Cardiovascular, Pulmonary, and Integrative Functional Phenotypes in COVID-19 - Effect of Fenofibrate
Conditions: Covid19
Sponsor: University of Pennsylvania

CAPRICORN Study 
 
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CARDIOVASCULAR, PULMONARY, AND RENAL PHENOTYPES IN COVID-19 SURVIVORS  
(CAPRICORN-19 STUDY) 
 
 
Version: V7. Date: May 8, 2023 
Sponsor: University of Pennsylvania 
ClinicalTrials.gov ID: NCT05080192 
Investigators: 
Julio A. Chirinos, MD, PhD (co-Principal Investigator) 
Jordana B. Cohen, MD, MSCE (co-Principal Investigator) 
 
Benjamin A. Abramoff, M.D., M.S (Co-Investigator) 
Robert M. Kotloff, MD (Co-Investigator) 
Nadine Al-Naamani, MD (Co-Investigator) 
Franklin Caldera (Co-Investigator) 
Matthew Hyman (Co-Investigator) 
Rajat Deo (Co-Investigator) 
Nathaniel C. Reisinger (Co-Investigator) 
Mark Kahn (Co-Investigator) 
 
Project Manager 
Katie Greene, MPH 
 
 
 
 
 
 
 

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Table of Contents 
BACKGROUND AND STUDY RATIONALE .................................................................................................... 6 
1 
INTRODUCTION ........................................................................................................................................ 6 
2 
STUDY OBJECTIVES ............................................................................................................................... 9 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 9 
3.1 
GENERAL DESIGN ...................................................................................................................................... 9 
3.2 
INCLUSION CRITERIA ................................................................................................................................ 10 
3.3 
EXCLUSION CRITERIA ............................................................................................................................... 10 
3.4 
SUBJECT RECRUITMENT .......................................................................................................................... 11 
3.5 
VULNERABLE POPULATIONS: ................................................................................................................... 11 
3.6 
STUDY PROCEDURES ............................................................................................................................... 11 
3.6.1 
Visit 1 .................................................................................................................................................. 11 
3.6.2 
Follow-up ............................................................................................................................................ 18 
3.7 
UNSCHEDULED VISITS .............................................................................................................................. 20 
3.8 
SUBJECT WITHDRAWAL ............................................................................................................................ 20 
4 
STATISTICAL PLAN ............................................................................................................................... 20 
4.1 
DATA ANALYSIS PLAN ............................................................................................................................... 20 
4.2 
POWER CALCULATIONS ............................................................................................................................ 21 
5 
STUDY ADMINISTRATION, DATA HANDLING, AND RECORD KEEPING ..................................... 21 
6 
STUDY MONITORING, AUDITING, AND INSPECTING ...................................................................... 21 
6.1 
STUDY MONITORING PLAN ....................................................................................................................... 21 
6.2 
AUDITING AND INSPECTING ...................................................................................................................... 22 
7 
ETHICAL CONSIDERATIONS ............................................................................................................... 22 
7.1 
RISKS ........................................................................................................................................................ 22 
7.2 
BENEFITS .................................................................................................................................................. 23 
7.3 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ..................................................................... 23 
8 
STUDY FINANCES .................................................................................................................................. 24 
8.1 
FUNDING SOURCE .................................................................................................................................... 24 
8.2 
SUBJECT STIPENDS OR PAYMENTS ......................................................................................................... 24 
9 
PUBLICATION PLAN .............................................................................................................................. 24 
 

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STUDY SUMMARY 
Title 
CARDIOPULMONARY AND RENAL PHENOTYPES IN COVID-19 
SURVIVORS  
 
Short Title 
CAPRICORN Study 
Methodology 
Longitudinal cohort 
Study Duration 
Approximately 5 years 
Study Center(s) 
Single center conducted at the University of Pennsylvania 
Objectives 
Primary objective: To assess organ specific phenotypes and 
biomarker profiles to characterize specific cardiovascular, pulmonary, 
renal and other abnormalities and their role in functional status, quality 
of life and prognosis in COVID-19 survivors. 
Specific objectives: 
(1) To characterize cardiac and extracardiac phenotypes in 
COVID-19 survivors (compared to control subjects without a 
history of symptomatic COVID-19), and their relationship with: 
(a) quality of life; (b) functional status; (c) aerobic capacity; (d) 
prognosis. 
(2) To determine if the severity of COVID-19 is associated with 
measures of organ-specific structure and function after 
recovery. 
(3) To perform prospective follow-up of the cohort for the 
development of death, heart failure-related hospitalizations, 
and other adverse cardiovascular outcomes. 
(4) To establish a biorepository for future discovery. 
Number of 
Subjects 
200 COVID-19 survivors and 80 controls are expected to be enrolled 
at Penn Medicine. 

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Main Inclusion and 
Exclusion Criteria 
Inclusion criteria: 
 
Subjects aged 18 years and older, male or female; 
 
Prior diagnosis of COVID-19 (acute symptoms consistent with 
COVID-19, confirmed by PCR, serologic or rapid antigen test) 
for the COVID-19 survivors group, or no confirmed or 
suspected prior history of symptomatic COVID-19 for the 
control group at the time of enrollment. 
Exclusion criteria: 
 
Pregnancy at the time of the index COVID-19 episode or at the time 
of the first enrollment in the study; potential participants who 
become pregnant after the index COVID-19 episode will not be 
invited to participate until at least 3 months post-delivery. Inability 
to provide informed consent. 
 
Known history of CVD (defined as HF, MI, coronary 
revascularization, serious arrhythmia, stroke, greater than 
moderate valvular heart disease, any cardiomyopathy, or 
PAD), glomerular disease or polycystic kidney disease prior to 
enrollment. 
 
End stage kidney disease (ESKD; defined as requiring 
persistent renal replacement therapy or prior kidney transplant) 
prior to enrollment 
 
History of chronic kidney disease (CKD) with eGFR <30 
mL/min/1.73m2 prior to enrollment. In participants without a 
history of CKD, a measurement of eGFR will not be required for 
enrollment. 

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Study procedures 
 
The phenotyping protocol will include brief questionnaires, a 
brief ultrasound examination, arterial tonometry, 
measurements of endothelial function, a 6-minute walk test, 
pulmonary function tests, Short Physical Performance Battery, 
impedance cardiography, blood, urine and breath condensate 
collection and 24-hour blood pressure monitoring. A subset of 
participants will be asked to complete a cardiopulmonary 
supine bike exercise test. All tests except for VO2 testing will 
be repeated at approximately 18-month intervals for a total of 3 
tests 
Statistical 
Methodology 
Statistical techniques will include t-tests, linear regression models, 
mixed models, network analysis, pathway analysis, and machine-
learning approaches. The relationship between phenotypic profiles 
and incident risk will be assessed using a combination of Cox 
regression, Poisson regression, and Kaplan-Meier survival analyses, 
as needed. Corrections for multiple comparisons will be performed 
with false discovery rate correction, Bonferroni correction, or principal-
components analysis-based correction, as appropriate.  
Data and Safety 
Monitoring Plan 
The Investigators will be responsible for the data quality management 
and the ongoing safety of subjects. 

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Background and Study Rationale 
1 
Introduction 
A1. With the ongoing spread of coronavirus disease 2019 (COVID-19), there is a growing 
population of COVID-19 survivors. COVID-19 is a public health crisis. Severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic, is 
associated with a high risk of pneumonia and multiorgan dysfunction.1-4 Despite containment and 
mitigation efforts, COVID-19 continues to spread. As the case fatality rate for COVID-19 is 
estimated at <1%,5 it follows that along with the pandemic increase of COVID-19 cases, there will 
be a marked increase of COVID-19 survivors in the general population. 
 
