Abstract
Background
Cardiovascular abnormalities may be caused by congenital or perinatal infections that cause cardiomyocyte injury and inflammation.
Aim of review
The purpose of this article is to review common congenital infections associated with cardiovascular sequelae, including pathogenesis, cardiovascular manifestations, diagnosis, treatment, prevention, and public health implications.
Key scientific concepts of review
Congenital rubella syndrome occurs from transplacental transmission of rubella virus and may cause patent ductus arteriosus, pulmonary valvular or pulmonary artery stenosis, or ventricular septal defect. Congenital HIV occurs from HIV transmission during pregnancy, delivery, or breastfeeding and may cause dilated cardiomyopathy, left ventricular dilation, thickening of the interventricular septum and posterior wall, or myocarditis. Enterovirus infection occurs from fecal-oral contact or respiratory transmission of enteroviruses such as coxsackievirus and may cause myocarditis and structural heart defects, especially ventricular septal defect. Zika virus infection occurs from mosquito bites, sexual contact, or transplacental transmission and may cause left ventricular hypertrophy, nondipping blood pressure, diastolic dysfunction, and valvular regurgitation. Other congenital viral infections that may cause cardiovascular disease include cytomegalovirus, parvovirus B19, and SARS-CoV-2.
Congenital syphilis occurs from transmission of Treponema pallidum during pregnancy or delivery and may cause aortitis, aortic aneurysm, and aortic regurgitation. Chagas disease occurs from Trypanosoma cruzi transmission through the feces of infected triatomine bugs, transplacental transmission, blood transfusions, and organ transplants and may cause arrhythmias, left ventricular wall motion abnormalities, complete heart block, ventricular dysfunction, and heart failure. Prevention of congenital infections may include vaccination, prenatal and perinatal screening, and other public health measures.
Graphical abstract
Highlights
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Cardiovascular abnormalities may be caused by congenital or perinatal infections.
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Pathogenic viruses include rubella virus, HIV, enterovirus, and Zika virus.
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Congenital syphilis and Chagas disease also cause cardiovascular disease.
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Prevention may include vaccination, screening, and other public health measures.
1
Introduction
Cardiovascular abnormalities arising from congenital or perinatal infections have been broadly reported and extensively investigated [ , ]. Specific infections may cause structural congenital heart abnormalities or increase the risk of developing cardiac complications at different stages of life. Although viral infections are more common, bacterial and parasitic agents also are important. Infections associated with cardiovascular abnormalities may be asymptomatic in pregnant women, clinically evident, or life-altering for their offspring [ ].
Various mechanisms of cardiac injury have been identified in relation to congenital infections, including direct injury to cardiomyocytes during viral infection and cellular damage caused by the host immune response [ ]. Although the immune response is important for viral clearance, it also may induce cardiac cytolysis in infected cells and exacerbate cardiac damage. If acute myocarditis is not fully resolved, persistent viral infection may trigger an inflammatory process that injures cardiomyocytes and causes permanent cardiac muscle remodeling [ ].
Infections linked to congenital heart abnormalities or cardiac problems later in life including rubella, HIV, enteroviruses, and Zika virus [ , ]. Other congenital viral infections may be associated with cardiovascular disease, including cytomegalovirus, parvovirus B19, and SARS-CoV-2. In addition, congenital syphilis, which has been increasing in incidence over the past decade, may cause long-term cardiovascular abnormalities [ ]. Furthermore, Chagas disease continues to be a major global health problem that causes cardiac morbidity and mortality ( Table 1 ).
