In 2007, the American Heart Association Congenital Cardiac Defects Committee conducted an extensive review on the contribution of genetics to the origin of CHD, with an insight on the available diagnostic genetic tools and their applications. Chromosome analysis and FISH technology were indicated as important tools to detect the chromosomal 22q11 deletion, which is associated with a series of CHD, including Tetralogy of Fallot, interrupted aortic arch type B, truncus arteriosus, cono-ventricular VSDs, and aortic arch anomalies (35, 36). Another common microdeletion, at chromosome 7q11.23, has been identified by FISH and associated to Williams-Beuren syndrome, an autosomal dominant disorder characterized by specific cardiovascular anomalies, including supravalvular aortic stenosis, often in conjunction with supravalvular pulmonary stenosis and peripheral pulmonary stenosis. The review also provides a list of single genes, whose mutation, thanks to the DNA Mutation Analysis technique, was found to be associated to a number of heart defects (i.e., GATA4 in ASD/VSD; CFC1 in TGA, FBN1 in Marfan syndrome, etc.) (33).

With the development of new genomic techniques, such as chromosomal microarray and next-generation sequencing (NGS), the discoveries of new gene mutations and numerous pathogenic copy number variants (CNVs) and have significantly advanced the understanding of causes of CHD (37). An updated summary of knowledge of the genetic contributions to the pathogenesis of CHD has been reported in 2018 by the same American Heart Association Congenital Cardiac Defects Committee that conducted the initial investigation on the genetic basis of heart defect in 2007 (38).

As more and more young patients with severe types of CHD are surviving into their adulthood, thanks to the advances in surgical strategies of intervention, ascertaining the genetic cause of the defect is an important determinant in providing more accurate prognosis for the CHD and outcomes for CHD–related interventions. Furthermore, determining whether there is an underlying genetic pattern to the heart defect can help evaluate associated extracardiac organ involvement and identify genetic reproductive risks for other family members.

Although genetic factors play an important role in the development of CHD, accounting for about the 20% of all defects, it has become increasingly evident that some CHD might be preventable through interventions addressed to reduce environmental exposure (39). Indeed, environmental factors are identified as the cause of approximately 5–10% of CHD, as estimated by the World Health Organization. Epigenetic changes during pregnancy can influence the development of child’s heart structure (40–42). Epigenetic mechanisms implicated in the pathogenesis of CHD include DNA methylation, histone modifications, higher-order chromatin structure, and the activity of non-coding RNA species reviewed in Lim et al. (43).

Epidemiological studies have suggested an association of CHD with various types of environmental factors to which pregnant women and their fetuses may be exposed, such as air pollutants, pesticides, solvents, metals, radiations, contaminants, and chemicals (44, 45). Lifestyle and socioeconomic determinant might constitute risk factors too (45, 46).

Among the main mechanism of action of exposure to chemical pollutant are DNA methylation, oxidative stress, inflammatory processes, and epigenetic mechanism (47–55).

It is conceivable that the impact of epigenetics is not restricted to the embryonic heart development, but the same responsible mechanisms could rather influence the aging clock of the congenitally defective heart.

Advances in cardiac surgery and postoperative care during the past few decades have led to more people with CHD living longer with a better quality of life. Despite the progresses in this field, it is estimated that death rates in the population from 20 to > 70 years of age may be twice to seven times higher for the ACHD population than for their peers (56).

Residual hemodynamic abnormalities and new sequelae, after childhood surgical repair, might manifest later on in life, adding on to superimposed acquired heart disease and to the comorbidity of the natural aging process of the heart. It is now widely acknowledged that age represents the largest risk factor for cardiovascular disease, as cardiac aging entails a series of pathophysiological changes, impairing the myocardium at structural, cellular, molecular, and functional levels (57). These changes are highly relevant to cardiomyocytes, because they are postmitotic cells and thus not replenished by proliferation. Therefore, diminished myocardial reserves, due to a physiologic age-associated disruption of cardiac homeostasis, leads to increased vulnerability to cardiovascular diseases that occurs with aging.

Several environmental factors can contribute to accelerate the heart aging clock in ACHD people. Sedentary behavior and physical inactivity are among the leading modifiable risk factors worldwide for cardiovascular disease and all-cause mortality. Sedentary behavior is increasingly recognized as a risk factor for cardiovascular disease, independent of physical activity (58). The global childhood inactivity crisis is worrisome for the consequence on metabolic and cardiovascular disease (59). Children with CHD may be even less active than their healthy peers, although this evidence is matter of debate (60–63). In addition, very little is known about sedentary behavior in this population. A cross-sectional study with 316 children and adolescents with CHD seen in an outpatient clinic of a reference hospital showed the prevalence of excess weight was 26.9%, which is similar to the prevalence of that described in the literature for children without congenital disease (64).