A2. COVID-19 survivors may be at an elevated risk of major adverse cardiovascular events 
(MACE). Pneumonia is the prominent feature of COVID-19.1 Over the last several years, we and 
others demonstrated that survivors of pneumonia (irrespective of etiology), instead of going back 
to their pre-infection baseline health trajectories, enter a trajectory of increased risk of MACE,6-20 
including new onset heart failure, myocardial infarction (MI), and stroke, as demonstrated in 
Figure 1. For example, we identified 591 pneumonia cases in the Cardiovascular Health Study 
(CHS) and 680 pneumonia cases in the Atherosclerosis Risk in Communities (ARIC) study.6,7 In 
CHS, 206 participants (35%) experienced a MACE during the 10 years after their pneumonia 
hospitalization. Of these, 104 (51%) experienced MI, 35 (17%) experienced stroke, and 67 (33%) 
experienced fatal coronary heart disease events. Between 91 days and 1 year following 
hospitalization, compared to matched controls, the HR for MACE was 2.10 (95% confidence 
interval [CI] 1.59-2.60); during the second year after hospitalization, the HR was 1.89 (95% CI 
1.46-2.33). We found similar risk of MACE following pneumonia hospitalization in ARIC. In both 
cohorts, we observed that the risk associated with pneumonia was markedly higher than the risk 
associated with traditional risk factors (diabetes, hypertension, and smoking, among others).  
 
Figure 1. Adjusted risk of myocardial infarction or stroke (left panel) and heart failure 
(independent of myocardial infarction; right panel) after hospitalization for pneumonia in the 
Cardiovascular Health Study. Adapted from Corrales-Medina et al. JAMA. 2015, 313(3):264-74 
and Corrales-Medina… Chirinos JA. Am Heart J. 2015; 306–312.e6

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A3. There is a multifaceted pathophysiologic relationship between pneumonia and 
cardiovascular (CV) disease. As previously discussed,9 the pathogenesis of CV complications 
of acute pneumonia is complex, and involves systemic inflammation, endothelial dysfunction, 
increased arterial stiffness, abnormal arterial hemodynamics, abnormalities in coronary perfusion, 
and direct myocardial damage from a variety of factors. Importantly, some of these factors may 
result not only in acute complications, but also in long-term consequences for CV health. 
Moreover, systemic inflammation may persist for months after resolution of the acute event.21 
Inflammatory processes govern the progression of atherosclerosis from fatty streaks to advanced 
atherosclerotic 
plaques 
and 
their 
complication 
and 
evolution into clinical 
CV events such as MI 
and stroke.22  Acute 
and 
chronic 
inflammation can lead 
to 
endothelial 
dysfunction, increase 
arterial stiffness and 
impair 
pulsatile 
arterial 
hemodynamics (all of 
which can mediate CV 
risk independently of 
atherosclerosis).23 
Even in the absence 
of 
systemic 
inflammation, 
progression 
of 
vascular and target 
organ damage initially 
sustained 
during 
acute 
pneumonia 
events could mediate 
long-term CV risk. 
 
A4. Because of its unique pathophysiology, COVID-19 may distinctly predispose patients 
to chronic pulmonary disease, MACE and micro- and macrovascular damage/dysfunction. 
COVID-19 may predispose patients to particularly elevated risk of CV damage due to its 
distinctive proinflammatory and prothrombotic pathophysiology (Figure 2). In the acute phase, 
COVID-19 is associated with a relatively high incidence of thromboembolic events, MI, stroke, 
and 
severe 
arrhythmias.24,25 
Hyperinflammation 
and 
micro- 
and/or 
macrovascular 
thromboembolic or in situ thrombotic complications have been observed acutely and sub-acutely 
in COVID-19 in the vasculature of the lungs, spleen, brain, gut, kidneys, and periphery,26-28 even 
with therapeutic anticoagulation.28 Thromboses have been identified several weeks following 
critical illness, suggesting a protracted duration of pro-thrombotic risk post-hospitalization. 
Importantly, viral inclusion bodies within endothelial cells and sequestered mononuclear and 
polymorphonuclear cellular infiltration of the endothelium are seen in COVID-19, along with 
evidence of endothelial cell apoptosis.37 This is consistent with the presence of endotheliitis, which 
could lead to acute and chronic vascular dysfunction resulting in target organ dysfunction and 
increased CV risk. Thromboembolic disease may also result in reduced aerobic capacity and 
exercise intolerance due to potentially chronically effects on the pulmonary vasculature.29,30 
Figure 2. Conceptual model: Overview of the association of COVID-19 
with microvascular and macrovascular disease, kidney dysfunction, 
and cardiovascular events 

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Furthermore, studies demonstrate the potential for persistent restrictive lung disease several 
months following recovery from acute COVID-1931 and possible risk of pulmonary fibrosis.32 
 
A5. COVID-19 may also predispose patients to clinical and subclinical kidney target organ 
damage, which could mediate long-term CV risk. Hospitalization for pneumonia of all causes 
is associated with a persistently elevated risk of subsequent CKD.33,34 For example, in a Swedish 
cohort of 284,198 men born from 1952-1956, there were 5,822 initial pneumonia episodes 
observed over 37 years of follow up.33 In the year following the first episode, pneumonia was 
associated with a 14.5-fold (95% confidence interval [CI] 10.41-20.32) elevated hazard of incident 
CKD; there was a 5.2-fold (95% CI 3.91-6.93) elevated hazard of incident CKD in the first five 
years following pneumonia. COVID-19 is particularly associated with a high incidence of acute 
kidney injury.35,36 The mechanisms of acute kidney injury in COVID-19 seem to be largely 
immune- and coagulopathy-mediated, including marked interstitial inflammation, microangiopathy 
with peritubular and glomerular erythrocyte aggregation and fibrin thrombi, endothelial damage, 
and tubular necrosis.35,37 The presence or severity of acute kidney injury is often missed in 
hospitalized patients, and many patients may have subclinical kidney injury that is not identified 
by typical measurements (i.e. creatinine-based eGFR) during hospitalization.38,39 Even among 
individuals without evidence of acute or persistent kidney damage while hospitalized, the 
hyperimmune and coagulopathic mechanisms of COVID-19 may predispose COVID-19 survivors 
to an elevated risk of subsequent decline in kidney function. Our group has preliminary data 
demonstrating a strong association of decline in kidney function with elevated 1- and 3-year risk 
of MACE, regardless of baseline kidney function (see A8. Preliminary Data). Thus, decline in 
kidney function among COVID-19 survivors may be an important mediator of future CV risk in 
these patients. 
 
