Cardiovascular disease (CVD) continues to be the leading cause of death globally, affecting more than 19 million people yearly. In the first year of the SARS-CoV-2 pandemic, the number of CVD deaths increased from 874,613 in 2019 to 928,741 in 2020, the highest rise of single-year cases since 2015 [1]. In 2022, Xie et al. found that COVID-19 patients showed elevated risks and experienced increased incidences of CVD in a 12-month period [2]. With an increasing number of patients presenting with adverse cardiac outcomes, such as myocarditis, arrhythmias, and myocardial injury, further investigation into the effects of COVID-19 on cardiac health is needed. Since the emergence of COVID-19 in 2019, the global impact of this viral infection has been extensive, causing widespread morbidity and mortality [3]. COVID-19 can also affect more vulnerable populations, such as pregnant individuals, to a higher degree. The group recently reviewed how COVID-19 infection can worsen cardiovascular health during and after the gestational period, especially as long-term effects can disproportionately impact vulnerable groups [4]. This complex issue necessitates comprehensive investigation to understand the virus’s influence on molecular, cellular, and organ tissue systems. This information can then in turn be translated to improve both maternal and fetal health. Initially, the focus was primarily on one or two variants; however, subsequent waves and mutations have presented new challenges [5]. From the beginning, COVID-19 has evolved with thousands of variants and mutations. Before, COVID-19 was simply a respiratory infection, but now people know that all organ systems are infected.

While the exact mechanism of how COVID-19 affects the heart is not concrete, the following proposed mechanism highlights a direct and indirect pathway taken. The structure of SARS-CoV-2 consists of two spike proteins that bind to Angiotensin I-converting enzyme 2 (ACE2) receptors. Upon entry to the cells, SARS-CoV2 downregulates ACE2 and upregulates TNF-α, an inflammatory cytokine. The downregulation of ACE2 inhibits Angiotensin 1–7 but promotes Angiotensin II (Ang II), which is known for its hypertensive properties ^[6][7][6,7]. This, in turn, promotes TGF-β1, which increases collagen production and ultimately leads to fibrosis and heart failure. Additionally, when SARS-CoV-2 enters the cell, it causes direct damage to the myocardium ^[6][7][6,7]. Different cardiac cells have different interactions with SARS-CoV-2. Endothelial cells that line the vessels of the heart have increased rates of apoptosis due to the virus. This, in turn, causes blood clots to form along with the blockage of arteries. Furthermore, the direct invasion of pericytes, which help regulate endothelial function, can lead to dysfunction and apoptosis as well [8]. Cardiomyocytes affected via the ACE2 receptor and acting through an endosomal protease-dependent pathway increase cytokine production, sarcomere destruction, and apoptosis.

2. Long Term Implications

2.1. Long COVID

In April 2020, researchers first became aware of post-COVID-19 syndrome when patients noticed residual symptoms ^[9][59]. Understanding the long-term effects of COVID-19 can provide a more comprehensive picture of the disease’s impact beyond the acute phase. It will allow healthcare professionals, researchers, policymakers, and the general-public to grasp the full spectrum of health consequences associated with COVID-19, ranging from physical to social to psychological implications. It is also crucial to understand how COVID-19 can impact individuals of all demographics. Adding in the factors of race, sex, and underlying comorbidities adds complexities to the problem at hand and, in turn, makes this public health emergency a complex scientific problem. To find a solution, or at least come close to one, people need to tackle the problem from all angles. Investigating the long-term effects of COVID-19 fuels scientific research and advancements in understanding the disease, and it facilitates ongoing studies to identify underlying mechanisms, risk factors, and potential treatment options. By studying long-term effects, researchers can contribute to the collective knowledge base and facilitate the development of evidence-based guidelines for prevention, treatment, and long-term care. Post-COVID-19 syndrome, Long COVID, or post-acute sequelae of COVID-19 (PASC) is the persistence of COVID-19 infection/symptoms after 12 weeks involving multi-organ systems ^[10][31]. It has been estimated that at least 65 million people present with Long COVID, the highest age group affected being 36- to 50-year-olds. As more studies are being conducted and findings are being uncovered, people have learned that possible signs and symptoms are cardiovascular, thrombotic, and cerebrovascular disease, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), dysautonomia, postural orthostatic tachycardia syndrome (POTS), and type 2 diabetes. These symptoms can carry on for years, and some even for a lifetime (ME/CFS and dysautonomia) ^[11][50]. In more recent months, there have been new observations of the manifestation of long-term effects. In a recent study based in the UK and Hong Kong, after 21 days (about 3 weeks), there was a greater risk for many extrapulmonary conditions, such as heart failure, deep vein thrombosis, and atrial fibrillation ^[12][60]. As time has passed, there is reason to believe that the potential long-term effects of COVID-19 can become another public health emergency. Another meta-analysis points out the most common long-term effects from 6 months post-infection, and the majority align with the clinical symptoms. These include fatigue, hair loss, headache, and dyspnea ^[13][61]. As there are many biological implications for the immune response in the body, studies were performed to indicate whether these immune markers were still present in the body post-COVID-19 infection. A study based in France noted that for those whose symptoms had not fully resolved, there was still no indication of physiological irregularities, such as lymphopenia ^[14][62]. Lymphopenia has been found to be an indicator of the severity of disease progression in COVID-19 patients ^[15][63]. In terms of cardiovascular disease, evidence depicts cardiovascular outcomes to be significantly higher after COVID-19 compared to pre-exposure, supporting the idea that there is an increase in adverse cardiovascular outcomes due to COVID-19 [2].

