Risks of Cardiac Events With COVID-19 Vaccination or SARS-CoV-2 Infection

More than 6.3 billion doses of coronavirus disease 2019 (COVID-19) vaccines were administered worldwide by the end of September 2021. Even though myocarditis and pericarditis were not reported as adverse effects in the COVID-19 vaccination trials, there have been numerous reports of suspected cases in the general population.

mRNA: Messenger ribonucleic acid.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; RNA: Ribonucleic acid; mRNA: Messenger ribonucleic acid.


  • Myocarditis risk increased within a week of receiving the first dose of both adenovirus and messenger ribonucleic acid (mRNA) vaccines, and the risk increased even more after the second dose of both mRNA vaccines.
  • There was no evidence of an increase in the risk of pericarditis or cardiac arrhythmias following vaccination except in the 1–28 days following a second dose of the mRNA-1273 vaccine.
  • Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there was a higher risk of myocarditis, pericarditis, and cardiac arrhythmia in the same population.
  • The risk of myocarditis after vaccination with the two mRNA vaccines was higher in people under the age of 40.
  • Extra myocarditis events per million people within 28 days of vaccination (events variable with doses and types of vaccines) were estimated to be significantly lower than events following SARS-CoV-2 infection.

Figure 1 shows the number of excess events due to exposure per 1 million exposed.


  • It was hard to ascertain whether the findings were causal.
  • Hospital admission codes and death certificates were used to define outcome measures, thus accounting for referral bias, and had restricted sensitivity analysis.
  • Restricted data set was used for interpretation.
  • The biological plausibility of the observed reduced risks of pericarditis and arrhythmia linked to vaccination was unclear.
  • Study involved several comparisons, leading to erroneous inferences.
  • The control outcomes were chosen to assess the validity of the association between cardiac events and vaccination, while control outcomes for SARS-CoV-2-positive test were challenging to interpret.


Adults who received the SARS-CoV-2 vaccine had a small risk of myocarditis after the first dose of both adenovirus and mRNA vaccines and after the second dose of both mRNA vaccines. SARS-CoV-2 infection, on the other hand, was linked to a significant increase in the risk of myocarditis, pericarditis, and cardiac arrhythmia-related hospitalisation or death.

Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2021;10.1038/s41591-021-01630-0.

NON-2022-15052 - Date of creation January 2023

The Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19

  • Thromboembolic complications are a major cause of morbidity and mortality in coronavirus disease 2019 (COVID-19) patients.
  • High incidences of thrombosis (86%) and massive pulmonary embolism (36%) have been reported in critically ill COVID-19 patients admitted to the intensive care unit (ICU) due to severe respiratory distress.
  • SARS-CoV-2 infection, directly and indirectly, causes dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction, which interact with each other and are exacerbated by cardiovascular risk factors.


To provide insights on the pathogenic basis of thromboinflammation and endothelial injury in COVID-19, as well as discuss therapeutic strategies targeting these mechanisms.

Study outcomes

  • Evidence suggests that SARS-CoV-2 infection causes dysregulated immune responses (Figure 1), platelet hyperactivation (Figure 2), and endothelial dysfunction (Figure 3), which leads to a higher rate of thromboembolic events in severely ill COVID-19 patients.
  • Therapeutic strategies targeting inflammation, platelet hyperactivation, thrombosis, and endothelial dysfunction, in addition to vaccines or antiviral agents, may improve clinical outcomes, including mortality, in COVID-19 patients (Figure 4).

FAS: Fas cell surface death receptor; IFN: Interferon; IRFs: IFN-regulatory factors; IκBα: Nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha;
MAVS: Mitochondrial antiviral-signalling protein; MDA5: Melanoma differentiation-associated gene 5; NF-kB: Nuclear factor-kB; PD-1: Programmed cell death protein 1; RIG-I: Retinoic acid-inducible gene I; RNA: Ribonucleic acid.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; vWF: Von Willebrand factor.

