheepsattayakorn, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received Date: July 23, 2022

Published Date: August 10, 2022



A  comprehensive search was carried out in mainstream bibliographic databases or Medical Subject Headings, including Scien Direct, PubMed, Scopus, and ISI Web of Science. The search was applied to the articles that were published between January 1999 and July 2022.  With strict literature search and screening processes, it yielded 30 articles from 91 articles of initial literature database.   

Several previous studies hypothetically reported that the prevalence of diabetes mellitus, hypertension, and dyslipidemia, and obesity in persons older than 60 years were significantly rising. The effects of changes on the immune status and insulin secretion in patients with diabetes are still questionable, whereas several previous studies demonstrated trigger higher stress conditions of the effects of SARS-CoV-2 (COVID-19) contributing to hyperglycemia in patients with diabetes.

Despite the increased risk of adult respiratory distress syndrome (ARDS) and multi-organ dysfunction in early COVID-19 phase or in long COVID-19 phase after diabetes, diabetes alone is not related to an increased risk of respiratory infection, including COVID-19. Diabetes, diabetic traits, and diabetic blood proteins may have the most causal effect on the angiotensin-converting enzyme 2 (ACE 2) expression, particularly, in the lung, thus, diabetes can trigger the risk of COVID-19 infection and increase chance of worst outcome in the long COVID-19 phase, and finally, COVID-19 patients with diabetes mellitus will have poor prognosis during long COVID-19 phase. 

In conclusion, dyslipidemia, high serum levels of cholesterol, low serum levels of HDL, hypertension, and obesity with high expression of ACE 2 in adipose tissue, an epidemic of the last century in conjunction with COVID-19 pandemic, particularly, in the over-60-year-old population are the cardiopulmonary metabolic or cardiometabolic events that could contribute to the COVID-19 disease worsening both in the early and long COVID-19 phases. Treatment type of cardiopulmonary metabolic or cardiometabolic diseases or disorders did not impact the COVID-19 status, but non-treatment of these diseases or disorders could importantly increase COVID-19 incidence. Monitoring of the cardiopulmonary metabolic or cardiometabolic risk factors is urgently needed.      

Keywords :  COVID-19, cardiopulmonary, cardiometabolic, diabetes, dyslipidemia, human health, hypercholesterolemia, hypertension, impact, metabolic, obesity, pulmonary, SARS-CoV-2, statins



 ACE 2: angiotensin-converting  enzyme 2,

ALI:  acute lung injury,

ARDS: acute  respiratory  distress  syndrome,

BALF: bronchoalveolar fluid,

BMI:  body-mass  index,

COPD: chronic obstructive pulmonary disease,

CRP: C-reactive  protein,

CVD : cardiovascular  disease,

FEV1 : forced expiratory volume in 1 second,

FVC : forced vital capacity,

HD : hemodynamics,

HDL :  high-density  lipoprotein,

HTN : hypertension,

ICS : inhaled corticosteroids,

ICU : intensive care unit,

IL : interleukin,

IPF : idiopathic pulmonary fibrosis,

LDL : low-density  lipoprotein,

LTB4 : leukotriene B4,

NO : nitric oxide,

PAP : pulmonary artery pressure,

PEF : peak expiratory flow,

PH : pulmonary hypertension,

TIA: transient ischemic attack,

TNF: tumor necrosis  factor,

UK: United Kingdom,

US: United States,

VFD: ventilator-free days 

Impact of Long COVID-19 on Cardiopulmonary Metabolic Syndrome : A Systematic Review and Meta-Analysis

Objectives  of  the  Study 

The  objectives  of  this  study  are  to  identify  the  better  understanding  on  the  mechanisms  of  interaction  between  the  cardiopulmonary  metabolic  or  cardiometabolic  or  metabolic  changes  and  SARS-CoV-2 (COVID-19), the  scientific  opinions  change  towards the  cardiometabolic  or  metabolic  changes-SARS-CoV-2 (COVID-19)  associations  over  time (particularly  after  3  months  of  acute  COVID-19  illness  phase, namely  “ long  COVID-19 ” (post-acute  COVID-19  illness  period))  and  place, and  the  changing  of  the  direction  and  shifting  of  certainty  of  research  findings  of  cardiopulmonary  metabolic  or  cardiometabolic  or  metabolic  change-SARS-CoV-2 (COVID-19)    studies  change  or  statins  treatment  benefit  in  pulmonary  diseases  or  disorders-possibly-related-long-COVID-19  phase.