A6. Several interrelated mechanisms of COVID-19 may be linked to acute multiorgan 
dysfunction and intermediate- and long-term target organ damage in COVID-19 survivors. 
In comparison to other bacterial and viral pneumoniae, inflammation and hypercoagulability in 
COVID-19 may be related to its unique interaction with the renin-angiotensin system (RAS). 
Angiotensin-converting enzyme 2 (ACE2), a counter-regulatory component of the RAS, facilitates 
SARS-CoV-2 entry into host cells in the respiratory tract.40 ACE converts angiotensin I (Ang I) to 
Ang II, which acts on the Ang II type 1 receptor (AT1R), resulting in vasoconstriction, sodium and 
fluid retention by the kidney, oxidative stress, inflammation, fibrosis, and impaired fibrinolysis.41,42 
In direct opposition to the cascade of physiological effects of the ACE/Ang II pathway, the net 
effect of the ACE2/Ang-(1-7) pathway is vasodilation and anti-inflammation. ACE2 hydrolyzes 
Ang II, converting it to Ang-(1-7). The conversion of Ang II to Ang-(1-7) diminishes the availability 
of Ang II to bind AT1R, forestalling the vasoconstrictive, proinflammatory, and prothrombotic 
effects of AT1R activation.41-45 Additionally, Ang-(1-7) acts on the Mas receptor, resulting in 
vasodilation, natriuresis, and a reduction in oxidative stress and inflammation.46,47 Collectively, 
Ang-(1-7) counteracts the pro-inflammatory and pro-fibrotic effects of Ang II in the heart and 
kidneys.48,49 In animal models, unopposed Ang II in the setting of diminished ACE2 upregulated 
inflammatory cytokines interferon-γ, interleukin-6, and monocyte chemoattractant protein-1, and 
increased phosphorylation of extracellular signal‑regulated protein kinase (ERK)1/2 and c-Jun N-
terminal kinase (JNK)1/2 signaling pathways.50 Furthermore, AT1R activation by Ang II has pro-
thrombotic effects, including enhanced platelet activation and impaired fibrinolysis, resulting in 
hypercoagulability.44,51,52 Ang II also stimulates plasminogen activator inhibitor-1, further 
promoting thrombus production.42 The pro-thrombotic effects of Ang II are downregulated by 
ACE2-mediated conversion into Ang-(1-7) and subsequent Ang-(1-7) signaling via MasR. ACE2 
is more prominently expressed in the kidneys than in the lungs, and direct viral invasion of the 
kidneys may promote systemic abnormalities in RAS activity.53,54 Dysregulation of this pathway 
may contribute to the hyperinflammation, hypercoagulability, and endothelial dysfunction in 
COVID-19, and may mediate both acute and long-term target organ CV and kidney damage.55,56 

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A7. The incidence, severity, and mechanisms of enduring CV effects of COVID-19 are 
unknown, and urgently require prospective, systematic evaluation. The current proposal 
aims to prospectively evaluate the natural history of cardiovascular and kidney disease in COVID-
19 survivors, and to identify risk factors for adverse mid- and long-term outcomes in these 
patients. Most studies evaluating COVID-19 hospitalizations rely upon administrative datasets, 
and are thus prone to misclassification of outcomes, unmeasured confounding, and confounding 
by indication for testing (e.g., those with underlying comorbidities are more likely to undergo 
frequent testing, whereas those without underlying comorbidities may not undergo follow-up 
testing at all). Administrative and retrospective studies also rely upon patients receiving all of their 
care within the same health system and do not adequately account for outmigration (e.g., due to 
change in insurance or change in geographic location) or loss to follow up, which may be 
exacerbated in the current setting due to high rates of unemployment and other economic 
pressures surrounding the COVID-19 pandemic. Administrative studies will also lack detailed, 
prospective, quantitative assessment of vascular function, a likely important mechanistic 
contributor to MACE in these patients. Moreover, to the degree that COVID-19 is a new disease 
and the mechanisms that may mediate its relationship with subsequent CV risk are unknown, it 
is essential to couple a careful assessment of incident CV events with deep mechanistic 
phenotyping of vascular and renal structure and function. Our team is experienced with these 
approaches and has been applying them in other settings (most notably, pneumonia of all cause, 
heart failure (HF) with preserved ejection fraction, and CKD). Our team also has a track record of 
translation of mechanistic phenotypes to the testing of novel candidate therapies. We aim to apply 
our experience and skills in the most expeditious fashion to contribute to a better understanding 
of intermediate- and long-term CV risk in the rapidly growing population of COVID-19 survivors. 
 
2 
Study Objectives 
Primary objective: To assess organ specific phenotypes and biomarker profiles to characterize 
specific cardiovascular, pulmonary, renal and other abnormalities and their role in functional 
status, quality of life and prognosis in COVID-19 survivors. 
Specific objectives: 
(1) To characterize cardiac and extracardiac phenotypes in COVID-19 survivors, and their 
relationship with: (a) quality of life; (b) functional status; (c) aerobic capacity; (d) 
prognosis. 
(2) To determine if the severity of COVID-19 is associated with measures of organ-specific 
structure and function after recovery. 
(3) To perform prospective follow-up of the cohort for the development of death, heart 
failure-related hospitalizations, and other adverse cardiovascular outcomes. 
(4) To establish a biorepository for future discovery. 
 
3 
Investigational Plan 
3.1 
General Design 
This is a prospective cohort study of 200 COVID-19 survivors and 80 control subjects without a 
known history of symptomatic COVID-19. Among survivors, we will prioritize subjects who had 
their index infection within the last 12 months. However, will allow for index infections acquired 
outside of this timeframe to facilitate enrollment. We will collect detailed measures of 
cardiovascular, pulmonary, renal structure and function, along with various other measures, as 
follows: 
(1) Endothelial function: flow-mediated brachial artery dilation and venous endothelial cell 
harvesting for molecular analyses. 

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(2) Arterial stiffness: carotid-femoral pulse wave velocity and carotid artery stiffness 
measurements. 
(3) Central pulse pressure and measurements of stroke volume and arterial compliance by 
impedance cardiography. 
(4) Subclinical atherosclerosis: carotid intima-media thickness and ankle-brachial index. 
(5) Pulmonary Function tests 
(6) Microvascular function: forearm ischemic vasodilation, and microvascular imaging with 
sublingual in vivo microscopy 
(7) A brief focused ultrasound test (liver, kidney, skeletal muscle, cardiac and carotid ultrasound), 
performed by a trained research team member.  
(8) Biosample collection (blood, urine and breath condensate) 
(9) A 6-minute walk test 
(10) A Kansas City Cardiomyopathy Questionnaire (KCCQ) 
(11) A subset of questions from the PROMIS Questionnaire to evaluate mental and physical 
function 
(12) A long COVID symptom Questionnaire 
(13) EQ-5D-5L Questionnaire 
(14) Social determinants of health questionnaire 
(15) Short Physical Performance Battery (SPPB) 
(16) In a subset of participants, we will also perform supine bicycle exercise tests to assess 
aerobic capacity (i.e., peak oxygen consumption, VO2). 
 
These tests are brief and in combination will take about ~5 hours. These assessments will be 
performed upon enrollment (baseline visit) and will be repeated at approximately 18-month 
intervals for a total of 3 tests (except for bicycle testing, which will only occur at baseline). 
Participants will also be followed prospectively for incident cardiovascular events via a 
combination of medical record reviews and phone calls as needed in order to adjudicate specific 
outcomes. Adjudication of all-cause death may be assisted using data from the Social Security 
Death Index. Expert clinical adjudicators will identify MACE (incident HF, MI, coronary 
revascularization, serious arrhythmia, stroke, peripheral artery disease [PAD], or death) by 
detailed review of hospitalization records.  
 
Given availability of staff and/or Center for Human Phenomics Sciences staff to complete study 
procedures such as endothelial cell harvesting, supine bike VO2 testing, and ultrasound, some 
participants may be asked to have their procedures done in different days to enhance data 
completeness and feasibility of scheduling. 
 
3.2 
Inclusion Criteria 
 
Subjects aged 18 years and older, male or female; 
 
Prior diagnosis of COVID-19 (acute symptoms consistent with COVID-19, confirmed by 
PCR, serologic or rapid antigen test) for the COVID-19 survivors group, or no confirmed 
or suspected prior history of symptomatic COVID-19 for the control group at the time of 
enrollment. 
 