ACE: Angiotensin-converting enzyme; Ang: Angiotensin; AT III: Antithrombin III; AT1R: Type 1 angiotensin receptors; BKR: Bradykinin receptors; DABK: Des-Arg(9)-bradykinin; C1q: Complement component C1q; C3: Convertase C3; C3b: Larger component formed by the cleavage of complement component 3; C5: Convertases C5; MAC: Membrane attack complex; MASP-2: Mannose-binding lectin-associated serine protease 2; H protein: Multifunctional protein and displays functions outside the complement system; N protein: Nucleocapsid protein; NO: Nitric oxide; PGI2: Prostacyclin; TF: Tissue factor; TFPI: Tissue factor pathway inhibitor; S protein: Spike protein.

ACE2: Angiotensin-converting enzyme 2; BK: Bradykinin; DOAC: Direct oral anticoagulant; DNase: Deoxyribonuclease; JAK: Janus kinase; MAC: Membrane attack complex;
NET: Neutrophil extracellular trap; NO: Nitric oxide; PD-1: Programmed cell death protein 1.


Repurposing currently available drugs are widely used as therapeutic strategy targeting thromboinflammation and endothelial injury in COVID-19 in addition to vaccines and antiviral drugs. Combination treatment may be required to combat the multifactorial pathogenicity of COVID-19 and improve clinical outcomes, including mortality.

Higashikuni Y, Liu W, Obana T, et al. Pathogenic basis of thromboinflammation and endothelial injury in COVID-19: Current findings and therapeutic implications. Int J Mol Sci. 2021.8;22(21):12081.

NON-2022-15052 - Date of creation January 2023

Depicting the Beats Automated Interpretation on Echocardiogram

  • Heart failure is a serious global health concern, and early management can reduce the disease burden on healthcare systems.
  • Echocardiogram is the most widely regarded primary method for assessing cardiac structure and function in diagnosing heart failure.
  • Manually interpreting echocardiograms can be time-consuming and prone to human error. As a result, a fully automated deep learning workflow for classifying, segmenting, and annotating two-dimensional (2D) videos and Doppler modalities in echocardiograms was developed.


  • A deep learning-based end-to–end workflow could automatically classify echocardiographic views and Doppler modalities and assess cardiac systolic and diastolic function parameters.
  • The external validation of the workflow in distinct cohorts from different countries, healthcare systems, and participants from Asia, Canada, and the USA showed the generalisability of automated measurements in men, women, and real-world clinical patients, with diverse ethnic backgrounds.
  • The variability of automatic measurements was lower than variability among manual measurements by expert sonographers.

  • The r coefficients and p values are for the log-transformed values.

    In Asia cohort: The correlations between automated and manual measurements ranged from r=0.88 for E wave (mean absolute error [MAE] 7.4 cm/s) to r=0.95 for left ventricular end systolic volume (LVESV) (MAE 10.2 mL). The correlation between automated and manual measurements was r=0.89 (MAE 5.5%) for LVEF, r=0.92 (MAE 0.7 cm/s) for e' lateral, and r=0.90 (MAE 1.7) for E/e' ratio.

    In Canada cohort: The correlations between automated and manual measurements ranged from r=0.67 for e’ medial (MAE 1.0 cm/s) to r=0.91 for LVESV (MAE 16.5 mL). The correlation between automated and manual measurements was r=0.75 (MAE 8.6%) for left ventricular ejection fraction (LVEF), r=0.78 (MAE 1.2 cm/s) for e’ lateral, and r=0.75 (MAE 2.2) for E/e’ ratio.

    In Taiwan cohort: The correlations between automated and manual measurements ranged from r=0.62 for left atrial end systolic volume (LAESV) (MAE 9.2 ml) to r=0.88 for e’ lateral (MAE 1.6 cm/s). The correlation between automated and manual measurements was r=0.75 (MAE 10.2%) for LVEF, r=0.87 (MAE 1.6 cm/s) for e’ lateral, and r=0.79 (MAE 1.8) for E/e’ ratio.