Psychomotor development is influenced by factors such as low birth weight, cyanosis, hospitalizations, repeated examinations, physical constraints and consequently, school and social withdrawal. Children with CHD reportedly have a developmental delay (65). A larger study analyzing data from the 1997 to 2011 National Health Interview Survey showed that children with CHD are more likely to report worse health overall, to need more healthcare services, and to have other health conditions (e.g., autism, intellectual disability, or asthma), compared to children without CHD (66). The caregivers of children with CHD undergoing cardiac surgery are also under stress due to the uncertainty of the surgical outcome and the stressful experience of being admitted to an intensive care unit. The stress may influence the children perception of their state and amplify their frailty (67). Restriction in physical activity might be medically or parentally imposed. Furthermore, parents might overprotect their children in fear of sudden complications during physical exercise.

Growing to an adult with CHD exposes to an often traumatic transition from pediatric care to a different care model that lasts through a lifelong trajectory (68). Surprisingly, these concerns seem to be contradicted by a study that measured Quality of life (QoL) in patients with CHD (69). This observational case control study showed that patients with CHD felt their environment was healthier, had more opportunities for leisure and were happier with their access to healthcare system than controls. Except for the need for more medical treatment in patients with great CHD defects, no significant differences were seen in the World Health Organization QoL-BREF Index according to the anatomical complexity.

RV failure in young CHD can be prevented by focused interventions, such as by reversing PAH through surgical correction of aortopulmonary shunts. However, this reversibility potential is lost beyond a certain point in time, and late correction leads to irreversible damage to the pulmonary vasculature resulting in chronic PAH development (i.e., Eisenmenger’s syndrome) (109). An interesting study has demonstrated how irreversible PAH-CHD is associated with a switch from a proliferative to a senescent vascular phenotype (110). In a shunt-induced PAH rat model, the authors found a significantly reduced level of genes associated with DNA repair (i.e., Rad51) and increased levels of survivin, a protein associated with apoptosis resistance, in irreversible vs. reversible PAH animals.

Senescence markers, such as p16^ink4A and p21^cip1, and SASP were also upregulated in irreversible PAH compared to reversible PAH. The vascular profile of irreversible shunt-induced PAH in rats was further corroborated in human lung explant tissue from patients with irreversible PAH-CHD vs. controls, confirming markers of senescence (survivin, p16^ink4A and p21^cip1) in human PAH-CHD tissue, and higher vulnerability to senescence of PAH-CHD tissue derived endothelial cells in response to shear stress. These observations have led the authors to the recommendation that PAH-CHD should be repaired in early infancy when PAH is still in at a reversible stage.

In the next sections, we will examine the mechanisms and pathways that lead to a progressively faster transition to irreversible aging of the congenitally defective heart.

As previously reported, one of the main features of senescent cells is the secretion of SASPs, including soluble signaling factors, proteases, and insoluble proteins/extracellular matrix (ECM) components released into the surrounding cellular environment. Specifically, the secretome of senescent cardiomyocytes and vascular smooth muscle cells is rich in the inflammatory cytokines IL-1 and IL-6 and tumor necrosis factor a (TNF-α), inducing inflammation in the local surrounding cardiac microenvironment and systemically (111, 112).

Systemic chronic inflammation and immune activation are crucial determinant in the pathogenesis of various cardiovascular diseases and therefore regarded as potential therapeutic targets. Accumulating evidence indicates chronic inflammation and immune senescence have a pathogenic relevance in the progressive deterioration of heart function in patients with CHD (113).

Anti-inflammatory treatment, immunomodulatory drugs, and refinement of surgery to avoid or limit the need for thymectomy should be considered to reduce the damage caused by chronic inflammation and immune senescence. Translational work involving scar-modifying treatments has mainly focused on myocardial infarction (MI), with the main aims being to develop interventions that will steer scar properties toward compaction, mechanical strength, and electrical integration. Besides conventional drug treatments, more recent attempts to influence fibroblast activation involve approaches modulating the production of extracellular matrix protein, blocking inflammatory mediators, and interfering with TGF-β or Smad3 signaling (147–149). The effectiveness and safety of such interventions in children with CHD remains unknown. More advanced is the translational attempt to improve the biocompatibility of prosthetic grafts by tissue engineering, which, by combining the use of autologous/allogenic cells and biocompatible scaffolds, holds the promise to create cardiovascular grafts with the potential to remodel, repair, and grow alongside the children’s growth. In particular, the immune-favorable and immune-privileged status of stem/progenitor cells has made these cell types the ideal candidates for correction of congenital pathologies through a tissue engineering approach (150–153). Moreover, pharmacological modulation of altered pathways could be applied to reduce autologous stem cells senescence ex vivo, in order to enhance their reparative ability upon implantation (154). The readers are directed to recent reviews and preclinical studies on this topic (19, 20, 133, 155, 156).