| Disease and pathogen (transmission) a | Pathophysiology | Cardiovascular pathology | Electrocardiogram and echocardiogram | Treatment | Prevention |
|---|---|---|---|---|---|
| Congenital rubella syndrome Rubella virus (respiratory, transplacental) | Rubella virus targets cardiac fibroblasts Actin assembly protein inhibition Disrupted structural scaffolding Dysregulated growth factor and cytokine proliferation Replacement of lost cardiac muscle with fibrotic tissue | Patent ductus arteriosus Pulmonary valve stenosis Pulmonary artery stenosis Ventricular septal defect | ECG: Right axis deviation Right ventricular conduction delay Increased R wave amplitude (right-sided leads) Right atrial dilation ST-segment elevation and depression T-wave inversion Abnormal Q waves Echocardiogram: PDA, VSD | Prenatal intramuscular immune globulin Supportive therapy Surgical correction of defects | Immunization (women of childbearing age) with measles, mumps, and rubella vaccine (live attenuated vaccine contraindicated during pregnancy) |
| HIV (transplacental, intrapartum, breastfeeding) | HIV integrated into cardiac myocyte DNA Binding of virion gp120 to CCR5 chemokine receptor Apoptosis Calcium metabolism disruption | Dilated cardiomyopathy Left ventricular dilation Thickening of interventricular septum and posterior wall Myocarditis | ECG: Prolonged QT interval, ventricular arrhythmias Echocardiogram: Congestive heart failure Left ventricular dysfunction Decreased ejection fraction | Highly active antiretroviral therapy | Early identification during prenatal period Cardiac screening in infants of HIV-positive mothers |
| Enterovirus Coxsackievirus (fecal-oral, respiratory, transplacental, during delivery) | Coxsackievirus tropism to cardiomyocyte receptors Inflammation Suppression of cellular proliferation | Myocarditis Ventricular septal defect Other structural defects | ECG: ST-segment depression or elevation Loss of P waves Ventricular tachycardia Supraventricular tachycardia Echo: Myocarditis | Supportive care including inotropes Intravenous immunoglobulin Pleconaril (investigational only, not approved for use) | Hand hygiene Contact precautions |
| Zika virus (mosquito bite, sexual contact, transplacental) | Viral phosphatidylserine binds to growth arrest-specific 6 protein of fetal cardiac mesenchymal stromal cells Decreased cell viability Apoptosis Mesenchymal origin markers affected, altering cellular phenotype | Left ventricular hypertrophy Nondipping blood pressure Diastolic dysfunction Valvular regurgitation | ECG: Arrhythmias Short P-wave duration Short QRS-complex duration Echocardiogram: Atrial septal defect Ventricular septal defect | No specific treatment available Supportive care Surgical correction of defects | No vaccine available Pregnant women: avoid contact with mosquitos in endemic regions: – Avoid travel to endeemic regions – Avoid sexual contact with travelers to regions – Mosquito repellant – Mosquito nets |
| Syphilis Treponema pallidum (transplacental, intrapartum) | Spirochete motility and corkscrew shape facilitate tissue invasion Vasa vasorum of adventitia invaded Arterial wall inflammation Lamina propria weakness Aneurysm formation | Late-stage syphilis: Aortitis Aortic aneurysm Aortic regurgitation Coronary artery disease | ECG (late syphilis): Ventricular hypertrophy ST-segment changes Echocardiogram: Aortic aneurysm Dilated cardiomyopathy Decreased ejection fraction Valvular disease Severe aortic regurgitation | Penicillin Treatment of cardiac complications Aortic aneurysm repair Aortic valve replacement Coronary artery bypass grafting | Universal screening for detection Treatment in pregnant women |
| Chagas disease Trypanosoma cruzi (triatomine bugs, transplacental, blood transfusion, organ transplant) | Trypomastigotes invade cardiomyocytes Parasitophorous vacuoles Differentiation into amastigotes Immune response triggered Proinflammatory cytokines T cells and macrophages target infected cardiomyocytes Lysis of infected cells | Acute stage: Arrhythmias Left ventricular wall motion abnormalities Later stage: Ventricular dysfunction Heart failure | ECG (acute stage): Right bundle branch block Left anterior fascicular block ECG (later stage): Ventricular arrhythmias Complete heart block Echocardiogram: Cardiomyopathy | Benznidazole Nifurtimox | Endemic countries: prenatal screening Non-endemic countries: screening pregnant women who have risk factors |
a Other congenital viral infections may be associated with cardiovascular disease including cytomegalovirus, parvovirus B19, and SARS-CoV-2.
The purpose of this article is to review common congenital infections associated with cardiovascular sequelae, including pathogenesis, cardiovascular manifestations, diagnosis, treatment, prevention, and public health implications.
2
Rubella
Rubella virus belongs to the Togaviridae family and is transmitted primarily through respiratory droplets. Congenital rubella syndrome is a devastating condition caused by maternal infection with the rubella virus during pregnancy. When a pregnant woman contracts rubella, the virus may cross the placental barrier and infect the developing fetus. Despite progress in vaccination programs, rubella remains a public health problem in many areas of the world, particularly in developing countries where vaccination coverage may be inconsistent. Cardiovascular disease is among the most severe outcomes of congenital rubella syndrome and may cause lifelong health challenges for affected individuals.
2.1
Pathogenesis
The risk of severe congenital defects is highest when maternal infection occurs during the first trimester, with an 85 % probability of major complications [ ]. The virus targets a variety of fetal tissues, including cardiac cells and cardiac fibroblasts. The effects of rubella virus on these cells disrupt structural scaffolding due to inhibited expression and disrupted function of actin assembly proteins in addition to growth factor dysregulation and cytokine proliferation ( Fig. 1 ) [ , ]. This disruption causes the replacement of lost cardiac muscle with fibrotic tissue, resulting in major structural and functional changes [ , ]. The persistence of these fibroblasts may cause chronic scarring, adverse ventricular remodeling, and extensive apoptosis [ , ].
