Involvement of cardiovascular system as the critical point in coronavirus disease 2019 (COVID-19) prognosis and recovery

Abstract

The novel coronavirus disease 2019 (COVID-19) pandemic has already caused more than 300,000 deaths worldwide. Several studies have elucidated the central role of cardiovascular complications in the disease course. Herein, we provide a concise review of current knowledge regarding the involvement of cardiovascular system in the pathogenesis and prognosis of COVID-19. We summarize data from 21 studies involving in total more than 21,000 patients from Asia, Europe, and the USA indicating that severe disease is associated with the presence of myocardial injury, heart failure, and arrhythmias. Additionally, we present the clinical and laboratory differences between recovered and deceased patients highlighting the importance of cardiac manifestations. For the infected patients, underlying cardiovascular comorbidities and particularly existing cardiovascular disease seem to predispose to the development of cardiovascular complications, which are in turn associated with higher mortality rates. We provide mechanistic insights into the underlying mechanisms including direct myocardial damage by the virus and the consequences of the hyperinflammatory syndrome developed later in the disease course. Finally, we summarize current knowledge on therapeutic modalities and recommendations by scientific societies and experts regarding the cardiovascular management of patients with COVID-19.

Graphical abstract

Abbreviations

RNA

ribonucleic acid

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

COVID-19

coronavirus disease 2019

SARS

severe acute respiratory syndrome

MERS

Middle East respiratory syndrome

SARS-CoV

severe acute respiratory syndrome coronavirus

MERS-CoV

Middle East respiratory syndrome coronavirus

ACE

angiotensin converting enzyme

ACEI

angiotensin converting enzyme inhibitor

ARB

angiotensin II receptor blocker

RAAS

renin–angiotensin–aldosterone system

O-GlcNAc

O-linked β-N-acetylglucosamine

IRF5

interferon regulatory factor–5

RT-PCR

real-time reverse transcription polymerase chain reaction

CT

computed tomography

IL

interleukin

CVD

cardiovascular disease

ICU

intensive care unit

1. Introduction

In early December 2019, the first cases of a pneumonia-like disease emerged in Wuhan, Hubei Province, China.¹ All cases were linked to a seafood market in the same city² and were confirmed to be associated with a novel RNA Betacoronavirus, which was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)^3,4. On February 11, 2020, the novel disease was named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), which declared a pandemic on March 11, 2020.⁵ COVID-19's high reproduction number has led to worldwide expansion of the disease⁶ and has gripped the world in a health and economic crisis.^{7 , 8}

2. Etiology – Pathophysiology of SARS-CoV-2 infection

2.1. Structure and genome sequence of SARS-CoV-2

SARS-CoV-2 is a round or elliptic Betacoronavirus and has a diameter of approximately 60–140 nm⁹. It belongs to the large family of coronaviruses, which are responsible for 5-10% of all respiratory tract infections.¹⁰ Coronaviruses have also been the cause of two previous infectious disease outbreaks; severe acute respiratory syndrome (SARS)¹¹ and Middle East respiratory syndrome (MERS).¹² Comparative homology analysis has revealed the close relation of SARS-CoV-2 with bat coronavirus (RaTG13) demonstrating an overall sequence homology of 96.2%,¹³ whereas the association with SARS-CoV (approximately 79% sequence identity) and MERS-CoV (approximately 50% sequence identity) was less significant⁴.

2.2. Viral cell entry

Angiotensin-converting enzyme 2 (ACE2), a type 1 membrane protein expressed in the intestine, kidneys, heart and type II alveolar cells in the lungs¹⁴ has been recognized as a cell receptor for SARS-CoV^{15 , 16} and can also serve as a cell receptor for the novel SARS-CoV-2.^{13 , 17} The spike glycoprotein (S protein) on the virion surface of SARS-CoV is responsible for receptor recognition and membrane fusion.¹⁸ Similarly, an S protein on the surface of the novel SARS-CoV-2 binds to the peptidase domain of ACE2 at least ten times more tightly than of (SARS)–CoV¹⁹ and subsequently causes membrane fusion, releasing its RNA into the host cell.^{19 , 20} Transmembrane Serine Protease 2 (TMPRSS2) is essential for viral entry being involved in S protein priming and the cleavage of the site.²¹ Ou et al. reported that phosphoinositide 5-kinase (PIKfyve), two-pore segment channel 2 (TPC2), and cathepsin L are also critical for viral entry,²² Once endocytosis is completed, SARS-CoV-2 RNA is translated into viral polyproteins, which are assembled with genome RNA into virions and transported through exocytosis out of the host cell.²³ The SARS-CoV-2 binding to the ACE2 receptors and the subsequent membrane fusion and viral invasion result in the downregulation and the loss of the catalytic effect of ACE2 receptors at the external site of the cell membrane.²⁴

3. Epidemiology of COVID-19

On January 24, 2020, the first three cases of COVID-19 were reported in Europe, all located in France.²⁵ At that point, Asia had already recorded 1312 COVID-19 cases and 41 deaths.²⁶ In Greece, the first confirmed patient with COVID-19 was reported on February 26, 2020.²⁷ As of May 18, 2020, the WHO has confirmed 4,819,372 cases, 316,961 deaths, and 1,864,269 recovered patients worldwide.²⁸ The overall fatality rate is currently at 6,6%; however, there are wide variations depending on age, comorbidities, and country.²⁹ In comparison, SARS-CoV had 8,098 confirmed cases and 774 deaths from November 2002 to July 2003 (mortality 9.6%)³⁰ and MERS-CoV had 2,494 confirmed cases and 858 deaths from September 2012 to September 2019 (mortality 34.4%).³¹

The high sequence homology of SARS-CoV-2 with bat coronavirus¹³ and the vast number of coronaviruses carried by distinct bat species^{32 , 33} have suggested that SARS-CoV-2 has originated from bats.¹³ The transmission of SARS-CoV-2 occurs mainly from person to person through respiratory droplets34, 35, 36 and has an incubation period ranging from 2 to 14 days³⁷ or in extreme cases up to 32 days.³⁸ Li et al. analyzed the first 425 cases in Wuhan by January 22, 2020 and estimated the mean incubation period of COVID-19 at 5.2 days with the 95^th percentile of the distribution at 12.5 days.³⁶ Airborne transmission³⁹ and transmission through the oral-fecal route⁴⁰ have also been recorded. Of note, Zou et al. reported that the viral load of SARS-CoV-2 in asymptomatic patients was comparable to that in symptomatic patients,⁴¹ suggesting potential transmission by asymptomatic patients in concordance with other studies also reporting transmission from asymptomatic SARS-CoV-2 carriers.^{42 , 43} Despite the ability of SARS-CoV-2 to infect different pet species,⁴⁴ the risk of human contamination from pets has not been elucidated so far.⁴⁵

On January 23, 2020, the WHO estimated the basic reproductive number (R₀) of COVID-19 at 1.4-2.5.⁴⁶ Liu et al suggested that SARS-CoV-2 has a higher R₀ in comparison to SARS-CoV, estimating the mean R₀ of SARS-CoV-2 at 3.28 by analyzing data from 12 studies.⁴⁷ However, as there has not been adequate evidence regarding how asymptomatic carriers contribute to the transmission rate of this novel infectious disease and how each treatment or preventive strategy affects it, the accurate estimation of R₀ is difficult.