In the last decade, different strategies have been proposed with the aim of avoiding reoxygenation injury during and after CPB. A study comparing propofol combined with low dose fentanyl and midazolam showed that the former is superior in reducing inflammation and oxidase stress and in improving post-operation recovery in children with CHD undergoing cardiac surgery (157). The use of controlled reoxygenation using a partial pressure of oxygen in arterial blood (PaO2), similar to the patient’s preoperative oxygen saturation, has shown to decrease the markers of organ damage (troponin I), stress (cortisol), inflammation (IL-6, IL-8, IL10) and oxidative stress (8-isoprostane) in single-ventricle and TOF patients undergoing cardiac surgery (158, 159). Other studies in adults and small randomized controlled trials in children have suggested some benefits (i.e., reduction of oxidative stress injury) in keeping the blood at normal body temperature throughout surgery (“normothermia”) as opposed to the standard hypotermic procedure, whereby the blood is cooled down during the operation (160, 161).

Senescent vascular cells can drive an irreversible state of vasoconstriction through a paracrine inflammatory mechanism. Therefore, their eradication could be an effective modality to halt the progression of PAH. Human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and the senolytic ABT263 reportedly induced apoptosis in senescent, but not in normal, endothelial cells. Interestingly, the senolytic treatment reversed the hemodynamic and structural changes associated with severe PAH in a rodent model (110). The pros and cons of senolytic therapy as a treatment of cardiovascular disease has been recently reviewed (162), although evidence supporting a benefit in children with CHD is lacking. The possible side effects on the young heart are also unknown.

Vitamin supplementation has been considered as a possible avenue for the primary prevention and treatment of cardiac defects. Peri-conceptional multivitamin use was associated with a reduced risk for CHD, particularly outflow tract defects and ventricular septal defects, but no risk reduction was evident when multivitamin use was started after the first month of pregnancy (163). Later studies focusing on folic acid showed that lower dietary folate intake during pregnancy was associated with increased risk (164). Moreover, maternal folate supplementation was significantly associated with a decreased risk of CHD, with this effect being possibly ascribed to anti-apoptotic protection of neural crest cells which participate in the formation of the truncus arteriosus and its division into the pulmonary artery and aorta (165, 166). However, another large study conducted in cohorts from Denmark and Norway found no association between individual-level of maternal folic acid supplementation and offspring heart defects. The authors concluded that, although most likely not harmful, the preventive effect of maternal folic acid supplementation indicated by time trend analyses should be questioned, at least in regions with sufficient intake of dietary folate (167).

Several studies reported that up to 90% of children with CHD undergoing corrective surgery have post-operative serum vitamin D concentrations below 50 nmol/L (168–170). Importantly, there was statistically significant direct correlation between serum vitamin D concentrations and post-operative cardiovascular dysfunction (171). The abrupt decline in vitamin D concentrations during surgery coincided with the initiation of cardiopulmonary bypass (170, 171). Usual low-dose daily supplementation is inadequate to maintain post-operative vitamin D concentrations above 50 nmol/L in the CHD population (172).

As previously mentioned, the oxidative stress has been identified as one of the major contributors to the cardiovascular aging process. Elevated oxidative stress in the senescent myocardium has several consequences such as enhanced protein oxidation/nitration, activation of inflammatory response, proteostasis impairment, mitochondrial dysfunction and endoplasmic reticulum (ER) stress (88).

The ER plays key roles in the synthesis, folding, and translocation of secretory and membrane proteins and in calcium homeostasis and lipid biosynthesis (173). A variety of environmental stresses, including nutrient deprivation, hypoxia, calcium depletion, and cytotoxic drug administration, can cause the accumulation of unfolded proteins in the ER, thereby inducing the ER stress response. In the developing heart, an excessive or too prolonged activation of the UPR may reduce expression of essential proteins, adversely affect cell function, and eventually lead to cell death.

