European Journal of Cardiovascular Medicine

Cardiovascular involvement in COVID-19 is now well documented. Evidence accrued from  post-mortem studies in the first wave documentation of Endotheliitis and Myocarditis. Post second wave saw incidence of cardiac involvement as the predominant pathology determining morbidity and mortality.

Besides change in Predilection of organ system involvement, it was seen that age of incidence was lowered.

Second wave saw predominant involvement of the heart ( isolated ) between the age group of 16-35 years (which still persists ). Later half of 2023 saw paediatric referral for unexplained chest pain; for Echocardiography.

Age of incidence ranged from 5-13 years.

A specific template of structural involvement and functional abnormality was available by this period.

The same Echocardiographic parameters were tested in these patients whose symptomatology suggested

COVID Heart.  Echocardiographic studies revealed presence of all the features and few additional features specific in paediatrics population only. Presence of SEC (Spontaneous Echogenic Contrast) in the basal and mid portion of LV was a universal pathognomonic finding.

Endotheliitis due to direct invasion of virus and Myocarditis by Cytokines storm or direct invasion (still debatable) has now been the two Established pathologies responsible for Cardiac involvement in COVID.

Clinical spectrum range from Mild Troponin elevation to Heart failure can be seen.

CMR & Endomyocardial Biopsy are the gold standard of diagnosis but not feasible.

Hence establishing Valid; Reproducible patterns in 2D Echocardiography and Strain imaging ( many studies have been published now ) along with laboratory test supporting coagulopathy can help establish  Echocardiography as a Sensitive diagnostic modality for identifying COVID HEART.

This was a prospective observational study done at a tertiary care centre and results of one year (August 2023 to July 2024 ) were presented.

Patients selection was based on specific symptomatology of severe episodes, transient pain over precordium not linked to any aggravating factor, any diurnal variation.

Associated with palpitation and mild respiratory discomfort.

Each episode tested for 5 to 10 min with spontaneous recovery and back to normal activities; completely Asymptomatic and normal effort tolerance between the episodes.

Another presentation was fatigue and recent onset reduced  effort tolerance.

Only those patients who had no previous history of any cardiac  illness or had disease of any organ system ( Clinically and by routine investigation )

All patients underwent routine clinical examinations which had to be normal for inclusion in the study.

12 channel ECG was performed in all patients quantitative Troponin-T was done in all studied patients.

All patients underwent 2D TTE and Strain imagine and analysis by Vivid T9 ultra ( G.E. Healthcare system Chicago, USA ).

Echo was repeated after 2 Months and 6 months respectively.

Lab Investigation –         .

• Troponin-I

• D-Dimer

• Serum CRP

• Serum Ferritin
• Interleukin – 6
• X-Ray Chest (PA view)

above all lab investigations was done in all patients

A total of 50 patients were included in this study. The mean age of the study population was 8± 2.4 years; Predominantly males. Chest pain, palpitations and reduced effort tolerance were  the most common symptoms ( 80%, 50%, 40% ). Rhythm, disturbance tachycardia,  Bradycardia was the most important finding of occasional atrial fibrillation (5 %) .

ECG -:

1. Sinus Rhythm in all patients
2. Tachycardia ( Sinus ) was noted in 20% cases
3. Occasional Bradycardia
4. poor R-Wave Progression from V1-V3 was the typical finding noted in majority of the Patients (75% cases )

Lab Results -:

1. Dimer Value was raised by 3-4 times in all the patients studied.
2.  D Dimer values were used to monitor recovery / efficacy of treatment.
3. Serum CRP was raised in the majority ( 90% ) of cases.
4. Troponin-I values did not show any significant nor incremental  increase with time
5. Other inflammatory markers were also infrequently tested and were found to be raised
6. X-Ray Chest PA- Normal ( NAD ) – in all the patients studied

2D TTE and AFI :-     a) At Presentation

               Following Characteristic findings were observed

• PLAX

- sluggish mid and distal interventricular septum ( LAD ) mild spontaneous Echogenic contrast around mitral valve, mild MR ( Central Jel )

• SAX

- Mild Hypokinesia with thinning of Antero-Septal (Majority) or  Septal (20%) or Anterolateral (few). 

- Thinning and Hypokinesia of  IVS  led to stretching  of that segment which resulted in an  OPERCULUM  like appearance over the rest of the heart in Systolic frame.