Gender differences have been reported in the epidemiology of COVID-19, as women have lower infection and mortality rates than men.^{29 , 48} A recent study in patients with heart failure found that circulating levels of ACE2 were higher in men than in women, suggesting increased ACE2 tissue expression, which could contribute to susceptibility to SARS-CoV-2 infection and disease progress.⁴⁹ However, further studies are needed to elucidate the gap between sex difference and COVID-19 susceptibility and prognosis.

4. Cardiovascular complications in patients with COVID-19

4.1. Myocardial injury

Myocardial injury has been a remarkable finding, which contributes to worse prognosis (Figure 3, Figure 4 ) in most patient cohorts with COVID-19 so far^{34 , 48 ,} 50, 51, 52, 53, 54, 55, 56(Table 1 ), and being reported in >50% of deceased patients in most included studies. (Table 3 ) Case reports of probable COVID-19-induced myocarditis claim the direct myocardial injury by SARS-CoV-2.57, 58, 59, 60 According to the fourth universal definition of myocardial infarction by the European Society of Cardiology (ESC), myocardial injury is defined as being present when blood levels of cardiac troponin are increased above the 99th percentile upper reference limit.⁶¹ Most of the published reports have used the same or similar definitions (Appendix).^{34 , 48 ,} 52, 53, 54, 55, 56 The exact underlying mechanism for the COVID-19-mediated myocardial damage is not clear;⁶² however, the following four hypotheses are the main mechanisms considered so far (Fig. 1):

Figure 3.

Comparative analysis of myocardial injury frequency between total and severe patients with COVID-19. The number of patients included in the whole cohort vs. severe cases in the depicted cohort studies (n whole cohort/severe cases): Huan³⁴ et al. 41/13, Wang⁵² et al. 138/36, Shi⁵⁴ et al. 416/97, Guo⁵⁵ et al. 187/46, Wei¹⁷² et al. 101/37, Guan⁷⁹ et al. 1099/173, Zhang¹⁶⁷ et al. 140/58, Wu⁵⁰ et al. 201/84, Guan¹⁶⁶ et al. 1590/254, Huang⁸⁰ et al. 221/25, and Goyal¹¹² et al. 393/130. Bar graphs represent: (A) the percentage of patients who developed myocardial injury, (B) median age of patients, (C) the percentage of patients with arterial hypertension, (D) the percentage of patients with DM and (E) the percentage of patients with preexisting CVD in the whole cohort (black) and among the severe COVID-19 cases (red) per study. DM: diabetes mellitus and CVD: cardiovascular disease.

Figure 4.

Comparative analysis of myocardial injury frequency between recovered and deceased patients with COVID-19. The number of recovered patients vs. deceased patients in the depicted cohort studies (n recovered patients/deceased patients): Yang⁵³ et al. 20/32, Zhou⁴⁸ et al. 37/54, Shi⁵⁴ et al. 40/57, Chen⁵⁶ et al. 161/113, Ruan⁵¹ et al. 82/68, Mehra¹⁷⁰ et al. 8395/515, and Shi¹¹⁷ et al. 609/62. Bar graphs represent: (A) the percentage of patients who developed myocardial injury, (B) the median (Zhou⁴⁸, Ruan⁵¹, Chen⁵⁶, and Shi¹¹⁷) or mean (Yang⁵³ and Mehra¹⁷⁰) age of patients, (C) the percentage of patients with arterial hypertension, (D) the percentage of patients with DM, and (E) the percentage of patients with preexisting CVD in recovered (green) and deceased patients with COVID-19 (red) per study. DM: diabetes mellitus and CVD: cardiovascular disease.

Table 1.

Frequency of cardiovascular comorbidities, preexisting cardiovascular disease, and cardiovascular complications in patients with COVID-19

	n	Median age, years	CV comorbidities			Pre existing CVD	CV complications
			Current smoker	HTN	DM	CVD	Myocardial injury	HF	Arrhythmia
Guan79	1099	47	12.6	15.0	7.4	2.5	N/A	N/A	N/A
Huan34	41	49	7.3	14.6	19.5	14.6	12.2	N/A	N/A
Wang52	138	56	N/A	31.2	10.1	14.5	7.2	N/A	16.7
Zhang167	140	57	1.4	30.0	12.1	5.0D	N/A	N/A	N/A
Wu50	201	51	N/A	19.4	10.9	4.0	4.5	N/A	N/A
Guan166	1590	48.9A	7.0B	16.9	8.2	3.7	N/A	N/A	N/A
Huang80	221	45	7.7C	14.5	9.5	2.3	1.7	N/A	N/A
Xu168	90	50	N/A	18.9	5.6	3.3	N/A	N/A	N/A
Zhou48	191	56	5.8	30.4	18.8	7.9D	17.3	23.0	N/A
Ruan51	150	N/A	N/A	34.7	16.7	8.7	N/A	N/A	N/A
Shi54	416	64	N/A	30.5	14.4	10.6D 4.1E	19.7	N/A	N/A
Guo55	187	58.5A	9.6	32.6	15.0	11.2D	27.8	N/A	5.9
Chen56	274	62	4.4	33.9	17.2	8.4	43.8	24.4	N/A
Mehra170	8910	49A	5.5	26.3	14.3	11.3D 2.1F 3.4G	N/A	N/A	N/A
Goyal112	393	62.2	5.1	50.1	25.2	13.7D	N/A	N/A	7.4
Lechien171	1420H	39.2A	14.3	9.2	1.7	1.8	N/A	N/A	N/A
Wei172	101	49	7.9	20.1	13.9	5.0D	15.8	N/A	N/A
Richardson173	5700	63	N/A	56.6	33.8	11.1D 6.9F	N/A	N/A	N/A
Shi117	671	63	N/A	29.7	14.5	8.9D 3.3E	N/A	N/A	N/A

CV: cardiovascular, CVD: cardiovascular disease, DM: diabetes mellitus, HF: heart failure, HTN: hypertension, n: total patients, and N/A: not applicable. ^A Mean age, ^B Former and current smoker, ^C Smoking history, ^D Coronary artery disease, ^E Chronic heart failure, ^F Congestive heart failure, ^G Arrhythmia, and ^H Only patients with mild-to-moderate COVID-19 included.