Interestingly, a recent study showed that exposure of mouse embryos to short-term gestational hypoxia induced the UPR in cardiac progenitor cells and caused common types of heart defect in about 50% of newborns (174). One of the early UPR responses was PERK-dependent attenuation of protein synthesis, which was expected to result in the reduction in embryo growth rate. However, in mouse embryos exposed to hypoxia, the translation block was only affecting the levels of specific proteins that are immediately and continuously available for cardiomyocyte maturation. In particular, gestational stress resulted in reduced FGFR1 translation, which profoundly reduced FGF signaling in cardiac progenitor cells of the second heart field, whereas other receptor tyrosine kinases characterized by rapid recycling were not affected (174).

In the above mouse model, the induction of the UPR was reversible but FGF-1 signaling was persistently abrogated (174). However, it is tempting to speculate that persistent hypoxia after birth may cause a progressive exhaustion of the UPR, leading to accumulation of unfolded proteins in the ER and mitochondria. A study from Jian et al. examined this possibility on myocardial samples from patients with cyanotic congenital cardiac defects (175). They found that the upregulation of HIF-1α in the hypoxic myocardium was associated with a marked induction of the chaperone GRP78/Bip in cardiomyocytes, suggesting an activation of the UPR. Then, they assessed the activity of the key signaling pathways of UPR, ATF6α, and PERK, and found that, at variance with the mouse embryo hypoxia model, ATF6α was significantly upregulated whereas ERK signaling was not significantly different between the cyanotic and acyanotic groups. This was interpreted as a compensatory mechanism, as pharmacological inhibition or silencing of ATF6α promoted cardiomyocyte apoptosis following long-lasting in vitro hypoxia or hypoxia/re-oxygenation (175).

The regulation of UPR under hypoxia may involve a group of hypoxia-microRNAs. For instance, miR-199a-5p is reportedly downregulated in hypoxic myocardial samples from children with CHD (139). This is mediated by the activation of IL-6/IL-11/STAT3 signaling. Binding of pSTAT3 to the promoter region of miR-199a-2 gene, more significantly under hypoxic conditions, reduced the expression of pri-miR-199a-2, a precursor of miR-199a-5p, thereby activating its UPR targets, GRP78 and ATF6 (176, 177).

Recent findings indicate that cardiac aging is accompanied by a gradual derailment of proteostasis, which predisposes the heart to the development of age-related cardiac diseases, including atrial fibrillation (99).

Unfolded proteins can accumulate in cardiomyocytes due to genetic mutations, such as in desmin-related cardiomyopathy, but also as the consequence of cellular stress that damages nascent or aging proteins, or normal wear and tear. When terminally misfolded proteins exceed the UPR capacity, they are targeted for degradation through the ubiquitin–proteasome or autophagy–lysosomal pathways. Eventually, accumulation of misfolded proteins in aggresomes occurs when protein misfolding is not fixed. It is well acknowledged that the functionality of these regulatory proteostasis checkpoints is damaged during aging, with senescent cells becoming unable to maintain proteostasis and causing the heart to suffer from age-associated proteinopathies (178).

Ubiquitin plays a key role in the degradation of unfolded or misfolded proteins by targeting ubiquitin chains in the ubiquitin–proteasome or autophagy system. Failure to eliminate the abnormal protein aggregates causes the cells to move to apoptosis and death. SUMOylation is an essential component of the ubiquitination proteasome system. SUMO (Small ubiquitin-like modifier) conjugation pathway is abundantly expressed in the heart and implicated in cardiovascular development via modifying transcription factors necessary for normal cardiovascular development (179). A balanced post-translational SUMO conjugation-deconjugation pathway is essential for normal cardiac development. In fact, both hetero- and homo-zygous SUMO-1 knockout mice exhibited ventricular defects with high mortality rates, which were rescued by cardiac re-expression of the SUMO-1 transgene (179). Moreover, transgenic mice with cardiac-specific expression of SENP2, a SUMO-specific protease that deconjugates sumoylated proteins, resulted in premature death of mice due to atrial and/or ventricular septal defects. Surviving mice showed growth retardation, and developed cardiomyopathy with impaired cardiac function with aging (180).