Several  previous  studies  hypothetically  reported  that  the  prevalence  of  diabetes  mellitus, hypertension, and  dyslipidemia, and  obesity  in  persons  older  than  60  years  were  significantly  rising [1].  The  effects  of  changes  on  the  immune  status  and  insulin  secretion  in  patients  with  diabetes  are  still  questionable [2], whereas  several  previous  studies  demonstrated  trigger  higher  stress  conditions  of  the  effects  of  SARS-CoV-2 (COVID-19)  contributing  to  hyperglycemia  in  patients  with  diabetes [3].  Increasing  serum  levels  of  the  high-density  lipoprotein (HDL)  can  suppress  the  platelet  over-activity  and  the  coagulation  cascade [4].  The  association  between  hypertension (HTN)  and  SARS-CoV-2 (COVID-19)  is  still  questionable  and  is  independent  from  aging  or  not [5].  Obesity  can  induce  mesenchymal  dysfunction  and  exacerbating  the  COVID-19-related-cytokine-storm  that  promoting  pulmonary  fibrosis [6].       


Methods of  the  Study 

Search Strategy  and  Inclusion  Criteria

A  comprehensive  search  was  carried  out  in  mainstream  bibliographic  databases  or  Medical  Subject  Headings, including  ScienDirect, PubMed, Scopus, and  ISI  Web  of  Science.  The  search  was  applied  to  the  articles  that  were  published  between  January  1999  and  July  2022.  Our  first  involved  performing  searches  of  article  abstract/keywords/title  using  strings  of  [(“ COVID-19 ”  or  “ SARS-CoV-2 ”, “ cardiopulmonary ”, “ cardiovascular ”, “ cardiometabolic ”, “ metabolic ”, “ pulmonary ”  or  “ lung ”, “ renal  ”  or  “ nephrological ”, “ endocrinological .”, “ diabetic ”, ” brain ”, “ spinal  cord ”, “ nervous  system ”, “ esophagogastric ” or  “ gastroesophageal ”, “ gastrointestinal ”, “ musculoskeletal ”, “ bony ”, and “ cartilaginous ”, “ hypertension ”, “ hypertensive ”,  “ obese ”, “ obesity ”, “ cholesterol ”, “ hypercholesterolemia ”, “ statins ”  ].  After  a  first  approach  of  search, published  articles  focusing  on  cardiometabolic  or  metabolic  diseases  or  disorders  that  related  to  SARS-CoV-2  or  COVID-19  were  retained  and  the  information  on  COVID-19-related  cardiometabolic  or  metabolic  type  of  diseases  or  disorders  was  extracted  for  having  a  crude  knowledge  involving  their  themes.  Another  round  of  publication  search  was  conducted  for  adding  the  missing  published  articles  that  were  not  identified  by  the  first  round. 

All  keywords  combinations  from  one  disease  type  and  climatic  variable  to  bind  the  population  of  cases  under  consideration.  Search  string  for  disease  groups  include  [ “ SARS-CoV-2 ”  or  “ COVID-19 ”  or  “ cardiopulmonary ”  or  “ cardiovascular ”  or  “ cardiometabolic ”  or  “ metabolic ”  or  “  ”  or  “ pulmonary ”  or  “ lung  ”  or  “ endocrinological ”  or  “ diabetic ”  or  “ renal ”  or  “ nephrological ”  or  “ nervous  system ”  or  “ brain ”  or  “ spinal  cord ”  or  “ esophagogastric ”  or  “ gastroesophageal ”  or  “ musculoskeletal ”  or  “ bony ”  or  “  cartilaginous ”  or  “ hypertension ”  or  “ hypertensive ”  or  “ obese ”  or  “ obesity ”  or  “ cholesterol ” or  “ hypercholesterolemia ” or “ statins ” ].  The  initial  literature  databases  were  further  manually  screened  with  the  following  rules : 1) non-SARS-CoV-2 (COVID-19)-related  articles  were  excluded; 2) articles  that  did  not  report  a  human  health  related  to  SARS-CoV-2 (COVID-19)  were  not  considered, such  as  commentary  articles, or  editorial; 3) non-peer  reviewed  articles  were  not  considered  to  be  of  a  scholarly  trustworthy  validity; and  4) duplicated  and  non-English  articles  were  removed.  The  articles  were  carefully  selected  to  guarantee  the  literature  quality, which  is  a  trade-off  for  quantity. 