Table 3.

Frequency of cardiovascular comorbidities, preexisting cardiovascular disease, and cardiovascular complications in patients who died due to COVID-19

	n	Median age, years	CV comorbidities			Pre existing CVD	CV complications
			Current smoker	HTN	DM	CVD	Myocardial injury	HF	Arrhythmia
Guan166	50	N/A	N/A	56.0	26.0	16.0	N/A	N/A	N/A
Yang53	32A	64.6B	0	N/A	21.9	9.4	28.1	N/A	N/A
Zhou48	54	69	9.3	48.1	31.5	24.1C	59.3	51.9	N/A
Ruan51	68	67	N/A	42.6	17.6	19.1	N/A	N/A	N/A
Shi54	57	N/A	N/A	N/A	N/A	N/A	73.7	N/A	N/A
Guo55	43	N/A	N/A	N/A	N/A	N/A	72.1	N/A	N/A
Chen56	113	68	6.2	47.8	21.2	14.2	76.6	49.4	N/A
Mehra170	515	55.8B	8.9	25.2	18.8	20.0C 5.6D 6.8E	N/A	N/A	N/A
Shi117	62	74	N/A	59.7	27.4	33.9C 21.0F	30.6	19.4	N/A

CV: cardiovascular, CVD: cardiovascular disease, DM: diabetes mellitus, HF: heart failure, HTN: hypertension, n: total deceased patients, N/A: not applicable.

^A Only critically ill patients with COVID-19 were included in the study, ^B Mean age, ^C Coronary artery disease, ^D Congestive heart failure, ^E Arrhythmia, ^F Chronic heart failure.

Figure 1.

Clinical manifestations of cardiovascular disease after infection with SARS-CoV-2. (1) High ACE2 expression is detected in cardiac and vascular tissue and may therefore facilitate cellular entry of SARS-CoV-2 resulting in myocardial and vascular damage. (2) An aberrant T-cell and monocyte activation has been observed in patients with COVID-19 leading to a systemic hyperinflammatory response. Increased circulating proinflammatory cytokines may result in inflammatory cardiomyopathy or atherothrombosis, causing an acute coronary syndrome. Systemic inflammatory response can also activate the microvascular endothelium, provoking the dysfunction of the coronary microvasculature, and consequently resulting in myocardial ischemia and myocardial injury. (3) Decreased myocardial oxygen supply, due to severe COVID-19 respiratory complications and hypoxia, along with increased myocardial oxygen demand, mainly due to high systemic metabolic needs, can provoke myocardial injury and type 2 myocardial infarction. (4) The binding of SARS-CoV-2 to ACE2 is expected to lead to the internalization of ACE2 and loss of the external ACE2 catalytic effect. Therefore, the possible downregulation of ACE2 and the subsequent decrease of angiotensin 1-7 in patients with COVID-19 may also compromise heart function. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com. ACE2: angiotensin-converting enzyme 2, MI: myocardial infarction, and SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

4.1.1. Direct ACE2-mediated myocardial cell invasion

As already described, high ACE2 expression is detected in cardiac tissue,⁶³ and may therefore facilitate cellular entry of the virus resulting in endothelial dysfunction and myocardial damage (Table 6 ) In particular, ACE2 is widely expressed in cardiomyocytes, cardiac pericytes, and coronary endothelial cells.⁶⁴ Therefore, SARS-CoV-2 could directly enter cardiomyocytes and provoke myocardial injury. Furthermore, pericytes, which are perivascular mural cells with high ACE2 expression, have been suggested as target host cells by SARS-CoV-2.⁶⁴ Considering the essential role of cardiac pericytes in maintaining endothelial cell function in capillary vessels, their infection could lead to coronary microvascular dysfunction and cardiac injury.⁶⁴ SARS-CoV-2 has also been shown to infect human blood vessel organoids in vitro.⁶⁵ Recent pathology reports provided the evidence of direct endothelial cell infection and diffuse endothelial inflammation, which could suggest the induction of “endotheliitis” and endothelial dysfunction, potentially contributing to the destabilization of coronary plaques, atherothrombosis, and vascular disease.⁶⁶

Table 6.

Clinical relevance of cardiovascular and circulatory cells in patients with COVID-19 and potential underlying mechanisms leading to cardiovascular disease.

Contributing cells	Clinical relevance	Potential underlying mechanisms leading to CVD
Cardiovascular cells		Cardiovascular cell-related mechanisms:
Cardiomyocytes1	Wide expression of ACE2	SARS-CoV-2 uses ACE2 as a cell receptor → direct myocardial damage
Cardiac pericytes2	High ACE2 expression	SARS-CoV-2 uses ACE2 as a cell receptor → pericyte is a potential host cell targeted by SARS-CoV-2 in cardiac tissue capillary → capillary endothelial cells dysfunction → coronary microvascular dysfunction
Endothelial cells3, 4, 5	Evidence of direct SARS-CoV-2 infection of the endothelial cells and diffuse endothelial inflammation	Increased ACE2 expression by endothelial cells and evidence of direct viral infection of vascular organoids in vitro → endothelial inflammation (“endotheliitis”) and increased leukocyte infiltration in heart tissue → atherosclerotic plaque destabilization → acute coronary syndrome
Blood cells		Leukocyte-related mechanisms:
Lymphocytes6, 7, 8, 9, 10	↓ in all cases, especially in severe disease	•↓ in the number of lymphocytes and NK cells due to functional exhaustion and apoptosis → decreased viral clearance → direct viral infection of cardiomyocytes, cardiac pericytes, and endothelial cells
CD4+ T cells11, 12, 13, 14	↓ in severe disease ✓Autopsy-confirmed CD4+ T infiltration of myocardium	•Apoptosis of plaque infiltrating lymphocytes → plaque destabilization
CD8+ T cells15,16	↓ in severe disease	•CD4+ T cells infiltration of myocardium → inflammatory cardiomyopathy
NK cells14,15	↓ in all cases	•↑ in the number of neutrophils → neutrophil plugging → epicardial and/or microvascular obstruction
Neutrophils17, 18, 19	↑ in severe disease	Platelet-related mechanism: Platelets become activated → platelets adhere to vascular endothelium promoting further recruitment of leukocytes to vascular wall → vascular inflammation and tissue inflammation → inflammatory cardiomyopathy, atherothrombosis, and vasculitis
Platelets177,178	↓ in severe disease

ACE2: angiotensin-converting enzyme 2, COVID-19: coronavirus disease 2019, CV: cardiovascular.