- Slight Anterolateral bulge ( junction of Hypokinetic and normal segment .

- Aforesaid Finding led to increase in transverse diameter leading to oval shape in Diastole frame

-Trivial SEC – Mid cavity around mitral valve

- No RWMA observed  in other segments

• 4 CH.
• Mild Hypokinesia of Apical ( Reverse semilunar shape ) and apicolateral segment.
• Effaced or thinned out septal Endothelium
• Mild to moderate spontaneous Echogenic contrast free flowing across mitral valve in basal and mid cavity with some lateralisation towards the septum

• 2 CH.
• Mild Hypokinesia of anterior and anteroapical segment. SEC in basal and mid cavity with lateralisation to anterior wall

• APLAX.
• Mild Hypokinesia Mid and distal IVS with increase transverse diameter of   terminal apical segment   mild free flowing  SEC- confined over mitral valve in systolic frame.

AFI :-

               Peak global longitudinal strain was at a lower limit of normal.

Bulls Eye :-

               Regional strain was reduced in apicolateral ( in all patients ) followed by Anteroseptal, Septum

And the Anterior segment.

Strain Derived EF :-

               4 CH. Ejection fraction reduced with EF 50±  5%-10% less than 2 CH. – EF

               2 CH. Ejection Fraction was almost normal 60± 5%

PSD :-

               Normal or mild increase in apicolateral segment 

PST :-

               Mild increase value apicolateral and anteroseptal segment

RV Strain:-

               PGLS and Tapse in normal range

LA Strain:-

               Reservoir strain was normal and good EF

AT PRESENTATION

1. b) Follow up 2D TTE and AFI – after 6 months

TTE

Follow-up screening after 6 months of treatment revealed:

PLAX – Restoration of LV cavity shape to normal Trivial SEC

SAX – No RWMA (no operculum seen)

SAX circular in both diastolic and Systolic frame

4 CH. – Repair of septal Endothelium with correction of apical remodeling    Trivial SEC

2 CH. – Correction of apical anterior remodeling     trivial SEC

APLAX - Correction of Apical remodeling   trivial SEC

AFI

               Normal PGLS with restoration of regional strain value to normal

               PSD – Normal values no Dys-synchrony

               PSI – Normal values

AFTER:  SIX MONTHS

Paediatric referral for unexplained chest pain for cardiac evaluation was the reason behind the study.

With structural cardiac involvement due to COVID-19 documented Echocardiographic ally in young adults^1® patients of

Paediatric age group were also evaluated in the same manner.

Echocardiography revealed all the findings seen in young adults with spontaneous Echogenic Contrast confined to the basal and mid cavity of LV as an additional universal finding.

Characteristic wall motion abnormality in LAD.

Producing an operculum like appearance in the systolic frame of SAX.

Septal Endothelial effacement / thinning best evidence in 4CH. Mild Hypokinetic mimicking in Infraction in Apicolateral, Anteroseptal and Anterolateral segment. This resulted in reduced 4CH. Stain based EF. Mild deduction in peak global longitudinal strain. Reduced Regional stain in Apicolateral and Anteroseptal segment. Border line or normal PSD and increased regional PST values (Apicolateral, Anteroseptal).

The surprising finding was the presence of free-flowing spontaneous Echogenic contrast confined to the basal and mid cavity segment of LV in systolic frames. The LA dimension and function was normal.

SEC was consistently present in all the cases studied and became a “ESSENTIAL DIAGNOSTIC CRITERIA of inclusion of cases in this study.

Free flow with confinement to the basal and mid cavity of LV was confirmed in other views is systolic frame via PLAX ( basal and mid cavity ) SAX mid cavity ( MV ) views ( where it was seen around mitral valve ). 2CH. ( similar distribution ) PLAX ( Over mitral Valve in Systolic frame ).

In our study no evidence of SEC was seen in RV and RA. RV showed normal dimension and systolic function.

Studies have demonstrated that the main pathological manifestation of cardiac damage in COVID-19 is the so called Endotheliitis with dysplasia and activation of Endothelial Cyst leading to Haemorrhage, Thrombosis of intramural arteries and necrosis^2®

(COVID-19  Heart Lesions in children clinical diagnostics and Immunological changes / International journal of molecular sciences )

No convincing evidence were obtained for direct involvement of SARS COVID-2 in induction of Myocarditis. This fact once again confirms the theory that pathogenesis of a Severe course of COVID-19 is based predominantly on immune damage to Cardiac and Vascular Endothelium and formation of Microthrombus.