Lysosomes are one of the main components of the autophagy pathway, which is crucial for maintaining cardiomyocyte morphology and function by regulating organelle turnover and cardiac remodeling. Alterations of mitochondrial function can impair processes such as cardiomyocyte differentiation, response to ischemic events, apoptosis, and autophagy (181). Mitophagy, the degradation of mitochondria by the autophagy machinery, is dysfunctional in primary human derived from subject with Down Syndrome and this is associated with low Parkin and p62 levels and delayed PINK1 activation (182). Moreover, mTOR hyperactivity and reduced ATG proteins involved in autophagosome formation contribute to downregulation of mitophagy (182). Organelle dysfunction could contribute to accelerated aging in patients with Down Syndrome-related CHD (183).

Therapies specifically targeting the ER stress and proteostasis in heart disease are at experimental stage. Some pharmacological agents used in clinical settings such as angiotensin II type 1 receptor antagonists and the antidiabetic agent pioglitazone may inhibit UPR pathways. Pharmaceutical AMPK activators reduce cardiac ER stress and prevents the progression of HF (173). Additional drugs include small-molecule activators of the heat shock response, such as geranylgeranylacetone, currently used in Japan for treatment of ulcers, and UPR_ER activators, such as the ATF6 pathway activator compound (184). The rationale for the use of these compounds is to activate stress response pathways to enhance cytoprotection against protein misfolding and aggregation. However, strategies to reduce protein synthesis could negatively interfere with regenerative processes. In contrast, the use of chemical chaperones such as 4-phenylbutyrate or agents that reduce misfolded protein concentrations may represent a more effective modality in CHD, where the UPR is exhausted and protein misfolding accrues slowly over time. In these conditions, activation of autophagy (e.g., rapamycin or spermidine), pharmacological proteasome induction, and interfering RNA–based therapeutics represent additional promising options (185). On the other hand, inhibition of autophagy might represent a target for treatment of some cardiovascular diseases which are not caused by the overexpression of a mutant protein, and are rather associated to excessive activation of autophagy, like myocardial infarction, and atrial fibrillation (99). Nonetheless, inhibitors of autophagy, such as bafilomycin, can cause cellular toxicity (186).

Moreover, longevity genes and proteins could have a significant impact in delaying age-related cardiac dysfunction (187). In this respect, we discovered that a genetic polymorphism of the BPIFB4 gene is associated with exceptional longevity. The related mutant protein forms a complex with 14-3-3 and HSP90, activating the prosurvival eNOS—Akt signaling. Supplementation of the longevity genes significantly improved cardiac function in different models of age-related cardiac disease (188–191) and reverse immune senescence (192). It would be interesting to determine the expression of BPIFB4 in CHD and, if this is found downregulated as in elderly cardiovascular patients (193), to assess the benefit of supplementation on cardiac cells from CHD patients and CHD models.

Personalized interventions are urgently needed for the treatment of rare cardiac diseases characterized by an alteration in protein disposal. For instance, the Koolen-de Vries syndrome (KdVS) is a rare monogenic disorder characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1 ± mice have an impaired autophagic clearance of damaged mitochondria and tend to accumulate ROS which in turn cause defective neuronal and cardiac functions. An FDA-approved drug, 13-cis retinoic acid, can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1 ± mice by promoting autophagosome-lysosome fusion. Hence, KANSL1 could represent a possible therapeutic target to treat autophagy and KdVS (194).

With the heart being a highly metabolic organ that is reliant on the maintenance of cellular-energetic homeostasis, mitochondria are important determinants of cellular longevity. It is, therefore, not surprising that defects in mitochondrial bioenergetics have been related to normal cardiac aging (195–197). Many factors contribute to the age-related reduced energetic capacity of the cardiac mitochondria including increased ROS, mutation and deletions in the mitochondrial genome, and dysregulation of proteostasis and mitochondrial biogenesis throughout the organism lifespan as well as in the embryonic development (95, 198).

Accruing evidence suggests that mitochondria maturation and processing not only serve as the powerhouse enabling the heart to beat but also play a critical role in regulating embryonic and neonatal heart development in mammals (199). The normal assembly of respiratory chain components, i.e., the oxidative phosphorylation (OXPHOS) complexes, in embryonic hearts is paramount to prepare the heart to undergo the fetal to neonatal metabolic shift -from anaerobic glycolysis to aerobic oxidative phosphorylation- after birth (199). Several studies have reported how defective OXPHOS in embryonic hearts leads to severe heart defects and embryonic or neonatal lethality in mouse models and human patients (200–202).