CVD: cardiovascular disease, NK: natural killer, and SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

4.1.2. Systemic Hyperinflammation

Viral infections are recognized as one of the most frequent causes of infectious myocarditis, which trigger the activation of the host antiviral immune response, including natural killer cells, macrophages, and virus-specific T lymphocytes.⁶⁷ Similarly, an aberrant T-cell and monocyte response has been observed in patients with COVID-19 leading to a systemic hyperinflammatory response characterized by increased proinflammatory cytokine and chemokine production (tumor necrosis factor, IL-2, IL-6, IL-7, and CCL2 among others)^{34 , 48 , 50 , 68 , 69} (Table 5) (Fig. 2). This could lead to consequent myocardial damage as suggested by autopsy reports describing inflammatory mononuclear cell infiltration in cardiac tissues of patients with fulminant myocarditis and high SARS-CoV-2 viral load.^{59 , 70} Systemic inflammation could further stimulate tissue-resident macrophages and leukocyte adhesion molecule expression on the endothelial cells of preexisting atherosclerotic lesions, enhancing their propensity to be disrupted and cause an acute coronary syndrome.^{62 , 71} Elevated circulating cytokines can also activate the microvascular endothelium, provoking dysfunction of the coronary microvasculature, and consequent myocardial ischemia and injury.⁷² In line with this concept, blockade of IL-6, which is central in leukocyte transmigration into peripheral tissues, has shown promising results in severe cases of COVID-19.^{73 , 74} Despite the low severity and low mortality of COVID-19 in children⁷⁵ there have been reports of severe Kawasaki-like disease (which is a type of vasculitis) cases across Europe.⁷⁶ Macrophage activation syndrome-like manifestations, classically associated with rheumatic diseases including Kawasaki disease,⁷⁷ have also been reported in patients with COVID-19 supporting the hypothesis that the increase of Kawasaki-like presentations could be a result of COVID-19-induced systemic hyperinflammation and consequent vasculitis.⁷⁸

Table 5.

Clinical value of cardiovascular and inflammatory biomarkers in patients with COVID-19

Cardiovascular biomarkers	Clinical relevance
Troponin	↑ in severe COVID-19 as compared to nonsevere COVID-19
	➢The median value of high-sensitivity troponin I was increased >2-fold in 36 patients who required ICU as compared to 102 patients who did not require ICU care52
	↑ in deceased patients compared to discharged patients
	➢The median value of high-sensitivity cardiac troponin I was increased >7-fold in 54 deceased patients with COVID-19 as compared to 137 discharged patients48
	➢The median value of high-sensitivity cardiac troponin I was increased >10-fold in 68 deceased patients with COVID-19 as compared to 82 discharged patients51
NT-proBNP	↑ in severe COVID-19 as compared to mild COVID-19
	➢The median value of NT-proBNP was increased >2-fold in 60 patients with severe COVID-19 as compared to 198 patients with mild COVID-1981
	↑ in deceased patients as compared to discharged patients
	➢The median value of NT-proBNP was increased >10-fold in 80 deceased patients with COVID-19 as compared to 93 recovered patients56
	➢Elevated NT-proBNP (≥285 pg/mL) were reported in 85% (68/80) of the deceased patients with COVID-19 as compared to 18% (17/93) of the recovered patients56
	➢An NT-proBNP increase of 100 pg/mL was associated with 1.37-fold risk of in-hospital death according to univariate Cox proportional hazards regression analysis of 54 patients with severe COVID-19174
D-Dimer	↑ in severe COVID-19 as compared to nonsevere COVID-19
	➢Elevated D-Dimers (>0.243 μg/mL) were reported in 61% (23/38) of the severe COVID-19 cases as compared to 28% (12/43) of the nonsevere COVID-19 cases167
	↑ in patients with ARDS as compared to patients without ARDS
	➢The median value of D-Dimer was increased >2-fold in 84 patients with COVID-19 who developed ARDS as compared to 117 patients who did not develop ARDS50
	↑ in deceased patients as compared to recovered patients
	➢The median value of D-Dimer was increased >8-fold in 54 deceased patients with COVID-19 as compared to 137 discharged patients48
Inflammatory biomarkers
CRP	↑ in severe COVID-19 as compared to nonsevere COVID-19
	➢The median value of CRP was increased 1.66-fold in 55 patients with severe COVID-19 as compared to 81 patients with nonsevere COVID-19167
	↑ in deceased patients as compared to discharged patients
	➢The median value of CRP was increased >3-fold in 68 deceased patients as compared to 82 discharged patients51
	➢CRP>100 mg/L was reported in 60% (59/98) of the deceased patients as compared to 14% (21/145) of the recovered patients56
IL-6	↑ in severe COVID-19 compared to nonsevere COVID-19
	➢The median value of IL-6 was increased ≈3-fold in 85 patients with refractory COVID-19 as compared to 70 patients with nonrefractory COVID-19175
	↑ in deceased patients as compared to discharged patients
	➢The median value of IL-6 was increased ≈2-fold in 68 deceased patients compared to 82 discharged patients51
Procalcitonin	↑ in severe COVID-19 as compared to nonsevere COVID-19
	➢The median value of procalcitonin was increased ≈2-fold in 50 patients with severe COVID-19 as compared to 68 patients with nonsevere COVID-19167
	↑ in patients who required ICU care as compared to no ICU care
	➢Procalcitonin ≥0.1 ng/mL was reported in 50% (6/12) of the patients who required ICU care as compared to 22% (6/27) of the patients who did not require ICU care34
Neutrophil-to-lymphocyte ratio (NLR)	•8% higher risk of in-hospital mortality for each unit increase in NLR, as estimated in an analysis of 245 patients with COVID-19176
	•Patients with NLR in the highest tertile had a >15-fold higher risk of death as compared to patients in the lowest tertile after adjustment for potential confounders176

ARDS: acute respiratory distress syndrome, COVID-19: coronavirus disease 2019, CRP: C-reactive protein, ICU: intensive care unit, IL-6: interleukin 6, NLR: neutrophil-to-lymphocyte ratio, and NT-proBNP: N-terminal (NT)- proB-type natriuretic peptide.

Figure 2.