Rubella virus flourishes on embryonic tissue and may continue to replicate after birth. The slowed growth and doubling potential caused by the rubella virus antigens inhibit cell multiplication and cause defects in the development of various organs, including the heart [ , ]. Tissues infected with rubella virus also may undergo cellular injury without an inflammatory or immune response because of impaired tissue maturation, virus-induced ischemia, and thrombosis, which may deprive the cardiovascular system of nutrition and oxygen supply [ , ].
2.2
Cardiovascular manifestations and diagnosis
Cardiac manifestations are classified by the National Heart, Lung, and Blood Institute as simple (single structural defect) or complex (multiple defects) [ , ]. The most common cardiovascular manifestations of congenital rubella syndrome diagnosed by echocardiogram or cardiac catheterization are patent ductus arteriosus, pulmonary valve or pulmonary artery stenosis, and ventricular septal defect. Patent ductus arteriosus is present in 65 % of patients who have congenital rubella syndrome and is characterized by a persistently open ductus arteriosus, which normally closes after birth [ ]. Pulmonary valve or pulmonary artery stenosis may occur alone or in conjunction with patent ductus arteriosus [ ]. Ventricular septal defect enables abnormal shunting of blood between the right and left ventricles [ ].
Diagnosis of congenital rubella syndrome typically involves clinical and laboratory evaluations. Recent infection is confirmed by serologic testing for rubella-specific immunoglobulin M antibodies or a marked rise in immunoglobulin G (IgG) titers. Virus isolation from clinical specimens may be performed [ , ]. Electrocardiogram findings resulting from congenital rubella include right axis deviation, right ventricular conduction delay, increased R wave amplitude in the right-sided leads, and right atrial dilation. Findings that correlate with ischemia include ST-segment elevation in leads I, II, and aVF and depression in aVR and the right precordial leads, T-wave inversion, and deep Q waves [ ].
2.3
Treatment
The use of prenatal intramuscular immune globulin has been evaluated as an option to decrease viral shedding and the risk of fetal infection, but further validation of this treatment is needed [ ]. When congenital rubella syndrome is identified, the risk of major sequelae is communicated to the mother. Detailed ultrasound examinations and reassessment of viral RNA throughout the entire pregnancy are recommended [ ]. Postnatal treatment includes cardiovascular and metabolic supportive therapy and surgical correction of structural cardiac defects [ ].
2.4
Prevention and public health implications
Due to the lack of effective treatment, the prevention of congenital rubella syndrome focuses on early immunization, which has markedly decreased the incidence of this disease since the introduction of the vaccine in 1968 [ ]. Women of childbearing age are immunized with the measles, mumps, and rubella vaccine before becoming pregnant; the live attenuated vaccine is contraindicated during pregnancy because of potential teratogenic effects [ ]. In the United States, congenital rubella syndrome is uncommon, with only five cases reported between 2013 and 2016 [ ]. Between 2000 and 2016, rubella cases worldwide decreased by 97 %; however, between January 2019 and December 2020, there were 526 cases of rubella infection reported in Europe, highlighting the importance of immunization before pregnancy. Children with congenital rubella syndrome are considered contagious until at least one year after birth, unless two negative cultures are obtained one month apart after age three months [ , ]. Cardiovascular disease associated with congenital rubella is a major global problem despite advances in vaccination and public health. Understanding the pathophysiology, manifestations, and treatment of these conditions is important for improving the outcomes of affected individuals. It is also important to maintain high vaccination coverage and effective public health measures to prevent rubella infections and protect future generations from the severe consequences of congenital rubella syndrome.
3
HIV
Congenital HIV, resulting from vertical transmission during pregnancy, poses major clinical challenges. The progression to AIDS in these patients is characterized by markedly diminished CD4 + T-lymphocyte counts and elevated viral loads, indicating severe immunosuppression. HIV infection predisposes affected individuals to opportunistic infections and systemic complications. Pediatric AIDS patients are at an increased risk of developing cardiomyopathy [ , ]. Since the advent of antiretroviral therapy, the incidence of HIV and AIDS has markedly declined. However, congenital HIV remains particularly challenging because of its association with cardiomyopathy, which can be present in up to 74 % of infected children. The development of cardiomyopathy in these patients is strongly correlated with low CD4 + T-lymphocyte counts and high viral loads [ ].