    In Asia cohort: The area under the receiver operating characteristic curve (AUC) was 0.96 (95 % confidence interval [CI] 0.92–0.99) for determining participants with systolic dysfunction (LVEF 40%), 0.95 (0.88–0.99) for an e’ lateral wave velocity less than 10 cm/s, and 0.96 (0.92–0.99) for an E/e’ ratio of 13 or higher.

    In Canada cohort: Based on automated measurements, the AUC was 0·91 (0·88–0·94) for identifying participants with LVEF less than 40%, 0.88 (0.84–0.92) for an e’ lateral velocity less than 10 cm/s, and 0.91 (0.88–0.94) for an E/e’ ratio of 13 or higher.

    In Taiwan cohort: The AUC was 0·90 (0·89–0·90) for identifying participants with LVEF less than 40%, 0.94 (0.93–0.95) for an e’ lateral velocity of less than 10 cm/s, and 0.91 (0.89–0.93) for an E/e’ ratio of 13 or higher.


    Deep learning algorithms can automatically annotate 2D videos and Doppler modalities with the same precision as expert sonographers. The use of an automated workflow may speed up access, improve quality, and reduce costs in the diagnosis and management of heart failure around the world.

    Tromp J, Seekings PJ, Hung CL, et al. Automated interpretation of systolic and diastolic function on the echocardiogram: A multicohort study. Lancet Digit Health. 2022;4(1):e46–e54.

    NON-2022-15052 - Date of creation January 2023

    Plasma Atherogenic Indices Are Independent Predictors of Slow Coronary Flow

    • Coronary slow flow (CSF) is a microvascular disorder characterised by the slow entry of radiopaque contrast agents into distal vascular structures during coronary angiography in the presence of normal or near-normal epicardial coronary arteries.
    • Although the pathophysiology of CSF is not fully understood, new evidence points to a role for subclinical diffuse atherosclerosis in the aetiology of CSF.


    The aim of this study was to look into the connection between atherogenic indices and CSF.


    Patients included in the study:

    • 130 patients with CSF
    • 130 controls with normal coronary flow (NCF)

    Using conventional lipid parameters,

    • Atherogenic indices (atherogenic index of plasma [AIP],
    • Castelli risk indices I and II [CRI-I and II]) were calculated.


    • When compared to the control group, patients with CSF had greater atherogenic indices and lower HDL-C values.
    • Atherogenic indices, such as atherogenic index of plasma (AIP), Castelli risk index II (CRI-II), current smoking, and male sex, were found to be independent risk factors for CSF (Figure 1).
    • White blood cell count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, neutrophil cell count, platelet count, low-density ipoprotein cholesterol triglyceride, non-high–density lipoprotein cholesterol, AIP, atherogenic coefficient, CRI I and II values were considerably higher in the CSF group than in the control group.

    AIP: Atherogenic index of plasma; CI: Confidence interval; CSF: Coronary slow flow; CRI-II: Castelli’s risk index II; PLR: platelet/lymphocyte ratio. p-value <0.05 was considered significant.


    AIP and CRI-II levels were independent predictors of CSF. Prospective studies in larger patient cohorts may shed more light on the role of atherogenic dyslipidaemia in the pathophysiology of CSF.

    Afsin A, Kaya H, Suner A, et al. Plasma atherogenic indices are independent predictors of slow coronary flow. BMC Cardiovasc Disord. 2021;21:608.

    NON-2022-15052 - Date of creation January 2023

    Statins Score Well in Reducing Risk of CVD and Death in Low-Risk T2DM Patients

    In a study published by Malmborg M et al. in the Journal of the American Heart Association, the authorspresented results of a large retrospective study that investigated if primary prevention with and highadherence to statins reduced the associated risk of cardiovascular events or death in a low-riskpopulation with Type 2 Diabetes Mellitus (T2DM). Statins are commonly used in the primary andsecondary prevention of Cardiovascular Disease (CVD) in patients with T2DM. However, data regarding theeffect of statins on cardiovascular risks in a low-risk population with T2DM is limited.