Mechanistic insights into viral and inflammatory myocardial and vascular tissue damage in COVID-19. Two phases of COVID-19 have been described: a) an early phase where tissue damage is mainly induced directly by the virus and b) in some severe cases a 2^nd phase, where aberrant immune response (hyperinflammation) is the cause of tissue damage (upper panel). A large number of proinflammatory cytokines (TNFα, IL-2, IL-6, and IL-7) and chemokines (MCP-1 and IP-10) have been found increased in the circulation of patients with more severe disease. Circulating cytokines can activate endothelial cells and upregulate the expression of leukocyte adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. This could lead to the transmigration of leukocytes into peripheral tissues, such as the myocardium, and cause inflammatory tissue damage (lower panel). This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com. ACE2: angiotensin-converting enzyme 2, CVD: cardiovascular disease, DM: diabetes mellitus, HTN: hypertension, ICAM-1: intercellular adhesion molecule 1, IL: interleukin, IP10: interferon γ-induced protein 10, MCP1: monocyte chemoattractant protein-1, mono: monocytes, TNFα: tumor necrosis factor alpha, and VCAM-1: vascular cell adhesion molecule.

4.1.3. Imbalance between myocardial oxygen supply and demand

Myocardial injury can be the result of a mismatch between myocardial oxygen supply and demand, being classified as type 2 myocardial infarction.⁶¹ Severe respiratory complications and potential subsequent hypoxia are common findings in patients with COVID-19.^{48 , 53 ,} 79, 80, 81 In a meta-analysis of 19 studies, including a total of 2,874 patients, the most predominant chest x-ray finding was bilateral pneumonia (72.9%, 95% CI 58.6–87.1%) with ground glass opacity being reported in 68.5% (95% CI 51.8–85.2%) of patients.⁸² In addition, ground glass opacity was the most frequent chest CT finding (97.6%) in a Chinese cohort of 83 patients with COVID-19-related pneumonia and was associated with severe outcomes in all (100%) patients.⁸³ Hypoxia may also contribute to the development of tissue inflammation, which in turn may lead to cardiac damage.⁸⁴ Furthermore, hypotension, a frequent clinical sign in sepsis and in cytokine storm syndrome, can also reduce myocardial oxygen supply.⁷² On the other hand, systemic infection and fever increase the metabolic needs of peripheral tissues and end organs resulting in a rise of the metabolic demands of the myocardial cells.⁸⁵ The decrease in diastolic perfusion time during tachycardia can induce inadequate subendocardial perfusion in patients with coronary artery disease, resulting in cardiac injury.⁸⁶ Therefore, the viral infection caused by SARS-CoV-2 may provoke myocardial oxygen supply and demand imbalance, which is translated into myocardial ischemia and injury.

4.1.4. Loss of ACE2-mediated cardioprotection

ACE2 plays an important role in the renin–angiotensin system by catalyzing the conversion of the vasoconstrictor angiotensin II to the vasodilator angiotensin 1-7, which exerts antiarrhythmogenic and antiremodeling protective effects in the cardiovascular system.^{87 , 88} Angiotensin 1-7 has also antiproliferative effects on vascular smooth muscle cells⁸⁹ and cardiac fibroblasts.⁹⁰ Additionally, ACE2 has a counterregulatory function to ACE1, which hydrolyzes angiotensin I to the octapeptide angiotensin II and inactivates the vasodilator bradykinin.⁹¹ The activation of angiotensin II elicits heterogeneous signaling cascades in the vasculature, which can result in the expression of proinflammatory mediators and endothelial dysfunction.⁹² The binding of SARS-CoV-2 to ACE2 is expected to lead to the internalization of ACE2 and loss of the external ACE2 catalytic effect.^{24 , 93} Therefore, the possible downregulation of ACE2 and the subsequent increase of the proatherosclerotic angiotensin II together with the decrease of the cardioprotective angiotensin 1-7 in patients with COVID-19 may ultimately compromise heart function.^{94 , 95} Remarkably, severe COVID-19 has been associated with hypokalemia and higher blood pressure, supporting suggestions of decreased ACE2 function and augmented levels of angiotensin II after SARS-CoV-2 infection.⁹⁶

4.1.5. Heart failure

Current data regarding the incidence of heart failure among patients with COVID-19 are limited (Table 1). Viral infections are the most common cause of myocarditis⁹⁷. Despite the high recovery rates, nearly one out of three biopsy-proven myocarditis patients will later develop dilated cardiomyopathy.⁹⁸ Recurrent viral myocarditis and persistent viral replication have also been associated with the deterioration of myocardial function.^{99 , 100} Similarly, fulminant myocarditis, which may be a clinical manifestation of COVID-19,^{57 , 58} can result in left ventricular systolic dysfunction and even cardiogenic shock.^{101 , 102}

Viruses can also contribute to the etiology of heart failure through immune-mediated and inflammatory myocardial damage.¹⁰³ Acute systemic inflammation and septic shock can result in an increase of left ventricular end-diastolic volume together with the depression of myocardial function.^{104 , 105} Moreover, an excessive T lymphocyte response in enterovirus-induced myocarditis has been reported to provoke left ventricular dilatation and/or dysfunction.¹⁰⁶ Finally, high levels of circulating cytokines, such as TNF-α, IL-1β, and IL-6 have been shown to cause the deterioration of myocardial cell contraction and relaxation in vitro ^{107 , 108} and could suggest a potential relation between COVID-19-induced hyperinflammatory syndrome and myocardial dysfunction.

Chen et al. reported heart failure as a complication in 24.4% (n = 43) of a Chinese COVID-19 population (n = 176), using age-related amino-terminal pro-brain natriuretic peptide cutoffs, which yielded 90% sensitivity and 84% specificity for acute heart failure;⁵⁶ there was a remarkable difference in the prevalence of heart failure between COVID-19 survivors and nonsurvivors (3.2% vs. 49.4%).⁵⁶ Another study including 191 patients reported heart failure as a cardiovascular complication in 23.0% (n = 44) of the population, 63.6% (n = 28) of whom had a fatal outcome⁴⁸ (Table 3). Lastly, in a meta-analysis of 43 studies involving 3,600 patients, the prevalence of heart failure as a complication was 17.1% (95%, CI: 1.5–42.2%) among critically ill patients as compared to 1.9% (95% CI: 0.0-26.0%) among non-critically ill patients.¹⁰⁹