After invasion by Virus Endothelial cells losses - ACE II activity which subsequently leads to reduced Angiotensin II inactivation and decreased conversion to Angiotensin 1-7.

Decreased Angiotensin 1-7 suppresses Nitric Oxide Production. Which triggers increased Thrombogenicity due to leucocyte and platelet adhesion and vasoconstriction.^3®

Vascular Endothelium is coated by gel like component known as glycocalyx that regulates vascular blood flow by providing an antithrombotic surface via antithrombotic binding to the Heparan sulphate  ( A Major component of glycocalyx )

Although the circulating antithrombin level has been reported to be in normal range on presentation in COVID-19 Patients.

If the Glycocalyx is disrupted the local antithrombogenic activity of the Endothelial surface may be altered.

SamJada DM et al^4® measured Angiopoietin 2 , D Dimer, CRP and Creatinine in 40 patients in ICU and found Angiopoietin 2 as the best predictor for poor outcome.

D Dimer was Estimated in all the patients in the study and was found to be 3-4 fold higher than normal values. Increases in D

Dimer levels were greater than what we found in young adults. Levels of  D Dimer decreased with treatment.

Secondly Angiotensin 2 is stored in the Endothelial cells and secreted along with Endothelial damage reportedly Angiotensin 2 levels are associated with coagulation disorder organ damage and death in Bacterial sepsis.

Localized Coagulopathy in the absence of generalised evidence is still under evaluation however the predominant role of  Endotheliopathy due to direct endothelial invasion with SARS COVID 2 and indirect damage caused by inflammation are part of the complex thrombo inflammatory process.

COVID-19 infection has been postulated to cause coronary microvascular dysfunction ( CMD ) which can lead to Subendocardial Ischemia perfusion defects have been demonstrated in patients with history of COVID-19 infection using cardiac MRI.

CMD could be the probable cause for wall motion abnormalities and Endocardial effacement noted in our patients.

Coronary Microvascular dysfunction may cause global wall motion abnormalities which slowly recovers over time.

The rate of recovery can be variable for individual segments with Anterior and Apical segments Showing slower recovery as compared to others. Thus produces the characteristic finding on Echocardiogram.

Newer evidence Pertaining to disturbance of regional perfusion instead of global perfusion post severe COVID infection is emerging. Follow up Studies are underway to determine reversibility of initial changes.

COVID-19 Patients have global as well as regional Myocardial dysfunction and Endocardial dysfunction and Coagulopathy (secondary to Endocardial damage). Endocardial Dysfunction and associated coagulopathy is the predominant pathology in Paediatric population (C.F. absence of coagulopathy in young adults ); It was also substantiated by greater elevation of D Dimer Values C.F. young adults.

These Echo findings demonstrate the consequences of both Myocarditis and Endotheliitis with coagulopathy. Hence Echocardiography should be considered a diagnostic modality of choice in such a situation.

Limitations: -

The current study has its inherent limitations. The small sample size prohibits us from generalising the entire spectrum size of COVID-19 patients.

CMR emerging could not be performed as well as few laboratory tests due to lack of availability and financial constraints.

As this was a single central hospital-based study selectors bias could have influenced the results with sicker patients being excluded from analysis

1. Spectrum of Myocardial involvement in Patients with COVID-19 an Echocardiographic study.
2. ( Manoj Kumar Dubey, Avinash Mani, Vineeta Ojha )
3. COVID-19 Heart lesions in children; clinical diagnostic and immunological changes
4. ( International Journal of Molecular Sciences )
5. The Coagulopathy Endotheliopathy and Vasculitis of COVID-19
6. ( Toshiaki iba Jeen Mary Connors Jerrold Hlery inflammation research Springer Nature Switzerland AG 2020
7. SamJada DM et al Angiopoietin 2 as a marker of Endothelial activation is a good prediction factor for Intensive Care Unit admission of COVID-19 patients
8. Ojha V et al Cardiac magnetic resonance imaging in COVID-19; A Systematic review of cardiac magnetic resonance imaging findings in 199 patients ( Thoracic imagine 2021 ) Doi 10.1097.