3.3 
Exclusion Criteria 
 
Pregnant women; 
 
Inability to provide informed consent. 
 
History of CVD (defined as HF, MI, coronary revascularization, serious arrhythmia, 
stroke, greater than moderate valvular disease, any cardiomyopathy, or PAD), 
glomerular disease or polycystic kidney disease prior to enrollment. 

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 
End stage kidney disease (ESKD; defined as requiring persistent renal replacement 
therapy or prior kidney transplant) prior to enrollment 
 
History of chronic kidney disease (CKD) with eGFR <30 mL/min/1.73m2 prior to 
enrollment. In participants without a history of CKD, a measurement of eGFR will not be 
required for enrollment. 
 
3.4 
Subject Recruitment 
We will screen patients who received care at Penn Medicine for acute COVID-19 as well as 
patients referred to the post-COVID-19 clinic. We will also consider interested participants who 
reach out to us as a result of advertisements or other outreach efforts. Patients who meet the 
inclusion criteria will be identified and participants will be approached by a member of the study 
team for participation in the study. The study team will answer questions the subject has 
regarding participation, prior to signing the consent document. 
3.5 
Vulnerable Populations: 
Children, pregnant women, fetuses, neonates, and prisoners are not included in this research 
study. 
3.6 
Study Procedures 
3.6.1 Visit 1 
A member of the study team will approach the patient for participation in the study and review 
the informed consent document with them. The study team will answer questions the subject 
has regarding participation, prior to signing the consent document. 
 
After signing consent for participation in the study, the subject will undergo a series of brief 
procedures designed to obtain key phenotypes of various organ systems. All study procedures 
will be performed by a trained research team member. In combination, these procedures take 
~2 hours.  
 
 
Quality of Life Assessments: Subjects will then be given time to complete the short version of 
the Kansas City Cardiomyopathy Questionnaire (KCCQ), EQ-5D-5L, PROMIS Questionnaire 
and the long COVID symptom and impact tools.57 
 
Brief ultrasound protocol: we will use an Airexplorer Mach30 (SuperSonic Imagine; France; 
510K K191007) ultrasound device. The ultrasound protocol will include the interrogations listed 
in Table 1 and schematized in Figure 1. This ultrasound protocol is brief and in will take ~ 
approximately 30 minutes in total. In patients in whom these areas are not accessible 
(amputation, bandages covering skin in areas of interrogation) or if time does not permit, the 
respective ultrasound acquisitions will not be performed. This procedure carries no known risks. 
 
Table 1. Ultrasound scanning protocol 
 
Acquisition 
Description 
Phenotypes of 
interest 
Probe 
Liver and 
kidney 
Liver shear wave elastography in the supine to 
slightly left lateral decubitus position, with the 
probe on the lower right intercostal spaces, mid 
axillary line. B-mode, color Doppler and shear 
wave elastography acquisitions, followed by 
Liver stiffness, 
echogenicity 
Curved 
probe 

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unilateral kidney shear wave elastography from 
the anterolateral abdominal approach 
Pectoralis 
major, 
femoris 
rectus, and 
biceps 
thickness 
Pectoralis Major: Supine position. Right arm 
behind the neck. Probe on the right mid-axillary 
line, at the level of the angle of Lewis. Minimal 
compression. 
Femoris Rectus: Supine position. Knee extended 
and relaxed. Midpoint between the right patella 
and anterosuperior iliac spine. Minimal 
compression. 
Biceps: Supine position. Arms extended and 
relaxed. Midpoint between the acromion and 
elbow. Minimal compression. 
B-mode, color Doppler and shear wave 
elastography acquisitions. 
Muscle thickness 
(sarcopenia), 
stiffness, 
echogenicity, and 
perfusion  
High-
frequency 
linear array 
probe 
Carotid 
ultrasound 
Right common carotid B-mode with color Doppler, 
single plane. 
Carotid 
distensibility, wall 
stiffness, intima-
media thickness, 
pulsatility, wave 
intensity 
High-
frequency 
linear array 
probe 
Limited 
Cardiac 
and lung 
Ultrasound 
Limited parasternal, 4-chamber and 2-chamber 
view clips, mitral inflow and mitral/tricuspid 
annular tissue Doppler interrogations 
Limited lung scan for lung B lines 
Diastolic function, 
myocardial strain 
and stiffness 
Cardiac 
probe 

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Figure 1. Sample images of liver elastography, carotid flow, rectus femoris, and 
pectoralis major thickness. 
 
 
 
 
 
Pmj=pectoralis major; Pmi=pectoralis minor; R=rib 
 
 
 

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Carotid images will be processed offline to assess the following metrics: 
1) Carotid intima media thickness (CIMT): We will measure CC-IMT in near and far walls and in 
the anterior, lateral and posterior projections using automated edge-detection software 
(Carotid Studio; Quipu, Italy). A carefully trained technician will measure CIMT at these sites 
as the distance between the intimal-luminal and the medial-adventitial interfaces of the 
carotid artery wall,58 as done previously by our group.59-62 CIMT will be computed as the 
mean of all measurements.  
2) Carotid stiffness: We will perform time-resolved semi-automated wall tracking of the 
common carotid lumen diameter using view that best demonstrates both the near and far 
walls using automated edge-detection software (Carotid Studio; Quipu, Italy). As recently 
reviewed by our group, when performed assessments of local stiffness it is essential to 
avoid confounding by wave reflections.63 Carotid distension waveforms will be used along 
with calibrated carotid tonometry waveforms to calculate local carotid PWV (a measure of 
wall stiffness), using an expression equivalent to the Bramwell-Hill equation, which 
combines pressure and diameter (ln(Dia)P method), which is not susceptible to wave 
reflections:  𝑃𝑊𝑉= √
1
2𝜌
𝑑𝑃
𝑑𝑙𝑛(𝐷𝑖𝑎) , where PWV is calculated from the slope of the linear 
segment of the loop constructed from plotting pressure as a function of the natural logarithm 
of diameter64. 
 
Impedance Cardiography (ICG): Study subjects will undergo a resting impedance cardiogram 
(Z-logic; Exxer, Buenos Aires, Argentina) for the evaluation of cardiac output, stroke volume, 
and cardiac contractility, which will allow the estimation of arterial compliance and other 
parameters of interest. ICG will be performed depending on time and equipment availability. 
ICG is a form of plethysmography that utilizes changes in thoracic electrical impedance to 
estimate changes in blood volume in the aorta and changes in fluid volume in the thorax. The 
ICG procedure involves the placement of electrical leads (similar to ECG leads) on the patient’s 
neck and chest. A low-amplitude, high-frequency alternating current is delivered from some 
sensors while other sensors detect instantaneous changes in voltage. As suggested by Ohm’s 
law, when a constant current is applied to the thorax, the changes in voltage are directly 
proportional to the changes in measured impedance. The overall thoracic electrical impedance, 
called base impedance (Z0) is the sum of the impedances of the components of the thorax, 
including fat, cardiac and skeletal muscle, lung and vascular tissue, bone, and air. Changes 
from thoracic electrical impedance occur due to changes in lung volumes with respiration and 
changes in the volume and velocity of blood in the great vessels during systole and diastole. 
The rapidly changing component of chest impedance is filtered to remove the respiratory 
variation, leaving the impedance changes due to ventricular ejection. These impedance 
changes have been shown to be accurate predictors of stroke volume, and with the use of 
mathematical algorithms, ICG allows for accurate non-invasive measurements of stroke volume 
and cardiac output. 65,66 This procedure is non-invasive and does not produce pain or discomfort 
to the subject.   
 