4.2. Arrhythmias

Sustained ventricular arrhythmias are significant clinical features of acute myocarditis,¹⁰² which is increasingly being reported as a clinical complication of COVID-19.57, 58, 59, 60 Guo et al. reported sustained ventricular tachycardia or ventricular fibrillation in 5.9% (n = 11) of 187 patients in a designated hospital to treat patients with COVID-19 in China.⁵⁵ Arrhythmias could also be precipitated by electrolyte imbalances that have been observed in populations with COVID-19.⁵⁶ The interaction of SARS-CoV-2 with the renin-angiotensin-aldosterone system (RAAS) has caused increasing concern about sodium and potassium disorders, which may increase vulnerability to various tachyarrhythmias.^{96 , 110} In addition, hypoxia, a common clinical manifestation of severe COVID-19,^{48 , 53 ,} 79, 80, 81 has been associated with alterations of cardiomyocyte gap-junctions, which could contribute to the development of atrial arrhythmias, particularly atrial fibrillation.¹¹¹ A recent retrospective case series study characterizing the first 393 consecutive patients with COVID-19 in two hospitals in New York City found that patients who received mechanical ventilation were more likely to have atrial arrhythmias (18.5% vs. 1.9%).¹¹²

Arrhythmias can also be induced by novel medical therapies for COVID-19; despite the unclear data about the effectiveness of chloroquine phosphate and hydroxychloroquine sulfate for the treatment of COVID-19,¹¹³ the Food and Drug Administration of the United States of America issued an emergency authorization for their use under determined circumstances in patients with COVID-19.¹¹⁴ Both agents may increase the risk for Torsades de Pointes or other ventricular arrhythmias through QTc prolongation¹¹⁵ and could also lead to advanced types of atrioventricular block.¹¹⁶

4.3. The role of cardiovascular comorbidities and preexisting CVD in the development of CVD complications

Preexisting cardiovascular disease and cardiovascular comorbidities, including arterial hypertension and type 2 diabetes mellitus, are predictors of myocardial injury in hospitalized patients with COVID-19¹¹⁷ (Table 1, Table 2, Table 3, Table 4). An association between preexisting cardiac disease and higher frequency of cardiovascular complications has been previously shown among patients with pneumonia.^{118 , 119} Recent results indicate multi-organ tropism of SARS-CoV-2, including heart, vascular system, and the circulation, which is speculated to influence the course of the disease as well as aggravate preexisting conditions.¹²⁰ The increased myocardial expression of ACE2 in patients with cardiovascular disease and COVID-19^{121 , 122} has been suggested as a possible mechanism of myocardial cell invasion and injury leading to worse outcomes⁶⁴ (Fig. 1).

Table 2.

Frequency of cardiovascular comorbidities, preexisting cardiovascular disease, and cardiovascular complications in patients with severe COVID-19

	n	Median age, years	CV comorbidities			Pre existing CVD	CV complications
			Current smoker	HTN	DM	CVD	Myocardial injury	HF	Arrhythmia
Guan79	173	52	16.9	23.7	16.2	5.8	N/A	N/A	N/A
Huan34	13	49	0	15.4	7.7	23.1	30.8	N/A	N/A
Wang52	36	66	N/A	58.3	22.2	25.0	22.2	N/A	44.4
Zhang167	58	64	3.4	37.9	13.8	6.9A	N/A	N/A	N/A
Wu50	84	58.5	N/A	27.4	19.0	6.0	N/A	N/A	N/A
Guan166	254	N/A	N/A	34.6	17.7	7.9	N/A	N/A	N/A
Yang53	52	59.7	3.8	N/A	17.3	10.4	23.1	N/A	N/A
Huang80	25	51	8.0E	16.0	40.0	4.0	N/A	N/A	N/A
Shi54	97	N/A	N/A	N/A	N/A	N/A	49.5	N/A	N/A
Guo55	46	N/A	N/A	N/A	N/A	N/A	65.2	N/A	N/A
Han81	60B 15C	59B,D 57C,D	N/A	N/A	N/A	N/A	76.7B 80.0C	25.0B 33.3C	N/A
Arentz169	21	70D	N/A	N/A	33.3	42.9	N/A	33.3	N/A
Goyal112	130	64.5	4.6	53.8	27.7	19.2D	N/A	N/A	18.5
Wei172	37	N/A	N/A	N/A	N/A	N/A	32.4	N/A	N/A

CV: cardiovascular, CVD: cardiovascular disease, DM: diabetes mellitus, HF: heart failure, HTN: hypertension, n: total severe cases, and N/A: not applicable.

^ACoronary artery disease, ^B Severe COVID-19 ^C Critical COVID-19, ^D Mean age, and ^E Smoking history.

Table 4.

Frequency of cardiovascular comorbidities, preexisting cardiovascular disease and cardiovascular complications in patients with COVID-19 who recovered the disease.

	n	Median age, years	CV comorbidities			Pre existing CVD	CV complications
			Current smoker	HTN	DM	CVD	Myocardial injury	HF	Arrhythmia
Yang53	20A	51.9C	10.0	N/A	10.0	10.0	15.0	N/A	N/A
Zhou48	137B	52	4.4	23.4	13.9	1.5D	0.8	11.7	N/A
Ruan51	82B	50	N/A	28.0	15.9	0	6.2E	N/A	N/A
Shi54	40B	N/A	N/A	N/A	N/A	N/A	5.0	N/A	N/A
Chen56	161	51	3.1	24.2	14.3	4.3	16.5	3.2	N/A
Mehra170	8395B	48.7C	5.3	26.4	14.0	10.8D 1.9F 3.2G	N/A	N/A	N/A
Lechien171	264H	34.1C	15.9	10.6	1.5	1.9	N/A	N/A	N/A
Shi117	609	61	N/A	26.6	13.1	6.4D 1.5I	N/A	N/A	N/A

CV: cardiovascular, CVD: cardiovascular disease, DM: diabetes mellitus, HF: heart failure, HTN: hypertension, n: total recovered patients, N/A: not applicable.

^A Only critically ill patients with COVID-19 were included in the study, ^B Discharged patients, ^C Mean age, ^D Coronary artery disease, ^E Continuous variable representing the median value of cardiac troponin, pg/mL (2.0-28.0), ^F Congestive heart failure, ^G Arrhythmia, ^H Only patients with mild-to-moderate COVID-19 were included in the study, ^I Chronic heart failure.

In a cohort of 416 patients with COVID-19, individuals with cardiac injury were more commonly affected by arterial hypertension (59.8% vs 23.4%), diabetes (24.4% vs 12.0%), coronary heart disease (29.3% vs 6.0%), and chronic heart failure (14.6% vs 1.5%) as compared to patients without cardiac injury.⁵⁴ Similarly, 52 patients with COVID-19 with elevated troponin T levels had significantly higher rates of comorbidities including arterial hypertension (63.5% vs 20.7%), coronary heart disease (32.7% vs 3.0%), cardiomyopathy (15.4% vs 0%), and diabetes (30.8% vs 8.9%) in comparison to 135 patients with normal troponin T levels.⁵⁵ On the other hand, rates of smoking did not differ significantly between those with normal or elevated troponin T levels (8.1% vs 13.5%).⁵⁵ The data about the contribution of smoking to the severity of COVID-19 are conflicting. Although a preliminary meta-analysis of 1,399 Chinese patients with COVID-19 suggested that current smoking is not associated with increased risk of developing severe disease,¹²³ another systematic review of five studies including a total of 1,549 patients concluded that smoking is most likely associated with worse outcomes,¹²⁴ probably due to its detrimental effects in the lungs and cardiovascular system. On the other hand, decreased levels of ACE2 have been observed in smokers,^{125 , 126} while current smoking was reported in less than 17% of patients with severe disease in all 5 original studies included herein (Table 2).