3.1
Pathogenesis
Cardiac involvement in congenital HIV is multifactorial, including direct infection of cardiac myocytes, cellular apoptosis, alteration of the cellular calcium metabolism, and indirect effects such as decreased oxygen supply to cardiac tissue and the release of proinflammatory markers ( Fig. 2 ). In addition, the increased systemic immune response involves interactions with major histocompatibility complex class I, CD3 and CD8 lymphocytes, and the activation of the humoral immune system through antibody-antigen interactions. Specific cardiac antibodies, such as IgG antialpha-myosin antibodies, may be present in patients who have HIV and AIDS [ , ]. Myocardial dendritic cells also interact with HIV and activate the immune system, causing an immune and inflammatory response. This response includes the release of cytokines such as tumor necrosis factor-α, interferon-γ, and interleukin 2, which exacerbate the inflammatory cascade and contribute to cardiac inflammation [ ]. Macrophages and monocytes are the first cells infected by HIV through the binding of virion gp120 to the CCR5 chemokine receptor. HIV exerts a similar interaction with gp120 in cardiomyocytes and endothelial cells. HIV contains the protein Trans-Activator of Transcription (TAT), which can induce cardiomyocyte apoptosis. An indirect effect of HIV infection on cardiac tissue is associated with higher viral loads inducing CD4 lymphopenia, which may increase the likelihood of secondary opportunistic infections with cardiac tropism, such as cytomegalovirus and coxsackievirus B3 [ ].
3.2
Cardiovascular manifestations and diagnosis
HIV infection may cause major damage to cardiac tissue, leading to anatomic and functional disturbances. In HIV-positive children, the most common cardiac manifestation is dilated cardiomyopathy, which is associated with diastolic and systolic dysfunction. Subclinical structural manifestations are less frequently observed, such as left ventricular dilation, thickening of the interventricular septum and posterior wall, and myocarditis, but can be detected by histopathologic examination, magnetic resonance imaging scans, or electrocardiograms [ ]. During the first year after birth, primary cardiac manifestations identified by echocardiogram include congestive heart failure and left ventricular dysfunction. Abnormal ECG findings include prolonged QT interval and those associated with ventricular dysfunction. Cardiac dysfunction, defined by an ejection fraction <50 %, occurs in 21 % of children who have HIV. Children with perinatally acquired HIV are at an increased risk of having clinically major cardiomyopathy, including unrecognized cardiac dysfunction as measured by the myocardial performance index [ ]. Myocardial performance index may be an early predictor of cardiac dysfunction related to inflammation rather than elevated HIV viral load [ , ].
3.3
Treatment
The administration of highly active antiretroviral therapy is associated with a 50 % decrease in the incidence of cardiomyopathy in children who have perinatally acquired HIV infection. However, delayed initiation of therapy and low CD4 percentage (CD4 + lymphocytes <15 % of total lymphocytes) are independently associated with poorer outcomes. Left ventricular dysfunction is associated with higher HIV viral loads and lower CD4 counts, but improved function may occur with combination antiretroviral therapy. Although highly active antiretroviral therapy may be effective against HIV, some protocols are associated with the development of metabolic syndrome and hyperlipidemia, which may increase the risk of developing atherosclerosis [ , ]. In non-HIV-infected infants born to HIV-infected mothers, fetal exposure to antiretroviral therapy is associated with decreased left ventricular dimension, left ventricular mass, and septal wall thickness and increased left ventricular fractional shortening and contractility during the first two years after birth [ ].
3.4
Prevention and public health implications
Despite the decrease in mortality associated with highly active antiretroviral therapy, the global prevalence of congenital HIV remains high. Risk factors associated with increased morbidity and mortality include low socioeconomic status, duration of HIV-1 infection, low CD4 lymphopenia, high HIV-1 viral load, opportunistic infections, and limited access to health care. Most infected remain asymptomatic during early infancy. However, these risk factors underscore the importance of early identification and increased cardiac screening in infants born to HIV-positive mothers. Such measures may improve the outcomes related to cardiomyopathy in HIV-positive patients and decrease morbidity and mortality [ ].
4
Enteroviruses
Enteroviruses are single-stranded RNA viruses belonging to the Picornaviridae family [ , ]. These viruses are widespread and often exhibit a seasonal pattern, occasionally causing outbreaks in communities and hospitals [ , ]. Transmission typically occurs by fecal-oral contact or respiratory droplets, even when the infected individual presents only with fever [ , ]. Enteroviral infections during pregnancy may be underestimated as a cause of complications [ ]. Enterovirus infection, particularly caused by coxsackieviruses, may occur throughout pregnancy with vertical transmission and may cause spontaneous abortion, especially when the infection occurs during the first trimester [ , , ]. Newborns may contract the virus from transplacental transmission during pregnancy, intrapartum transmission at birth [ , ], or horizontal transmission from family members or hospital personnel [ , ].