With  strict  literature  search  and  screening  processes, it  yielded  30  articles (Table 1, 2)  from  91  articles  of  initial  literature  database.  Needed  article  information  was  extracted  from  each  article  by : 1) direct  information  including  journal, title, authors, abstract, full  text  documents  of  candidate  studies, publishing  year; 2) place  name  of  the  study  area; 3) study  period; 4) research  method  used; 5) type  of  variables  studied; 6)  types  of  COVID-19-realetd  cardiometabolic  or  metabolic  diseases  or  disorders  studied; and 7) the  conclusions  made  about  the  impacts  of  COVID-19-related  cardiometabolic  or  metabolic  diseases  or  disorders  on  human  health.  



Alveolar epithelial type II cells and alveolar macrophages likely receive cholesterol from circulating low density lipoprotein and high density lipoprotein (LDL, HDL) through the LDL receptor (LDLR) and scavenger receptor B type I (SR-BI), respectively. HDL is also the major source of the antioxidant vitamin E for type II cells. Class A scavenger receptors (SR-A) on macrophages play a role in clearance of oxidized alveolar lipids that may otherwise mediate cytotoxic and pro-inflammatory effects. The disposal pathway for cholesterol from type II cells and macrophages involves the cholesterol efflux transporters ATP Binding Cassette (ABC) A1 and ABCG1, and perhaps also SR-BI. ABCA1 also mediates basolateral surfactant efflux from type II cells; deletion of either ABCA1 or ABCG1 leads to severe surfactant proteinosis and lipidosis. Disordered cholesterol/phospholipid trafficking through the lung, such as with ABCG1 deletion, alters immune cell trafficking to the lung as well as the lung’s immune responsiveness to a variety of environmental exposures, indicating that there is intimate crosstalk between lipid and immune homeostasis in the lung.
(Source : Gowdy  KM, Fessler  MB.  Emerging  roles  for  cholesterol  and  lipoproteins  in  lung  disease.  Pulm  Pharmacol  Ther  2013; 26  (4) : 430-437.  DOI :  10.1016/j.pupt.2012.06.002 [14].)

The process of reverse cholesterol transport (RCT) is depicted and how inflammation impairs this process is described in the red boxes. Under physiological conditions, apolipoprotein A1 (APOA1), which is the major protein component of high-density lipoprotein (HDL), is secreted by the liver and the intestines, and is assembled into a pre-βHDL particle as a result of its interaction with the ATP-binding cassette transporter ABC subfamily A member 1 (ABCA1) on hepatocytes and enterocytes. ABCA1 on macrophages promotes cholesterol and phospholipid efflux onto these relatively lipid-poor pre-βHDL particles, initiating the process of RCT. ABCG1 promotes further cholesterol efflux onto HDL particles. Free cholesterol in HDL is esterified by the enzyme lecithin–cholesterol acyltransferase (LCAT), which gives rise to cholesteryl esters. Free cholesterol or cholesteryl esters in HDL may be directly cleared in the liver via scavenger receptor B1 (SRB1), which mediates a process of selective free cholesterol or cholesteryl ester uptake in which the lipid moiety of HDL is mostly removed and the protein portion is recycled into the circulation (not shown). Cholesterol deposited in the liver by RCT can either be recycled in the form of secreted triglyceride-rich, very low-density lipoproteins (VLDLs; the main protein component of which is APOB) or can undergo net excretion into the bile via ABCG5 and ABCG8. In humans, plasma cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl esters in HDL with triglyceride in VLDL. A lipolytic cascade mediated by lipoprotein lipase and hepatic lipase causes hydrolysis of triglycerides and results in the formation of cholesterol-rich and cholesteryl ester-rich LDL. Although most LDL is cleared in the liver, LDL may supply cholesterol to peripheral tissues and a small proportion is taken up into the arterial wall, where it is modified by oxidation or aggregation, leading to its uptake by macrophages. Modified LDL in the artery wall promotes Toll-like receptor (TLR) signalling in macrophages and it is taken up by these cells, leading to the formation of macrophage foam cells, the production of myeloperoxidase (MPO) and inflammation. IDL, intermediate-density lipoprotein; LDLR, LDL receptor.

(Source : Tall  AR, Yvan-Charvet  L.  Cholesterol, inflammation  and  innate  immunity.  Nat  Rev  Immunol  2015; 15 (2) : 104-116.  DOI :  10.1038/nri3793 [15])



Results  from  the  authors’  systematic  review  and  meta-analysis  of  11  published  articles [Table 1, 7-11]  were  all  demonstrated  positive  association  between  the  cardiopulmonary  metabolic  changes  and  COVID-19, particularly  in  the  long-COVID-19  phase  and  demonstrated  the  benefits  from  statins  therapy  in  various  pulmonary  diseases  or  disorders  that  could  be  related  to  long-COVID-19  phase, except  exhaled  nitric  oxide (NO)  levels, peak  expiratory  flow (PEF), organ  failure, ventilatory-free  days (VFD), intensive-care-unit (ICU)  mortality, and  the  patients’  survival [Table 2, 18-36].  Different  levels  of  dyslipidemia (elevated  low-density  lipoprotein  levels, low  levels  of  high-density  lipoprotein, cholesterol  levels (Figure  1, 2 [14, 15])  are  strong  predictors  of  lung [14]  and  cardiovascular  diseases (CVD) [37-39]  progression  that  are  related  to  the  exacerbation  of  COPVID-19  via  the  suppression  of  the  platelet  over-activity  and  the  coagulation  cascade  by  the  uses  of  antioxidants  and  the  antithrombotic  drugs [4]  in  the  long  COVID-19  phase.

Analysis of  107,310  HTN  patients  in  the  UK  biobank  data  revealed  that  around  3 %  of  them  developed  acute  and  chronic  respiratory  diseases, including  pneumonia  later [11].  Analysis  of  1,099  confirmed  COVID-19  patients  demonstrated  that  approximately, 15 %  of  the  patients  with  HTN  was  the  single  highest  risk  factor  of  COVID-19  infection [40].   Approximately, 35.8 %  of  the  HTN  patients  in  this  study  required  treatment  in  the  ICU, whereas  around  23.7 %  of  the  patients  had  HTN  as  the  most  frequent  co-morbidity [40].   

Despite the  increased  risk  of  adult  respiratory  distress  syndrome (ARDS)  and  multi-organ  dysfunction  in  early  COVID-19  phase  or  in  long  COVID-19  phase  after  diabetes, diabetes  alone  is  not  related  to  an  increased  risk  of  respiratory  infection, including  COVID-19 [41].  Diabetes, diabetic traits, and  diabetic  blood  proteins  may  have  the  most  causal  effect  on  the  angiotensin-converting  enzyme 2 (ACE 2)  expression, particularly, in  the  lung, thus, diabetes  can  trigger  the  risk  of  COVID-19  infection  and  increase  chance  of  worst  outcome  in  the  long  COVID-19  phase [42], and  finally, COVID-19  patients  with  diabetes  mellitus  will  have  poor  prognosis  during  long  COVID-19  phase [43].  In  the  United  States (US), approximately, three  fourth  of  adults  with  age  more  than  20  years  meet  the  criteria  for  the  diagnosis  of  obese  or  overweight (body  mass  index (BMI)  of  at  least  30  kg/m2) [44, 45].  Mainly, obesity  interfere  the  physiological  process  and  the  functions  of  immune  system  that  is  related  to  the  long  COVID-19  phase [46]

Increased serum  levels  of  troponin, a  muscle  and  myocardium  enzyme  may  be  related  to  higher  risk  of  embolic  stroke  of  unknown  origin  or  cardioembolic  stroke [47], a  cause  of  high  rate  of  stroke  or  stroke-related  fatalities  in   both  early  and  long  COVID-19  phases [48].  Due  to  its  pro-inflammatory  effect, a  state  of  hypercoagulopathy  could  be  induced  by  SARS-CoV-2 (COVID-19)  infection  that  increases  the  risk  of  thromboembolic  events, such  as  pulmonary  embolism  and  transient  ischemic  attack (TIA) [49, 50].                                            


Dyslipidemia, high  serum  levels  of  cholesterol, low  serum  levels  of  HDL, hypertension, and  obesity  with  high  expression  of  ACE 2  in  adipose  tissue, an  epidemic  of  the  last  century  in  conjunction  with  COVID-19  pandemic, particularly, in  the  over-60-year-old  population  are  the  cardiopulmonary  metabolic  or  cardiometabolic  events  that  could  contribute  to  the  COVID-19  disease  worsening  both  in  the  early  and  long  COVID-19  phases.  Treatment  type  of  cardiopulmonary  metabolic  or  cardiometabolic  diseases  or  disorders  did  not  impact  the  COVID-19  status, but  non-treatment  of  these  diseases  or  disorders  could  importantly  increase  COVID-19  incidence.    Monitoring  of  the  cardiopulmonary  metabolic  or  cardiometabolic  risk  factors  is  urgently  needed.         


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