Pulmonary Function Testing: We will perform a basic expired spirometry and measurements of 
CO diffusion capacity (DLCO) and lung volumes.67 We will utilize an FDA-approved Easyone Pro 
Lab Respiratory Analysis System (NDD systems Andover, Massachusetts; 510K K161534). In 
this test, subjects perform a forced expiration into a disposable probe meter (spirometry), primarily 
to determined forced vital capacity and forced expiratory capacity in 1 s (FEV1). As 
recommended, DLCO measurements will be performed in duplicate for enhanced accuracy. In 
these measurements, participants will inspire CO gas one deep inspiration, followed by an ~8-10 
second breath-hold, as tolerated, followed by normal breathing into the disposable mouthpiece 
for ~2 minutes, during which the machine measures the washout time of CO from the alveoli. 
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This test will in total ~20 minutes. Pulmonary function tests will not be performed if participants 
are receiving >2L/min of supplemental oxygen. 
 
Aerobic capacity: In a subset of participants who agree to additional testing, have no 
contraindications to exercise testing (such elevated fall risk or severely elevated blood pressure 
>180/100) and contingent on availability of equipment, personnel and funding, we will use a 
supine bicycle exercise protocol in conjunction with expired gas analysis to assess oxygen 
consumption (VO2) during exercise. This subset of subjects will perform a maximal exertion limited 
exercise test using a graded-exercise protocol. We will use a supine cycle ergometer designed 
for stress echocardiography (Stress Echo Ergometer 1505, Medical Positioning, Inc, Kansas City, 
MO). Subjects will undergo expired gas analysis with a Parvo Medics True One 2400 device 
(Parvo Medics, Sandy, UT) or equivalent. Resistance began at 15 W for 3 minutes, increasing to 
25 W for 3 minutes, and then increasing by 25 W every 3 minutes thereafter. Breath-by-breath 
information will be recorded. We will use custom-designed software already developed in Matlab 
(MathWorks, Natick, MA) at our lab for offline processing and quantification of all exercise data.68 
All data quantification will be blinded to treatment. Given costs considerations and funding 
availability, we will offer this additional component to former participants of the FERMIN trial 
(NCT04517396) but can be expanded to other participants as additional funding becomes 
available. 
 
 
Arterial tonometry: Carotid-femoral PWV will be measured with arterial applanation tonometry, 
which considered the clinical gold-standard method for the assessment of large artery 
stiffness.63,69,70 We will use a commercially available system (SphygmoCor CVMS, AtCor Medical) 
with a high-fidelity applanation tonometer (Millar Instruments). This involves sequential recordings 
of carotid and femoral arterial waveforms using a pen-like high-fidelity applanation tonometer 
placed on top of the artery on the body surface, along with electrocardiographic measurements 
so that the R wave of the QRS can be used as a time-reference point to compare both recordings 
and compute the pulse transit time between the carotid and femoral locations. Surface 
measurements of distance between carotid and femoral sites are performed to estimate intra-
aortic path length (80% of the direct body surface distance between the sites). Carotid-femoral 
PWV is computed as distance/transit time. Radial and carotid applanation tonometry will be 
performed as well. Brachial arterial pressures will be measured with a fully validated oscillometric 
device (Omron HEM 907-XL BP monitor; Omron Healthcare; 510K K032305 or BP+ device, 510K 
K121266). Arm circumference will be measured, and the appropriate cuff size will be placed. 
Radial waveforms will be calibrated with brachial systolic and diastolic pressures. Radial 
pressures will be used to calibrate the carotid pressure waveform, which serves as a surrogate of 
the central pressure waveform, and will be used to obtain central pulse pressure. 
 
Flow mediated dilation (FMD): Brachial artery FMD and hyperemic flow velocity, which evaluate 
conduit artery endothelial function and microvascular function, respectively,71,72 are important 
indicators of vascular health and predictors of CV risk.73,74 FMD will be measured using a semi-
automated device equipped with an ad hoc vascular ultrasound probe (UNEX Corporation, 
Nagoya, Japan). In this test, a brachial cuff is inflated to 50 mmHg above the systolic blood 
pressure, which is measured in advance. The inflation is held for 5 minutes, and the cuff is then 
deflated. The maximum diameter of the blood vessel of the same region is tracked continuously 
after deflation. The FMD is calculated as follows: FMD (%) = (maximum diameter − diameter at 
rest) × 100/diameter at rest.  Hyperemic brachial artery flow velocity will be determined by using 
pulsed wave Doppler to detect the peak flow velocity during the first 15 seconds post-cuff 
release.74-76 During the test, we will use wireless near-infrared spectroscopy (NIRS) devices to 
measure microvascular oxygenation as feasible. We will use a wireless PortaMon device and a 
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oxygenation at rest and during the FMD procedure. The NIRS devices are research-only devices 
and will not be used to make medical decisions. 
 
 
Ankle-brachial index (ABI): ABI uses non-invasive oscillometric blood pressure measurements 
in the ankle and upper arm to provide a measure of overt or clinically occult peripheral arterial 
disease. It is a well-established predictor of cardiovascular events and death.77-80 We will 
perform automated ABI measurements using a VaSera Device (Fukuda-Denshi; Japan; 510K 
K115121). 
 
Sublingual microscopy: Sublingual microcirculation will be visualized using sublingual 
capillaroscopy using a hand-held sublingual microscope (Microscan device; Microvision Medical; 
Amsterdam, Netherlands) by a trained technician.81 This is a research-only device and will not be 
used to make medical decisions. At least five videos of the sublingual microcirculation will be 
recorded from different positions and will undergo appropriate quality control.81,82 Videos will be 
analyzed using dedicated software (AVA 4.3C software; Microvision Medical; Amsterdam, 
Netherlands).83 We will calculate the Becker score,81 which is based on the principle that density 
of the vessels is proportional to the number of vessels crossing arbitrary lines. In this score, three 
equidistant horizontal and three equidistant vertical lines are superimposed on the microscopic 
image and vessel density is calculated as the number of vessels crossing the lines divided by the 
total length of the lines. Microvascular density, our primary metric of microvascular health, will be 
computed as the density of vessels <20 μm in diameter. We will also compute the proportion of 
perfused vessels as follows: 100 × (total number of vessels - [no flow + intermittent flow])/total 
number of vessels. Perfused vessel density, an estimate of functional capillary density, will be 
calculated by multiplying vessel density by the proportion of perfused vessels.81,84 
 
6-minute walk test: If they are able, participants will be asked to perform a 6-minute walk test. 
During this test, participants are asked to walk as far as possible during a 6-minute time interval. 
A corridor will be selected in which the participants can walk with minimal interference. During the 
procedure, one of the study staff members will supervise the test. Verbal prompts will be given, 
as suggested by the American Thoracic Society 2002 guidelines on the 6-minute walk 
procedure.85 During the test, we will use wireless near-infrared spectroscopy (NIRS) devices to 
measure microvascular oxygenation as feasible. We will use two wireless portamon devices and 
the wireless Brite device (Artinis medical systems; The Netherlands) to measure forearm, calf and 
brain oxygenation at rest and during the 6-minute walk test. The NIRS devices are research-only 
devices and will not be used to make medical decisions. 
 