4.1
Pathogenesis
Congenital enterovirus infection is defined as an infection presenting within the first 7 days after birth [ ]. The manifestations of congenital enterovirus infections are varied, ranging from asymptomatic to severe clinical presentations, including meningoencephalitis, hepatitis, myocarditis, and sudden death [ , ]. Congenital enteroviral myocarditis is most commonly caused by coxsackievirus B1 to B5 [ ]. The extent of heart damage in these infants may be affected by the level of maternal viremia and timing of maternal infection. Cardiac involvement is driven by the tropism of coxsackievirus toward cardiomyocyte receptors, which may cause inflammation, suppressed cellular proliferation, and structural cardiac defects and by viral protease 2A cleavage of dystrophin disrupting the sarcolemma in coxsackie B infections [ ]. Infections during early pregnancy induce changes in cardiac structure associated with decreased cardiomyocyte proliferation, whereas infections occurring during late pregnancy are associated with severe neonatal symptoms related to inflammation [ ].
4.2
Cardiovascular manifestations and diagnosis
Coxsackievirus infection may be associated with myocarditis and structural heart defects, especially ventricular septal defect [ , , ]. The clinical presentation of neonatal enterovirus infection typically is nonspecific and may include hypothermia, fever, poor feeding, rash, hypotension, respiratory failure, jaundice, and cytopenia [ ]. Most neonates with congenital enteroviral myocarditis become symptomatic between 3 and 5 days after birth. In these infants, enteroviral infection is typically disseminated and may be detected in blood, cerebrospinal fluid, or stool through polymerase chain reaction or culture [ , , ].
Electrocardiogram abnormalities in infants with enterovirus myocarditis may include ST-segment depression or elevation, loss of P waves, and arrhythmias such as ventricular and supraventricular tachycardia [ ]. Early echocardiography is important in infants suspected of having enterovirus infection to exclude the presence of myocarditis and guide therapy [ ]. Postmortem histologic findings may include inflammatory and neutrophil infiltrates in the myocardium and cardiomyocyte necrosis [ ].
4.3
Treatment
Although the treatment of coxsackievirus-induced neonatal myocarditis is primarily supportive, including the use of inotropes, intravenous immunoglobulin may be beneficial, particularly in severe cases [ , , ]. The antiviral medication pleconaril has been evaluated in clinical trials, but its efficacy is unproven [ , , ]. In severe cases with heart failure that is unresponsive to supportive measures, extracorporeal membrane oxygenation has been used, but general use is controversial because of limited availability and benefit as a short-term intervention [ , , ].
4.4
Prevention and public health implications
Mortality from neonatal enterovirus infection ranges from 30 % to 50 %, and 58 % of infants who survive may develop severe cardiac conditions, including dilated cardiomyopathy and ventricular aneurysms [ ]. As these viruses may cause cardiomyocyte necrosis, they may mimic the effects of myocardial infarction and cause scar formation that may result in aneurysm formation, left ventricular dysfunction, or dysrhythmias [ , ]. These factors are important to consider when providing postnatal care to affected infants. It is important that family members and health care personnel providing care to infected infants adhere to strict hand hygiene and contact precautions that may prevent transmission in nosocomial and household settings.
5
Zika virus
Zika virus is a positive-sense single-stranded RNA arbovirus belonging to the Flaviviridae family [ ]. It is transmitted primarily through the bite of infected mosquitoes, with Aedes aegypti and Aedes albopictus being the main vectors. Zika virus infection is most commonly acquired horizontally from mosquito bites; major routes of transmission include sexual contact and transplacental transmission. However, congenital Zika syndrome results from transplacental transmission of the virus [ ].
5.1
Pathogenesis
When Zika virus is transmitted vertically, it may cause congenital Zika syndrome because of the ability of the virus to infect progenitor cells such as neural progenitor cells and fetal cardiac mesenchymal stromal cells, resulting in decreased cell viability and apoptosis. Phosphatidylserine on the viral membrane binds to the growth arrest-specific 6 protein of fetal cardiac mesenchymal stromal cells. Furthermore, Zika virus affects mesenchymal origin markers, alters the phenotype of fetal cardiac mesenchymal stromal cells, and contributes to congenital heart defects ( Fig. 3 ) [ ].