Insufficient glycemic control in patients with diabetes has been strongly associated with the overall risk of serious infections.¹²⁷ A recent study revealed the central role of deregulated glucose metabolism in influenza virus-induced cytokine storm through O-GlcNAcylation of IRF-5.¹²⁸ Considering that a cytokine storm syndrome has been reported as a potential cause of COVID-19 complications.¹²⁹ a similar mechanism may be present in diabetic patients with SARS-CoV-2 infection. Lastly, Liraglutide, a glucagon-like peptide 1 receptor, has been found to increase ACE2 expression in rat models,¹³⁰ and could therefore facilitate viral infection in accordance with the aforementioned hypothesis of the potential ACE2 role in COVID-19 cardiovascular complications.

5. Current treatment strategies for CVD patients

There are limited data to guide the clinical treatment strategies for COVID-19 and its cardiovascular complications. The best possible approach should be reached with a multidisciplinary team, which includes specialized infectious disease advice, and should be based upon the available information provided by the World Health Organization or reputable societies (Table 7 ). Numerous clinical trials are currently testing experimental therapies or repurposing of current drugs for the treatment of COVID-19.¹³¹

Table 7.

Recommendations for the management of CVD patients with COVID-19 as suggested from Societies/Organizations/Experts.

Society/Organization/Expert and date issued	Recommendations	Precautions
American College of Cardiology179 6 March 2020	1.Make plans for quickly identifying and isolating cardiovascular patients with COVID-19 symptoms. 2.Advise all cardiovascular patients of the potential increased risk. 3.CVD patients should remain current with vaccinations, including the pneumococcal vaccine. 4.In geographies with active COVID-19 outbreaks, it may be reasonable to substitute telephonic visits for in-person routine. 5.General immunological health remains important for both providers and patients, including eating well, sleeping, and managing stress.	1.Patients with underlying cardiovascular disease are at higher risk of contracting COVID-19 and have a worse prognosis. 2.Classic symptoms and presentation of AMI may be overshadowed in the context of COVID-19, resulting in underdiagnosis. 3.For patients with heart failure or volume overload conditions, copious fluid administration for viral infection should be used cautiously. 4.It is reasonable to triage patients with COVID-19 according to underlying cardiovascular or other comorbid conditions for prioritized treatment.
ESC Council on Hypertension140 13 March 2020	Continuation of treatment with the usual antihypertensive therapy.	No evidence about ACEIs and ARBs in humans; however, preclinical evidence suggests that these medications might be rather protective.
Chinese Medical Association180 27 March 2020	Severe emergent cardiovascular diseases for which hospitalization and conservative medical treatment is recommended: 1.STEMI for whom thrombolytic therapy is indicated 2.STEMI presenting after exceeding the optimal window of time for revascularization 3.High risk NSTE-ACS (GRACE score≥140) 4.Uncomplicated Stanford type B aortic dissection 5.Acute pulmonary embolism, f) acute exacerbation of heart failure, and g) hypertensive emergency Severe cardiovascular diseases requiring urgent or emergent intervention or surgery: 1.Acute STEMI with hemodynamic instability 2.Life-threatening NSTEMI 3.Stanford type A or complex Type B acute aortic dissection 4.Bradyarrhythmia complicated with syncope or unstable hemodynamics 5.Pulmonary embolism presenting with hemodynamic instability for whom regular intravenous thrombolytic therapy might lead to excessively bleeding risk	1.Risk assessment 2.Protection for patients and medical staff 3.Adapting measures tailored to specific local epidemic situations 4.Consider conservative medical treatment as a top priority 5.Intervene in a uniquely equipped cardiac catheterization/electrophysiology laboratory specifically engineered with more than standard disinfection procedures 6.All suspected and confirmed patients with COVID-19 should be transported with standardized attention to relevant national regulations 7.For patients with confirmed or suspected COVID-19 undergoing emergent cardiovascular interventional procedures, preestablished plans for COVID-19 should be initiated 8.Patients diagnosed with COVID-19 should be transferred to an ICU with negative-pressure ventilation for continued treatment 9.Suspected patients with COVID-19 should be isolated in a single bedroom, and suspected infectious specimens should be handled with care
1) Heart Rhythm Society COVID-19 Task Force 2) Electrophysiology Section of the American College of Cardiology 3) Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association181 01 April 2020	1.Triage of procedures based on screening and personal protective equipment. 2.Postpone or cancel non-urgent, elective procedures. 3.Remote device monitoring. 4.Tele-medicine and digital health paradigms. 5.It is reasonable to temporarily stop class III antiarrhythmic drugs, with use of a reasonable alternative if there is evidence of QT prolongation. 6.ECG monitoring should be considered for patients on multiple QT prolonging medications and avoidance or careful monitoring may be required for congenital LQT patients.	1. The proposed HCQ therapy for COVID-19 is relatively short (e.g., 5-10 days), the risk of arrhythmic toxicity is likely quite low. There are specific precautions to be considered for select patients: A Patients with known congenital Long QT Syndrome B Patients with severe renal insufficiency should have the dose reduced (50% for CrCl <10 mL/min) C Patients on QT-prolonging drugs D Electrolyte imbalances must be corrected prior to use None of the above conditions is an absolute contraindication if use of HCQ is warranted. 2.Aggressive electrolyte correction can mitigate arrhythmic toxicity.
European Association of Cardiovascular Imaging182 3 April 2020	1.Cardiac imaging should be performed if appropriate and only if it is likely to substantially change patient management or be lifesaving 2.Use the imaging modality with the best capability to meet the request, but consider also the safety of medical staff regarding exposure 3.Elective non-urgent and routine follow-up exams may be postponed or even cancelled	Obligatory preventive measures during TTE and TOE: 1.Handwashing 2.FFP2/FFP3/N95/N99 masks and gloves 3.Protective clothing 4.Eye protection 5.Head cap 6.Full cover or dedicated scanners 7.Problem-focused study

ACE: angiotensin converting enzyme, ARB: angiotensin II receptor blocker, AMI: acute myocardial infarction, CrCl: creatinine clearance, CVD: cardiovascular, ECMO: extracorporeal membrane oxygenation, ESC: European Society of Cardiology, GRACE score: Global Registry of Acute Coronary Events score. HCQ: Hydroxychloroquine, HFOT: high flow oxygen therapy, NSTEMI: Non-ST-elevation myocardial infarction, PPE: personal protective equipment, STEMI: ST-elevation myocardial infarction, TOE: transesophageal echocardiogram, and TTE: transthoracic echocardiogram.