2.2. Long-Term Cardiovascular Complications

While the immediate impacts of COVID-19 infection are well-documented, the long-term consequences, especially in relation to cardiovascular health, remain a topic of ongoing research. In addition to the various extrapulmonary conditions that can stem from COVID-19, there are many cardiac complications that arise from COVID-19, which is a significant concern. COVID-19 can lead to several cardiovascular manifestations, ranging from mild symptoms to severe adverse effects ^[16][64]. As shown in Figure 1, these emerge as risks of conditions that are of higher severity when compared to acute conditions and may lead to further complications. Some individuals may continue to experience chest pain, heart palpations, and shortness of breath long after the initial infection ^[17][65]. These symptoms may be attributed to damage of the heart or ongoing inflammation. It is important to note that the long-term cardiac conditions associated with COVID-19 can affect individuals of all ages, including those with no prior history of cardiovascular disease. Even individuals with mild or asymptomatic cases may develop adverse cardiac outcomes later on. Therefore, it is crucial to monitor the cardiovascular health of all individuals who had been infected with COVID-19, regardless of the severity of their initial symptoms. Several mechanisms have been proposed to explain the cardiovascular complications connected with long COVID. These include persistent inflammation, endothelial dysfunction, immune dysregulation, and post-viral autoimmune responses. Many studies have found that post-COVID-19 infection, there was a higher risk of individuals developing heart arrhythmias, myocardial infarction, hypertension, and heart failure. The interesting part about this phenomenon is that these conditions may occur even without any previous history of CVD ^[18][66]. A recent report indicated that a patient 67 days (about 2 months) after being diagnosed with COVID-19 had abnormal findings when a cardiac MRI was obtained, with no previous underlying conditions ^[19][67]. Another factor to consider is that cardiac abnormalities can arise regardless of the age of the patient. It has been found in studies that there is a multiorgan system inflammatory response after COVID 19 in pediatric patients.

2.3. Effects of COVID-19 Vaccinations

When comparing the severities of the various variants, vaccination status plays a significant role in symptoms, risk of hospitalization, and death. In a study of unvaccinated COVID-19 patients, myocardial infarction was less present in Omicron patients compared to Alpha and Delta patients. With fully vaccinated patients, Omicron patients also showed lower rates of MI in comparison to Alpha and Delta patients ^[20][24]. Additionally, in some cases, vaccines can contribute to cardiovascular or other complications. For example, capillary leak syndrome (CLS) is a rare disease that can be triggered by SARS-CoV-2 and its vaccine. It is hypothesized to be an immune response to an infection via a cytokine storm. CLS occurs when plasma and protein leak out of the capillaries and can eventually cause hypovolemic shock or systemic hypotension. In a case study, a patient diagnosed with COVID-19 and no history of COVID-19 vaccinations suffered from a rapid progression of CLS. The patient, a fit 42-year-old male with no significant medical history, was admitted to the hospital for syncope and hypotension. Other than his blood pressure and increased levels of hemoglobin, all of his other vital signs and blood tests showed no abnormalities. However, over the course of his stay at the hospital, his blood pressure remained low, hemoglobin and hematocrit levels continued to increase, and protein levels decreased. After becoming plethoric and suffering from leg and chest pain, the patient suddenly became unresponsive and died of cardiac arrest ^[21][68]. In another case, a patient suffered from CLS after receiving their COVID-19 vaccination (Ad26.COV2.S—Johnson & Johnson vaccine). The patient experienced postvaccination side effects, and 48 h afterward was admitted to the emergency department. Ten hours after admission, the patient died. Throughout his stay, the patient’s blood pressure progressively dropped, and tests showed hemoconcentration and hypoalbuminemia ^[22][69]. These case reports, though not common, raise a question to the unknown mechanisms of both COVID infection and vaccination and how they eventually result in such fatal symptoms. Furthermore, as variants emerge and evolve, reinfection and post-acute sequalae have become common among patients. In a study with over 5 million patients, it was demonstrated that compared to people with no reinfection, people with reinfection showed increased risks of all-cause mortality, hospitalizations, and other adverse outcomes ^[23][70]. A specific risk factor was being unvaccinated or being vaccinated before reinfection, and that risk and burden of all-cause mortality increased with the number of reinfections ^[23][70]. In terms of cardiovascular complications, people with reinfection exhibited the most risk of cardiovascular disorders after pulmonary sequelae, although the cardiovascular disorders are not specified ^[23][70], and there is limited data on cardiac conditions upon reinfection. A recent report by CDC states that reinfection-associated severe outcomes have not been previously characterized, but between September 2021-December 2022, percentages of reinfections have rapidly increased, and the United States is also seeing higher numbers of severe outcomes related to reinfection ^[24][71]. Though it may be possible that new variants are evading vaccines, vaccination and antiviral treatment are still recommended to reduce the risk of adverse COVID-19 sequelae.