    The study group calculated the Proportion of DaysCovered (PDC) within 1 year in patients who purchased statins within 6 months following T2D diagnosis. The data was used to calculate composite outcomes ascombined end points of myocardial infarction (MI), stroke or all-cause mortality, whichever came first. Out of 77,170 patients, 42,975 (56%) were treated with statins, of whom 31,061 (72%) had a PDC ≥80%. The standardised 5-year risk in men aged 70 to 79 years treated with statins was 22.9% (95% CI, 21.5%–24.3%), whilst it was 29.1% (95% CI, 27.4%–30.7%) in untreated men, showing a significant risk reduction of 6.2% (95% CI, 4.0%–8.4%), p<0.0001 (Figure A). The reduction in CVD risk associated with statins increased with advancing age group (women: age 40–49 years, 0.0% [95% CI, −1.0% to 1.0%] and age 80–89 years, 10.8% [95% CI, 7.2%–14.4%]) (Figure B). The study group concluded that in a low-risk population with T2DM, use of statins was associated with a lower 5-year risk of a composite outcome of first MI, first ischaemic stroke, or all-cause mortality in all age groups for men and from age >50 years in women. In addition, the risk reduction increased with advancing age groups.



    Malmborg M, Schmiegelow MD, Gerds T, et al. Compliance in Primary Prevention with Statins and Associations with Cardiovascular Risk and Death in a Low¬Risk Population with Type 2 Diabetes Mellitus. J Am Heart Assoc. 2021;10(13):e020395.


    Same-Day Discharge for Elective PCI Reported Safe: Real-World Analysis

    An analysis of a large nationwide registry reported no serious consequences for same-day discharge following an elective Percutaneous Cardiovascular Intervention (PCI). The study included data from 819,091 patients who underwent an elective PCI procedure from 2009 to 2017. The proportion of patients opting for a same-day discharge elective PCIs rose from 4.3% to 19.5% for femoral-access and 9.9% to 39.7% for radial-access during this period, indicating a five- and four-fold growth respectively (Figure 1). Outcomes in 212,369 patients were analysed within this study, which reported that despite the growth in same-day discharges, there were no significant changes in the 30-day mortality rate. On the contrary, the 30-day risk of rehospitalisation fell after risk adjustment. These findings may represent an opportunity to reduce cost of hospitalisation, without compromising patient outcomes.

    Bradley SM, Kaltenbach LA, Xiang K, et al. Trends in Use and Outcomes of Same-Day Discharge Following Elective Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2021; 14:1655-66, 1667-69.


    STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management

    The Society of Thoracic Surgeons (STS) convened a multidisciplinary panel of experts, including members of the Society of Cardiovascular Anesthesiologists (SCA), the American Society of ExtraCorporeal Technology (AmSECT), and the Society for the Advancement of Blood Management (SABM) to review the latest data on patient blood management and update the 2011 update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Blood Conservation Clinical Practice Guidelines.

    The update emphasised upon the importance of an evidence-based, multimodal, and multidisciplinary approach to encompass optimisation of outcomes in patients at high risk for transfusion along with conserving blood resources.

    Highlights of the GuidelineUpdate:#

    Current Recommendations for Patient Blood Management Based on Intervention Type – ACC/AHA Class I Level A*

    Preoperative interventions

    Preoperative identification of high-risk patients should be performed, and all available preoperative and perioperative measures of blood conservation should be undertaken in this group as they account for the majority of blood products transfused.

    Blood products and derivatives

    Antithrombin III concentrates are indicated to reduce plasma transfusion in patients with antithrombin-mediated heparin resistance immediately before cardiopulmonary bypass.

    Blood salvage interventions

    Routine use of red cell salvage using centrifugation is helpful for blood conservation in cardiac operations using CPB.

    ACC/AHA: American College of Cardiology/American Heart Association; CPB: Cardiopulmonary bypass
    #Only Class I, Level A recommendations have been mentioned here.
    *Class I: Strong strength of recommendation where benefit>>>risk; Level A: High-quality evidence from more than 1 randomised controlled trial (RCT), meta-analyses of high-quality RCTs, one or more RCTs corroborated by high-quality registry studies.