The 6-minute walk test is an important phenotype because it offers an objective, well 
validated metric of exercise capacity. During this test, each patient determines the intensity of 
their exercise, and the test has been performed in thousands of older persons and thousands of 
patients with heart failure or cardiomyopathy without serious adverse events. 85 In order to be 
prudent, however, we will exclude patients with exertional chest pain, worsening chest pain during 
the previous month or a history of recent myocardial infarction (within a month), a resting heart 
rate of more than 120, a systolic blood pressure of more than 180 mm Hg, and a diastolic blood 
pressure of more than 100 mm Hg. These are consistent with current guidelines 85. 
 
Thermal images: thermal imaging patterns depend on vascular and neural function and have 
been associated with cardiovascular risk factors.86 For exploratory purposes, we will acquire 
thermal images of the face and bilateral hands will be obtained using a commercially available 
compact thermal camera (FLIR C2; FLIR, Wilsonville, OR). This device is for research only and 
will not be used to make medical decisions. Non-contact thermal imaging is used to detect 
patterns of skin surface heat emissions from patients with various conditions, which has been 
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associated with any known risks.  
 
Breath condensate collection: Exhaled breath condensate (EBC) analysis is a developing field 
with tremendous promise to advance personalized, non-invasive health diagnostics as new 
optimized analytical instrumentation platforms and detection methods are developed.87-93 Exhaled 
breath contains potentially valuable metabolomic content due to gas exchange with blood at the 
pulmonary alveolar membrane interface. Various disease states often significantly change the 
entire pattern and relative abundances of volatile organic compounds (VOCs) in exhaled breath.87-
93 We will collect the condensed exhaled fraction of alveolar air for about 5-8 minutes using a 
commercially available device (Turbo AAV 14; MEDIVAC, Parma, Italy). This system utilizes 
plastic air collectors coupled with a condenser equipped with a CO2 detector that routes collection 
of air (via an electronic valve) only when CO2 levels are consistent with alveolar air (as opposed 
to dead space air). This device is for research only and will not be used to make medical decisions. 
We will use only new or sterilized plastic collection tubes. Exhaled air condensate will be aliquoted 
and frozen at -80°C. This procedure carries no known risks.  
 
Urine collection: In all participants, 10-mL of urine will be collected and aliquoted. 
 
Venous endothelial cell harvesting: endothelial cells will be collected from the antecubital 
vein using 4 soft, flexible, sterile 0.021 inch J-wires which are briefly advanced through the 
standard intravenous catheter. A trained Research Nurse will place the intravenous catheter 
and advance the J-wire to obtain the cells.  Once the J-wire is advanced and pulled back 
through the venous catheter, the distal portion of the wire is transferred to a 50-ml conical tube 
containing a buffer solution for analyses. Analyses will include RNA sequencing to assess gene 
expression and fixing for immunohistochemistry. This procedure will be optional depending on 
the availability of a trained research nurse at the time of the visit.  
 
Venous blood collection: In all participants, we will collect 40 mL of venous blood, which will 
be aliquoted as plasma, serum, buffy coat (for future DNA extraction and potential future genetic 
testing as funding becomes available) and PAX gene tubes (for future RNA extraction). 
 
24-hour ambulatory blood pressure monitoring: Ambulatory BP monitoring will be performed 
using the SunTech Oscar2 ambulatory BP monitor to obtain 24-hour brachial blood pressure 
measurements as well as estimates of central blood pressure 94. Prior to placement of the 
monitor, resting BP will be measured on both arms while sitting and orthostatic blood pressure 
will be checked in one arm with a standing blood pressure checked approximately 3 minutes 
after rising. If the difference in systolic BP is <10mmHg the non-dominant arm will be used for 
monitoring; however, if the difference in systolic BP is ≥10mmHg the arm with higher pressure 
will be used. The mid-arm circumference will be measured and recorded and a cuff appropriate 
for the arm circumference will be used. Participants will be instructed to engage in usual daily 
activities and avoid strenuous exercise for the 24-hours in which the ABPM is in place. BP will 
be measured every 30 minutes for 24- hours. Participants will keep a diary documenting time to 
bed, time waking up, medications taken, and any other events of significance. 
 
Short Physical Performance Battery (SPPB): SPPB is a well-established and objective 
assessment tool to evaluate lower extremity function and mobility. It is predictive of all-cause 
mortality95 and incident disability96 and has been associated with incident cardiovascular 
events97 in older adults. A study team member will administer 3 physical tests and assess the 
participant’s balance, gait, strength, and endurance by examining their ability to stand for up to 
10 seconds with feet positioned in three ways (together side-by-side, semi-tandem and 
tandem), time to walk 4 meters, and time to rise from a chair and return to the seated position 5 
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an overall score range of 0 to 12, with 0 indicating the lowest physical performance, and scores 
of 12 indicating the highest performance.97 
 
Other data collection: 
 
We will perform: 
 
A research-grade review and quantification of available cardiac imaging studies 
(echocardiograms, cardiac MRIs, CT scans) in Dr. Chirinos’ imaging core lab. 
 
A medical record review including symptoms, past medical history, imaging, laboratory 
values, results of physical exams, vital signs, hemodynamic values, and other test results,w 
with special emphasis will be placed on collection of data related to the severity of the 
COVID-19 episode.  
 
We will also register data collected routinely in the post-COVID-19 clinic. 
 
The severity of the index COVID-19 episode will be determined using a hierarchical global 
rank score98-100 in which all subjects will be ranked based on the characteristics of their index 
COVID-19 episode according to 4 factors: (1) the number of days supported by mechanical 
ventilation (invasive or non-invasive) or extracorporeal membrane oxygenation; (2) The 
inspired concentration of oxygen/percent oxygen saturation (FiO2/SpO2) ratio area under the 
curve during the longest hospital admission; (3) For participants who didn’t get hospitalized, 
we will use a modified SOFA score that includes the cardiac, respiratory, coagulation and 
renal domains of the SOFA score because these components can be easily and reliably 
adjudicated using electronic medical record review. For the respiratory component of the 
SOFA score, we will apply a modified score used in which the arterial oxygen saturation is 
used instead of measured arterial oxygen saturation.   
 
Feasibility: all measurements will be acquired only whenever feasible. Some of these 
measurements may be non-feasible due to patient-specific factors including anatomic factors, 
technical difficulty and/or logistical issues. When measurements are not feasible, the reason will 
be systematically recorded. 
  
3.6.2 Follow-up 
A member of the study team will perform reviews of the subject’s electronic health record at 
regular intervals. Subjects will be contacted via telephone to assess whether they have been 
hospitalized or sustained any other adverse cardiovascular events. MACE will be defined as (1) 
acute coronary syndrome, (2) hospitalization for HF, (3) serious cardiac arrhythmia, (4) PAD, (5) 
cerebrovascular events, and (6) CV death.74,101-106 Event ascertainment will be an iterative 
process implemented every six months that will begin with querying each participant about the 
interval occurrence of any of the outcome events or any hospitalizations. Positive indications 
from study participants about a hospitalization or possible event will be followed by collection of 
selected medical records from the inpatient setting. Records will include administrative hospital 
codes and copies of relevant portions of the medical record, including admission and discharge 
notes, progress notes, laboratory studies, ECGs, radiographic studies, and any other diagnostic 
testing or procedure notes. Individual events will be defined as described in Table 2:  
 
 
Table 2. Summary of adjudicated outcome events 
Outcome Event 
Summary of Definitions 
Acute Coronary 
Syndrome 
New universal definition of MI by the American Heart Association.107 
Acute MI types 1-3: Acute myocardial injury with clinical evidence of acute 
myocardial ischemia and with detection of a rise and/or fall of cardiac troponin (cTn) 
values with at least 1 value above the 99th percentile upper reference limit (URL) 
and at least 1 of the following:  