Additionally, a mismatch between mitochondrial programming and the substrate availability was proposed as the major cause for the juvenile cardiomyopathy described in mice with cardiac ectopic expression of MFN2 AA (203). Another in vivo study showed that cardiac ablation of both peroxisome proliferator-activated receptor gamma coactivator 1-α (Ppargc1α) and peroxisome proliferator-activated receptor gamma coactivator 1-β (Ppargc1β), nuclear transcriptional coactivators required for mitochondrial biogenesis, caused mitochondrial dysfunction and late gestational defects in cardiac function and cardiomyocytes maturation (204).

Strong evidence indicates that mitochondrial dysfunction, in particular impaired mitochondrial biogenesis (highlighted by decreased mitochondrial mass and DNA content), participates in the development of HF (205–207). Myocardial ischemia, reperfusion, and chronic overload significantly damage the mitochondrial structure and function, severely compromising cellular viability. A recent study showed reduced mtDNA replication and depletion of mtDNA together with pathological changes of mitochondrial ultrastructure occurs early during the development of RV hypertrophy, preceding the clinical manifestation of HF (208). The reasons for these alterations remain unknown but the authors suggested that “these findings provide an important basis for the future development of mitochondrial oriented clinical and surgical treatment of patients with overloaded RV caused by CHD” (208).

As previously described in the mechanisms of cardiac aging, mitochondrial dysfunction leads to elevate ROS production also in fetal heart, an event that triggers the DNA damage pathway that blocks cardiomyocyte proliferation (199). A study conducted on TOF patients with RV hypertrophy showed an increase of 4-HNE on mitochondrial function and structure. This bioproduct of lipid peroxidation, a form of oxidative stress in aging heart, altered the energy production in the mitochondrion of RV leading to its failure and cardiomyocyte dysfunction (209). An in vivo genetic model of mitochondrial dysfunction has been achieved by inactivating the mitochondrial transcription factor A (tfam), which resulted in elevated ROS production and activated DNA damage response, thus causing cardiomyocyte cell cycle arrest and ultimately lethal cardiomyopathy (210). The authors further showed that inhibition of ROS or the DNA damage response pathway rescued the cell proliferation defect observed in cultured fetal cardiomyocytes in which Tfam was deleted, making these pathways potential targets of intervention to prevent cardiac aberration caused by some forms of mitochondrial dysfunction.

Genetic factors, like mtDNA mutations, might as well underlie the mitochondrial stress typical of some heart disease, as we have previously described in the etiology of CHD (211–213). A Chinese study conducted a systematic screening assessing mtDNA mutations among coronary heart disease patients (214). One three-generation family presenting evidence of coronary heart disease maternally inherited was identified, with 6/24 analyzed adults in this family exhibiting coronary heart disease of vary severity. The sequencing of the mitochondrial genomes of these individuals showed a tRNA^Thr 15910C > T mutation of the M7b’c haplogroup, which is predicted to destabilize the strongly conserved (24C-10G) base-pairing, thereby disrupting tRNA^Thr functionality. Interestingly, only limited changes in mitochondrial functionality were observed, suggesting that 15910C > T mutation is relatively mild and may by itself be insufficient to produce a clinical phenotype, nonetheless it represents an inherited risk factor for the development of coronary heart disease. This finding points out how the diagnostic process of mitochondrial disease of the heart can be very challenging, especially in CHD patients, as it goes asymptomatic in the early stages, and later it manifests itself as cardiomyopathy, HF, arrhythmia and so on (215–217).

Identifying early markers of mitochondrial dysfunction would be beneficial to prevent the later manifestations of cardiac disorders in CHD population. It has been suggested that mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) may have utility for predicting HF risk in some CHD, as elevated PBMCs respiration was found to be correlated with HF in post-Fontan SV-CHD young patients (218).

Current treatments are not effective in preserving mitochondrial structure and function and therefore accruing mitochondria dysfunction through repeated operations could rapidly lead to energetic deficits in cardiomyocytes of CHD patients. A novel therapy based on mitochondrial transplantation may become a game-changer in this clinical field. Autologous mitochondria isolated from the patient’s own body and then directly injected into the ischemic myocardium significantly ameliorated ischemia/reperfusion injury and enhanced myocardial cellular viability and post-ischemic functional recovery (219). The authors reported that improvement in energy generation were associated with upregulation cardioprotective cytokines. The initial uncontrolled clinical application in humans was performed in pediatric patients suffering from myocardial ischemia reperfusion injury following coronary artery occlusion and revascularization (220). In a subsequent pilot study, mitochondrial transplantation enhanced ventricular strain in patients requiring postcardiotomy extracorporeal membrane oxygenation for severe refractory cardiogenic shock after ischemia-reperfusion injury (221).