    Tibi P, McClure RS, Huang J, et al. STS/SCA/Am SECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management.
    Ann Thorac Surg. 2021;S0003–4975(21)00556-7.


    Exercise Training Proves Beneficial in Patients with Vasospastic Angina

    Coronary vasomotion abnormalities play central roles in the pathogenesis of ischaemic heart diseases, frequently involving endothelial dysfunction and coronary artery spasms. In patients with Vasospastic Angina (VSA), coronary vasomotion abnormalities can develop in epicardial coronary arteries as well asncoronary microvessels. Calcium Channel Blockers (CCBs)n are widely used for patients with epicardial coronary spasm; however, they have limited efficacy in patients with angina involving microvasculature. A recently published dual-protocol study in the International Journal of Cardiology by Sugisawa et al. evaluated effects of physical exercise on vasodilator capacity of coronary microvessels in patients with VSA taking CCBs.

    Protocol 1 involved measuring Myocardial Blood Flow (MBF) using adenosine-stress dynamic Computed Tomography Perfusion (CTP) in 38 VSA patients and 17 non-VSA controls. Protocol 2 consisted of a randomised-controlled trial, where 20 VSA patients were randomly assigned to either 3-month exercise training group (n=10) or nonexercise group (n=10).

    Protocol 1 group showed significantly decreased MBF on CTP in the VSA group compared with the controls (138±6 vs 166±10 ml/100 g/min, p=0.02). In the protocol 2, exercise capacity was significantly increased in the exercise group compared with the non-exercise group (11.5±0.5 to 15.4±1.8 vs 12.6±0.7 to 14.0±0.8 ml/min/kg, p<0.01). Similarly, MBF was found to be significantly improved after 3 months only in the exercise group (exercise group, 145±12 to 172±8 ml/100 g/min, p<0.04; non-exercise group, 143±14 to 167±8 ml/100 g/min, p=0.11), with non-significance between-group differences. The researchers provided first of its kind of evidence that showed impaired vasodilator capacity of coronary microvessels in VSA patients and beneficial effects of exercise training with CCBs to improve their physical performance (Figure A).

    Sugisawa J, Matsumoto Y, Takeuchi M, et al. Beneficial effects of exercise training on physical performance in patients with vasospastic angina. Int J Cardiol. 2021;328:14–21.


    Kallistatin Upregulation May Slow Down Abdominal Aortic Aneurysm Development

    Oxidative stress, inflammation and vascular smooth muscle cell apoptosis play a crucial role in the pathogenesis of Abdominal Aortic Aneurysm (AAA). Previous animal and in-vitro studies have reported human-kallistatin (KAL), a serine proteinase inhibitor, to inhibit formation of reactive oxygen species, inflammation, and cellular apoptosis. A recent research published in Nature Scientific Reports, by Krishna SM et al., investigated the role of KAL in AAA through experimental mouse models and patients.

    Development of AAA was inhibited in the calcium phosphate (CaPO4) and subcutaneous Angiotensin II (AngII) infusion mouse models by transgenic overexpression of the human KALgene (KSTg) or administration of recombinant human KAL (rhKAL). Blood samples of 272 men aged above 65 years with risk factors for an AAA showed a negative association between serum KAL and AAA diagnosis and growth (Spearman’s rho −0.173, p=0.004; Figure A). Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media down regulated markers of oxidative stress and reduced the rate of apoptosis. Conversely, upregulation of KAL in mouse models and patients reduced markers of oxidative stress, severity of aortic elastin degradation, and vascular smooth muscle apoptosis within the aorta. This action of KAL was associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tgmice and rodents receiving rhKAL. The researchers suggested KAL-Sirtuin 1 signalling may limit aortic wall remodelling and development of an aneurysm through reductions in oxidative stress and vascular smooth muscle cell apoptosis.

    Krishna SM, Li J, Wang Y,et al. Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis. Sci Rep. 2021; 11:17451.


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    2022 European Atherosclerosis Society Highlights