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• Symptoms of myocardial ischemia 
• New ischemic ECG changes 
• Development of pathological Q waves 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality in a pattern consistent with an ischemic etiology 
• Identification of a coronary thrombus by angiography or autopsy (not for types 2 
or 3 MIs). 
Percutaneous coronary intervention (PCI)–related MI (type 4a MI) and Coronary 
artery bypass grafting (CABG)–related MI (type 5 MI):  
• Coronary procedure-related MI ≤48 hours post-procedure, cTn >5-fold (type 4a 
MI) or >10-fold increase (type 5 MI) of the 99th percentile URL in patients with 
normal baseline values. Patients with elevated preprocedural cTn values must 
manifest a change from the baseline value of >20%.  
• In addition, at least 1 of the following: 
- New ischemic ECG changes (this criterion is related to type 4a MI only) 
- Development of new pathological Q waves 
- Imaging evidence of loss of viable myocardium that is presumed to be new 
- Angiographic findings consistent with a procedural flow-limiting complication 
such as coronary dissection, occlusion of a major epicardial artery or graft, or 
disruption of collateral flow 
- Isolated development of new pathological Q waves if cTn values are elevated 
and rising 
Types 4b (MI stent thrombosis) and type 4c MI (restenosis): must meet type 1 MI 
criteria.  
Coronary 
Revascularization 
Percutaneous angioplasty or stent placement for obstructive coronary artery disease 
or CABG 
Hospitalization 
for HF 
Hospitalization for clinical symptoms of HF in the setting of objective confirmatory 
evidence including radiographs, evidence of pulmonary congestion/edema, physical 
examination, invasive hemodynamic monitoring, or echocardiographic confirmation. 
Admission must include administration of intravenous diuretics, escalation of diuretic 
doses and/or use of inotropes, volume removal by ultrafiltration or renal replacement 
therapy for decongestion, or mechanical circulatory support. Relevant 
echocardiographic information will be reviewed to determine if the event is consistent 
with HF with reduced ejection fraction (EF <40%), mid-range EF (40-49%), or 
preserved EF (≥50%).108 
Incident Serious 
Cardiac 
Arrhythmia 
Categorized as follows: 
 Resuscitated cardiac arrest 
 Ventricular fibrillation 
 Sustained ventricular tachycardia 
 Selected instances of non-sustained ventricular tachycardia 
 Initial episode of atrial fibrillation or flutter, severe bradycardia or heart block 
 Postoperative tachyarrhythmias following CABG or other cardiac surgery 
Peripheral arterial 
disease 
One of the following must be present: 
 PAD with resultant amputation 
 Surgical or percutaneous revascularization procedures such as angioplasty and 
artery-artery bypass graft 
Cerebrovascular 
Events 
Categorized as follows: 
 
Intraparenchymal hemorrhage 
 
Subarachnoid hemorrhage 
 
Large-vessel cerebral infarction 
 
Cardioembolic cerebral infarction 
 
Small-vessel cerebral infarction 
 
Cerebral infarction not otherwise specified 
 
Transient ischemic attack: Acute disturbance of focal neurological or 
monocular function with symptoms lasting less than 24 hours and thought to 
be due to arterial thrombotic or embolic vascular disease 

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Death Events 
Cardiovascular death: 
 Atherosclerotic coronary heart disease death 
 Cerebrovascular death 
 Other atherosclerotic disease death (non-coronary/non-stroke) 
 Sudden cardiac death 
 Other CVD death (including death from HF) 
Other Death 
3.7 
Unscheduled Visits 
We anticipate no unscheduled visits. We anticipate that the only situation in which this would 
occur is if a study subject requests a meeting with the investigator to discuss any issues related 
to the study. 
3.8 
Subject Withdrawal 
Subjects may withdraw from the study at any time without impact to their care. The Investigator 
may also withdraw subjects who violate the study plan, to protect the subject for reasons related 
to safety, or for administrative reasons. It will be documented whether or not each subject 
completes the study. 
 
4 
Statistical Plan 
4.1 
Data analysis plan 
To characterize cardiac and extracardiac phenotypes in COVID-19 survivors, we will use latent 
class analysis with finite mixture modeling to classify individuals into mutually exclusive and 
exhaustive subgroups, maximizing within-group similarities and between-group differences on the 
basis of baseline covariates 109-112. Latent class models will be compared across successive 
numbers of subgroups and the optimal number of groups will be determined using the parametric 
bootstrap likelihood ratio test, Akaike’s Information Criterion, Bayesian Information Criterion, and 
sample-size adjusted BIC 113,114. We will use other clustering methods for corroboration of our 
identified phenotypes, including Gaussian mixture models via the expectation–maximization 
algorithm 79, and consensus clustering 115 to evaluate the stability of the discovered clusters. 
Descriptive statistics will compare patients across phenotypes using Student’s t-test, Wilcoxon 
rank sum, or Chi-square test, as appropriate. We will then assess for differences in quality of life 
and functional status across phenotypes using multinomial logistic regression. We will separately 
analyze the trajectory of each of the quantitative measures of vascular health and kidney function 
using mixed effects growth curve models.116 Where necessary, we will supplement these analyses 
with marginal models estimated by generalized estimating equations.117 We will assess for varying 
length of follow-up among subgroups to evaluate for any potential bias this may introduce. We 
will assess for effect modification by sex and race due to potentially important differences in 
COVID-19 outcomes118-120 and trajectory of vascular and kidney health.121,122 We will also use 
methods that classify participants according to their vascular and kidney health trajectories, using 
each individual parameter and extended to multiple parameters. We will use the latent class mixed 
effects model123,124 to analyze trajectories of vascular and kidney health within our study 
population. The latent class mixed effects model introduces an additional variable to represent 
class membership, which can be modeled through a multinomial logistic regression. 
 
The endpoint of MACE will be evaluated as a time-to-event endpoint from the date of discharge 
from the index hospitalization for COVID-19 and from the date of the first study visit, accordingly. 
We will examine the associations of severity of hospitalization, baseline covariates, and post-
discharge cardiac and extra-cardiac phenotypes with this failure-time event using Kaplan-Meier 
curves and Cox proportional hazards regression 125. We will use the multivariable Cox model to 

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estimate the effects of the primary exposure adjusting for baseline covariates. We will use time 
by covariate interaction terms and examine residual plots to assess the adequacy of model fit 126. 
If the proportional hazards assumption is violated, a time by predictor interaction term will be 
added to the model to allow for changes in the HR over time. Secondary analyses will evaluate 
death prior to the event as a competing risk, including incorporation of the composite outcome 
with the cumulative incidence function 127,128. We will assess for effect modification by sex and 
race due to sex- and race-related differences in COVID-19 outcomes 118-120 and risk of MACE 
121,129.  
4.2 
Power calculations 
We will enroll 200 COVID-19 survivors following recovery from their hospitalization and 80 
controls. For analyses of trajectory of vascular and kidney health, accounting for multiplicity 
across multiple outcome parameters at an alpha at 0.0025,130 we will have >80% power to 
observe, for example, a mean difference in slope of PWV of 0.8 m/s and eGFR of 4 
mL/min/1.73m2 per 18-month visit interval across COVID-19 survivors and non-COVID-19 
controls, assuming intraclass correlation coefficient of 0.1 and 20% loss to follow-up.131 For 
determining the association of hospitalization severity with risk of MACE, the most conservative 
endpoint in the study, we assumed a cumulative event rate of 5% over 5 years of follow-up 6,7, 
accounting for our exclusion of individuals with prior CVD. Assuming a retention rate of 80%, we 
will have 90% power at an alpha of 0.05 to detect a regression coefficient of 0.9 in the Cox 
model 132,133. In analyses evaluating for sub-phenotypes and risk factors for MACE, using a 
conservative Bonferroni approach to account for multiplicity across several risk factors 130, we 
will have over 90% power at an alpha of 0.005 to detect a regression coefficient of 0.9 for every 
standard deviation difference in parameter. Power calculations were performed using PASS16 
134. 
5 
Study Administration, Data Handling, and Record Keeping 
All information obtained as part of protocol will be maintained in locked research files. Electronic 
data will be stored in a password secured database (REDCap). This database will be available 
only with secure high-level password protection to safeguard the privacy of the participants. Any 
source documents for each patient involved in the protocol, other than the patient’s electronic 
medical chart, will be maintained in a centralized, secured location.  
 