The participation of ACE2 in the pathogenesis of COVID-19, acting as a cell receptor for SARS-CoV-2¹³ has caused increasing concern about the role of antihypertensive therapy with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in patients with COVID-19.¹³² An observational analysis in a cohort of 12,594 patients who were tested for COVID-19 in New York City indicated that previous treatment with medications acting on the RAAS was not associated with a higher risk of either testing positive for COVID-19 or developing severe COVID-19.¹³³ Of interest, another retrospective, multicenter study including 1,128 hospitalized hypertensive patients diagnosed with COVID-19 showed that inpatient use of ACEIs or ARBs was associated with lower risk of all-cause mortality compared to ACEI/ARB nonusers (adjusted HR, 0.42; 95% CI, 0.19-0.92).¹³⁴ Despite initial concerns that the use of RAAS inhibitors in patients with COVID-19 could increase ACE2 expression, and therefore facilitate viral entry,^{135 , 136} no evident association between RAAS use and more severe COVID-19 course has been observed in large clinical cohorts to date.^{49 , 133 , 134 , 137 , 138} Thus, the European Society of Cardiology and Heart Failure Society of America/American College of Cardiology/American Heart Association guidelines suggest no change in treatment with RAAS antagonists.^{139 , 140}

Chloroquine, an antimalarial agent with known anti-viral effects,¹⁴¹ has been proven to have beneficial effects against SARS-CoV infection,¹⁴² opening the possibility of its implementation in the prophylaxis and treatment of COVID-19. The available published data have been conflicting so far,^{113 ,} 143, 144, 145 highlighting the necessity of awaiting the results of randomized controlled clinical trials.

Another agent being tested in several clinical trials is Remdesivir¹³¹. It acts as a chain terminator during RNA replication and was initially developed for the treatment of Ebola virus disease¹⁴⁶. Activity of Remdesivir against SARS-CoV-2 has been indicated in vitro,¹⁴⁷ while clinical data have shown improvement in patients with severe forms of COVID-19.¹⁴⁸

In addition, severe forms of COVID-19 have been associated with nonspecific widespread immune reactions and cytokine storm syndromes.¹²⁹ In line with this, increased levels of inflammatory biomarkers have been associated with high risk of critical COVID-19 cases and death.^{34 , 48 , 50} Consequently, monoclonal IL-6 receptor inhibitors, such as tocilizumab and siltuximab, IL-1 receptor antagonists (Anakinra), fully human anti-interferon-gamma antibodies (Emapalumab), azithromycin, and corticosteroids are currently being investigated in clinical trials,¹³¹ as they have proven their efficacy against exaggerated immune activation.149, 150, 151, 152, 153 Finally, in view of colchicine's favorable anti-inflammatory profile,¹⁵⁴ including its use in the treatment of pericarditis and postpericardiotomy syndrome,¹⁵⁵ a prospective, randomized, controlled study in Greece (among others) will investigate the effects of colchicine in the prognosis of COVID-19.¹⁵⁶

6. Future perspectives

Epidemiologists have forecasted that 40%–70% of the world's population will be infected by SARS-CoV-2 in the coming year and will present with a wide range of clinical manifestations.¹⁵⁷ Apart from the direct effects of SARS-CoV-2 infection, patients who avoid infection may be affected by self-isolation and social distancing.¹⁵⁸ Hospital attendance and hospital admissions for diseases other than COVID-19 have been significantly decreased since the beginning of the pandemic.¹⁵⁹ There have been reports of significant decrease in the number of patients with acute coronary syndromes as well as large delays in presentation.¹⁶⁰ The reduced healthcare staffing levels along with the increasing ICU demands are causing services to become overwhelmed,¹⁶¹ while elective procedures and outpatient clinics are being postponed or cancelled.¹⁶² The impact of these factors on the care of cardiovascular patients warrants further investigation.

Cardiologists offering front-line services during the COVID-19 crisis have a pivotal role in the composition of appropriate therapeutic schemes. Because of the scarce ICU resources, critical care triage has become increasingly challenging. Possible delay in the management of urgent cardiac conditions could lead to a remarkable rise in morbidity and mortality. It is crucial for patients with new or worsening symptoms to be encouraged to seek medical assistance. The management of acute coronary syndromes, particularly ST-elevation myocardial infarctions, requires calculated measures,¹⁶³ particularly in the era of a pandemic. We believe that further research is needed toward the establishment of comprehensive guidelines, which will provide sufficient preparation and knowledge for such extraordinary conditions.

7. Conclusions

COVID-19 poses an outstanding clinical hazard to the general population and the healthcare community. Although most patients develop no or mild symptoms, approximately 20% experience severe or critical COVID-19 symptoms.¹⁶⁴

For the infected patients, underlying cardiovascular comorbidities and particularly preexisting cardiovascular disease are linked to worse outcomes,^{34 , 48 , 50 , 51 , 79 , 80 ,} 164, 165, 166, 167 while the development of cardiovascular complications, including myocardial injury, heart failure, and arrhythmias, are associated with higher mortality rates.^{34 , 48 ,} 50, 51, 52, 53, 54, 55, 56 ^{, 79 , 109 , 112} Continuous efforts are underway to uncover the pathogenetic mechanisms of COVID-19's cardiovascular complications and develop appropriate and targeted treatment strategies, with the repurposing of available drugs and identification of novel therapeutic targets. However, the acuteness and rapid spread of the COVID-19 pandemic has complicated the elucidation of effective, preventive, and therapeutic schemes.

On the whole, our knowledge of the pathogenesis, diagnosis, clinical course, and treatment of COVID-19 is expeditiously evolving. Nevertheless, in the wake of these unprecedented times, the scientific world has rallied united to progress in the understanding of COVID-19 and develop optimal treatment solutions.

Conflict of Interest

None.

Sources of Funding

Dr. K. Stellos is supported by grants from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 759248) and the DFG (SFB834 project number 75732319). Dr. C. Lazaridis is supported by a scholarship from the Hellenic Society of Cardiology.

Appendix A. Supplementary data

The following is the Supplementary data to this article: