LOnger-term Effects of COVID-19 INfection on Blood Vessels And Blood pRessure (LOCHINVAR) (LOCHINVAR)

• ClinicalTrials.gov Identifier: NCT05087290
• Recruitment Status: Recruiting
• First Posted: October 21, 2021
• Last Update Posted: May 3, 2022
• Sponsor: University of Glasgow
• Information provided by (Responsible Party): Sandosh Padmanabhan, University of Glasgow

Study Description

Brief Summary:

The COVID-19 pandemic is the biggest medical challenge in decades. Individuals with pre-existing cardiovascular diseases have a higher risk of severe disease and death from COVID-19. The SARS-CoV-2 virus causes infection by targeting a molecule on the walls of the cells lining the lungs and the blood vessels leading to injury. There are concerns that after recovery from COVID-19, the damage sustained by these cells may have long-term consequences including high blood pressure, stroke and heart attacks. The burden of high blood pressure as a result of the pandemic is unknown and a greater understanding of COVID-19 impact on blood pressure and its underlying mechanisms is urgently needed.

LOCHINVAR is based on our pilot study "COVID-19 blood pressure endothelium interaction study" (OBELIX,NCT04409847, IRAS 284453), which found that patients with normal blood pressure at the time of hospital admission with COVID-19 showed a nine-point higher blood pressure ≥12 weeks after recovery, compared to a group without COVID-19. LOCHINVAR will extend the OBELIX study aiming to establish if COVID-19 increases the risk of developing high blood pressure and investigating underlying mechanisms through detailed measurements of blood pressure, blood vessel function, hormones and chemicals in the blood, urine and stool.

The investigators will invite 150 adults without pre-existing high blood pressure who were discharged from hospital after an admission: half with COVID-19 and half without. Baseline visit will be ≥12 weeks after discharge for measurements of blood pressure, tests of heart and blood vessel health, blood, urine and stool samples along with questionnaires on mood and quality of life. Two further study visits follow, at 12 and 18 months.

This study will generate crucial evidence on the long-term impact of COVID-19 on blood pressure along with information on potential mechanisms of this effect with immediate, transferable impact on clinical practice and inform risk mitigation measures.

Condition or disease	Intervention/treatment
Hypertension; Covid19	Other: Cases; Other: Controls

Detailed Description:

The Coronavirus Disease-19 (COVID-19) pandemic is one of the biggest medical challenges in recent years. Whilst COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome, it also affects multiple organ systems, including the cardiovascular system(1-3). There are documented associations between severity of disease/mortality risk and advancing age, male sex and associated comorbid disease (hypertension, ischaemic heart disease, diabetes, obesity, COPD and cancer).(4,5) The most common complications include cardiac dysrhythmia(6,7), cardiac injury(8,9), myocarditis, heart failure, pulmonary embolism10 and disseminated intravascular coagulation(11).

The SARS-CoV-2 virus uses the ACE2 receptor (ACE2) to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes.(12) This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction.(12) In addition, ACE2 is expressed in several other organs including cells lining the blood vessels (endothelial cells), ACE2 is a key player in the renin-angiotensin system (RAS) which is important in blood pressure regulation and is a target for some of the commonly used drugs used in the treatment of blood pressure. While ACE2 is essential for viral invasion, it is unclear if the use of the common antihypertensive drugs ACE inhibitors or angiotensin receptor blockers (ARBs) alter prognosis in those with COVID-19 infection.(12) Furthermore, there is evidence that the normally occurring bacteria in the gut (gut microbiome) directly influences the makeup of the human immune system and has been implicated in severity of COVID-19 as well as in the magnitude of the immune system response to SARS-CoV-2 infection(13).

This study (LOCHINVAR) is based on the pilot study "COVID-19 blood pressure endothelium interaction study" (OBELIX), funded by the Chief Scientific Office. Preliminary results showed that participants who had COVID-19 infection had an 8.6mmHg increase in their average 24hr systolic blood pressure, compared to those that did not have COVID-19 infection. The investigators will increase our recruitment of potential participants to meet our sample size of 150 participants (75 SARS-CoV-2 +ve cases and 75 SARS-CoV-2 -ve cases) built on OBELIX. This study will allow us to have a better understanding of the risks of developing high blood pressure or uncontrolled blood pressure following COVID-19 infection. This will allow doctors to be able to make a recommendation on the current/long term management of people with high blood pressure beyond the pandemic.

Study Design

• Study Type: Observational
• Estimated Enrollment: 150 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Longer-term Effects of COVID-19 on Blood Vessels and Blood Pressure (LOCHINVAR) Phenotyping Study
• Actual Study Start Date: September 30, 2021
• Estimated Primary Completion Date: August 3, 2024
• Estimated Study Completion Date: August 3, 2024

Groups and Cohorts

Group/Cohort	Intervention/treatment
Cases; SARS-CoV-2 +ve cases	Other: Cases; All performed at baseline, 12 months and 18 months Medical and drug history Anthropometric tests Electrocardiogram Brachial flow mediated dilatation 6 minute walk test Blood sampling Urine sampling 24-hr Ambulatory Blood Pressure Monitor Questionnaires Optional: Stool sampling,24-hr Urine collection, Home Blood Pressure Monitor
Control; SARS-CoV-2 -ve cases	Other: Controls; All performed at baseline, 12 months and 18 months Medical and drug history Anthropometric tests Electrocardiogram Brachial flow mediated dilatation 6 minute walk test Blood sampling Urine sampling 24-hr Ambulatory Blood Pressure Monitor Questionnaires Optional: Stool sampling,24-hr Urine collection, Home Blood Pressure Monitor

Outcome Measures

Primary Outcome Measures :

1. 24-hour ABPM Systolic Blood Pressure [ Time Frame: 12 months ]
   Average 24 hour Ambulatory Blood Pressure Monitoring - Systolic Blood Pressure , (all day and night) at 12 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls

Secondary Outcome Measures :

1. 24-hour ABPM Diastolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Average 24 hour Ambulatory Blood Pressure Monitoring - Diastolic Blood Pressure, 24hr (all day and night) at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
2. Day ABPM Systolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Day Ambulatory Blood Pressure Monitoring (Average Systolic Blood Pressure) 8 am to 8 pm at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
3. Day ABPM Diastolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Day Ambulatory Blood Pressure Monitoring (Average Diastolic Blood Pressure), 8 am to 8 pm at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
4. Night ABPM Systolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Night Ambulatory Blood Pressure Monitoring (Average Systolic Blood Pressure) 8pm to 8 am at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
5. Night ABPM Diastolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Night Ambulatory Blood Pressure Monitoring (Average Diastolic Blood Pressure) 8pm to 8 am at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
6. 24-hour ABPM Heart Rate [ Time Frame: 12 months and 18 months ]
   24 hour Ambulatory Blood Pressure Monitoring - Heart Rate, 24hr (all day and night) at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
7. 24-hour Urine Sodium [ Time Frame: 12 months and 18 months ]
   24-hour Urine Sodium at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls

Other Outcome Measures:

1. % Flow Mediated Dilatation [ Time Frame: 12 months and 18 months ]
   % Brachial Flow Mediated Dilatation at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
2. Exercise tolerance - distance walked in 6 minutes [ Time Frame: 12 months and 18 months ]
   Exercise tolerance distance walked in 6 minutes at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
3. Quality of life and mood - difference in longitudinal changes in QoL and mood between groups [ Time Frame: 12 months and 18 months ]
   Patient Health Questionaire-9 (Minimal Depression 0-4, Mild Depression 5 - 9, Moderate Depression 10-14, Moderately Severe Depression 15 - 19, Severe Depression 20-27) and Euroqol (EQ5D-3L) Questionnaire (Mean EQ-5D and Standard Deviation) at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
4. Mean Home Systolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Mean Home Blood Pressure Measurements - Systolic Blood Pressure at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
5. Mean Home Diastolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Mean Home Blood Pressure Measurements - Diastolic Blood Pressure at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
6. Day Home Systolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Average Day Home Blood Pressure Measurements - Systolic Blood Pressure at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
7. Evening Home Systolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Average Evening Home Blood Pressure Measurements - Systolic Blood Pressure at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
8. Day Home Diastolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Average Day Home Blood Pressure Measurements - Diastolic Blood Pressure at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls
9. Evening Home Diastolic Blood Pressure [ Time Frame: 12 months and 18 months ]
   Average Evening Home Blood Pressure Measurements - Diastolic Blood Pressure at 12 months and 18 months in SARS-CoV-2 +ve cases and in SARS-CoV-2 -ve controls

Biospecimen Retention:   Samples Without DNA

With consent from participants

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Sampling Method: Non-Probability Sample

Study Population

Patients admitted through Queen Elizabeth University Hospital (QEUH) receiving units with suspected/confirmed COVID-19 during 01/09/2020-31/12/2021 and who are alive at discharge. Clinically suspected COVID-19 should have either fever, new onset cough and/or anosmia/dysgeusia and/or ≥2 of the following presenting features (fatigue/generalised weakness, headache, myalgia, sore throat/coryzal symptoms, breathlessness, anorexia/nausea/vomiting, diarrhoea, contact with known COVID-19 positive case). OBELIX participants who have given consent previously will be re-contacted.

Criteria

Inclusion Criteria:

• Age 30-60 years
• Admission between 01/09/2020 - 31/12/2021
• Clinically suspected or Confirmed COVID-19 Reverse Transcription-Polymerase Chain Reaction (RT-PCR) test confirmed COVID-19 on admission
• No history of hypertension or current drug treatment for hypertension

Controls

1. Age 30-60
2. No history of hypertension
3. No antihypertensive drugs
4. Confirmed RT-PCR test negative and admission through Queen Elizabeth University Hospital immediate assessment unit and acute receiving units 01/09/2020 to 31/12/2021 or no history of SARS-CoV-2 infection or COVID-19

Exclusion Criteria:

Inability to give informed consent/lack of capacity BMI >40 eGFR <60 ml/min Pregnancy History of

• Cancer within 5 years
• Persistent atrial fibrillation
• Severe illness, at investigator discretion Prescription of
• BP lowering drugs
• Oral Corticosteroid (chronic use)
• Immunosuppressive agents
• Oral NSAIDs (chronic use)

Contacts and Locations

Contacts

Contact: Stefanie Lip, BSc.,MBChB MRCP(UK); 01414522599; Stefanie.Lip@glasgow.ac.uk

Contact: Linsay McCallum, MBChB, MRCP UK, MSc, PhD; 01414516727; Linsay.McCallum@glasgow.ac.uk

Locations

United Kingdom

Professor Sandosh Padmanabhan; Recruiting

Glasgow, United Kingdom, G12 8QQ

Contact: Stefanie Lip, MBChB 0141 452 2599 Stefanie.Lip@glasgow.ac.uk

Sub-Investigator: Stefanie Lip, MBChB, MRCP UK

Sub-Investigator: Linsay McCallum, MBChB, MRCP UK, MSc, PhD

Sub-Investigator: Rhian Touyz, MBBCH, M Sc, Phd

Sub-Investigator: Christian Delles, MD

Sub-Investigator: Colin Berry, BSc, MBChB, MRCP UK, PhD, FRCP

Principal Investigator: Sandosh Padmanabhan, MBBS, MD, MRCP UK, PhD, FRCP

Sponsors and Collaborators

University of Glasgow

More Information

Additional Information:

OBELIX Study 

Publications:

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. No abstract available. Erratum In: Intensive Care Med. 2020 Apr 6;:

Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang C. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. 2020 Jul 1;5(7):802-810. doi: 10.1001/jamacardio.2020.0950.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:

Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, Brown TS, Der Nigoghossian C, Zidar DA, Haythe J, Brodie D, Beckman JA, Kirtane AJ, Stone GW, Krumholz HM, Parikh SA. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic. J Am Coll Cardiol. 2020 May 12;75(18):2352-2371. doi: 10.1016/j.jacc.2020.03.031. Epub 2020 Mar 19.

Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; the Northwell COVID-19 Research Consortium; Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 May 26;323(20):2052-2059. doi: 10.1001/jama.2020.6775. Erratum In: JAMA. 2020 May 26;323(20):2098.

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. Erratum In: JAMA. 2021 Mar 16;325(11):1113.

Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W, Wang YN, Zhong MH, Li CH, Li GC, Liu HG. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020 May 5;133(9):1025-1031. doi: 10.1097/CM9.0000000000000744.

Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020 May;17(5):259-260. doi: 10.1038/s41569-020-0360-5.

Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Prog Cardiovasc Dis. 2020 May-Jun;63(3):390-391. doi: 10.1016/j.pcad.2020.03.001. Epub 2020 Mar 10. No abstract available.

Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J. 2020 May 14;41(19):1858. doi: 10.1093/eurheartj/ehaa254. No abstract available.

Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.

Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, Madhur MS, Tomaszewski M, Maffia P, D'Acquisto F, Nicklin SA, Marian AJ, Nosalski R, Murray EC, Guzik B, Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, McInnes IB. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020 Aug 1;116(10):1666-1687. doi: 10.1093/cvr/cvaa106.

Segal JP, Mak JWY, Mullish BH, Alexander JL, Ng SC, Marchesi JR. The gut microbiome: an under-recognised contributor to the COVID-19 pandemic? Therap Adv Gastroenterol. 2020 Nov 24;13:1756284820974914. doi: 10.1177/1756284820974914. eCollection 2020.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lip S, Mccallum L, Delles C, McClure JD, Guzik T, Berry C, Touyz R, Padmanabhan S. Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study. Open Heart. 2022 Jun;9(1):e002057. doi: 10.1136/openhrt-2022-002057.

• Responsible Party: Sandosh Padmanabhan, Professor Sandosh Padmanabhan, University of Glasgow
• ClinicalTrials.gov Identifier: NCT05087290
• Other Study ID Numbers: GN20CA501; 21/WS/0075 ( Other Identifier: NHS Greater Glasgow and Clyde ); 299056 ( Other Identifier: IRAS ); RG2690/21/24 ( Other Grant/Funding Number: HEART Research UK )
• First Posted: October 21, 2021
• Last Update Posted: May 3, 2022
• Last Verified: April 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sandosh Padmanabhan, University of Glasgow:

Hypertension; COVID-19

Additional relevant MeSH terms:

COVID-19; Hypertension; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Vascular Diseases; Cardiovascular Diseases