Data collected will contain protected health information (PHI) including name, date of 
birth, and medical record number. Information about study subjects will be kept confidential and 
managed according to the requirements of the Health Insurance Portability and Accountability 
Act of 1996 (HIPAA). Research data will be stored in a centralized, secure location (locked 
cabinets in the PI's research space).  
 
Participant data, blood, and urine samples will be stored for future use. These stored 
elements will be used only for research purposes. A randomly assigned number rather than 
name will identify all collected samples and data. PHI will be treated with strict confidentiality 
and stored in a secured, limited access area. A secure database of patient information will be 
maintained. PHI will not be disclosed or shared with any parties outside of the research team 
unless required by law or by regulatory processes at Penn (such as audits). 
6 
Study Monitoring, Auditing, and Inspecting 
6.1 
Study Monitoring Plan 
The study PI will be responsible for ensuring the ongoing quality and integrity of the research 
study. 

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6.2 
Auditing and Inspecting 
The Investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc).  
7 
Ethical Considerations 
The protocol, amendments and continuing reviews will be submitted for review by the Penn IRB 
and other appropriate reviewing entities. 
7.1 
Risks 
There are minor risks to subjects who choose to participate in the study. The ultrasound 
examination, breath collection, arterial tonometry, NIRS, thermal imaging, and sublingual 
capillaroscopy have no known risks.  
 
Venipuncture: According to the 2010 WHO guidelines on phlebotomy, major risks associated 
with venipuncture include hematoma at the site of venipuncture in 2-3%, and vasovagal reactions 
and fainting in 1%.  
 
Endothelial cell harvesting: The risks associated with the procurement of venous endothelial 
cells are low and are analogous to the risks that occur with placement of a venous catheter, which 
include pain, superficial phlebitis/venous blood clots and infection.  
 
During various procedures (echocardiography, arterial tonometry), we will use adhesive 
electrodes attached to the participant’s skin to record the electrical signal from the heart. These 
may occasionally cause skin itching and irritation. 
 
Risks of pulmonary function tests: Our pulmonary function tests will not involve challenging 
(such as methacholine administration) and thus are very low risk. A potential risk is dizziness 
during forced maneuvers or shortness of breath during the 8-10 breath hold required for DLCO 
measurements. The tests may rarely cause sore chest muscles. There is a very low risk of 
pneumothorax from forced expiration.  
 
Risks of exercise testing: This test is used extensively for research purposes with minimal risk 
to subjects. The most significant risks of the test are dysrhythmias or other cardiovascular 
complications, which are extremely rare. These procedures will be performed by qualified 
personnel according to established American Heart Association Guidelines.135,136 Non-
revascularized myocardial ischemia, which may increase the risk of complications during exercise 
testing, is an exclusion criterion for the study. Furthermore, the procedure is voluntary and 
intended to only be performed in a subset of participants in the study and will not be performed in 
any participants with a contraindication to exercise, such as elevated risk of falls (as assessed by 
the investigators) or severely elevated blood pressure (>180/100). 
 
Subjects may feel uncomfortable as a result of pushing themselves during the maximal effort 
exercise test. Subjects will likely feel short of breath and fatigued as a result of the exercise test. 
Various other complaints, such as nausea, lightheadedness, and other aches and pains are also 
possible as a result of the maximal effort exercise study. Although exercise testing may result in 
exhaustion, rarely do people develop abnormal heart rate or heart complications during exercise 
tests. The risk of this happening is the same as if the participant would exert themselves during 
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We will perform ECG, heart rate, and blood pressures monitoring during our exercise test. In 
addition to the blood pressure (generally increases) and heart rate (generally increases) changes 
during exercise, we will also monitor arterial saturation. This will be done non-invasively using a 
pulse oximeter. Of note, oxygen levels can decrease with exercise, even in individuals without 
significant cardiopulmonary disease.137 If the arterial saturation falls to below 88% (“severe 
exercise induced hypoxemia”138), we will alert the patient’s primary care provider as this may 
prompt consideration for additional or alternative causes for arterial hypoxemia. 
 
Risks of FMD measurements: The cuff inflation used for FMD may cause temporary bruising. 
The inflation itself may cause tingling in the hand/digits, which resolves after deflation.  
 
Risks of ambulatory blood pressure monitoring: There is minimal physical risk from non-
invasive ambulatory blood pressure monitoring. A potential discomfort will be the squeezing from 
inflation of the blood pressure cuff, which may cause sleep disturbance for some participants. 
 
Risks of SPPB: The gait and balance tests may lead to falls and the repeat chair stand test 
require a vigorous effort. However, these tests were found to be efficient, practical, and safe to 
administer to thousands of older persons in a home setting without any injury or adverse 
outcome.139 
 
Risks of impedance cardiography: this procedure is not associated with any known risks. 
Electrodes or electrode gel may cause irritation or itching.  
7.2 
Benefits 
There may be no direct benefit to subjects as a result of their participation in the study. However, 
society in general may benefit as a result of scientific discoveries obtained during the course of 
this study. However, this study may provide novel information leading to the discovery and better 
understanding of long-term complications in COVID-19 survivors, which may in turn lead to newer 
approaches for their treatment or prevention. Results of research procedures will be shared with 
the patient or his/her providers upon request. 
 
7.3 
Informed Consent Process / HIPAA Authorization 
All subjects for this study will be provided with an IRB-approved consent form providing sufficient 
information for subjects to make an informed decision about their participation in this study. The 
formal consent of a subject, including signing the IRB-approved consent form, will be required 
before that subject undergoes any study procedure. Participants able to perform exercise testing 
will be offered the option to undergo VO2 testing.  
 
7.4 
Reporting of Incidental Findings 
The tests in this study will be quantified for research purposes and not for clinical interpretation 
purposes. However, when incidental findings are encountered in study procedures, the study PIs 
will communicate these to study subjects and providers as necessary, based on their clinical 
judgement. These findings include but are not limited to, pulmonary function testing results and 
abnormalities discovered during ultrasound acquisition. If a PI is unable to contact a subject via 
phone, they may choose to mail a letter or send a message via MyPennMedicine.  

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8 
Study Finances 
8.1 
Funding Source 
This study will be funded by the Investigators' discretionary funds. NIH funding will also be 
pursued.  
8.2 
Subject Stipends or Payments 
Participants will receive $250. Those additionally undergoing VO2 testing will receive an 
additional $150.  
9 
Publication Plan 
The Investigator and study team will prepare and lead publications arising from this study. The 
data may also become a part of collaborative endeavors and/or scientific consortia from which 
joint publications with other groups may result. As such, subjects are being consented for their 
data (devoid of PHI) to be shared with other investigators outside of Penn. 

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