Congenital diaphragmatic hernia and congenital heart disease (CHD) are frequently associated. In recent systematic review up to 15% of live born CDH patients also have CHD, though rates may be as high as 28% when stillborn and terminated CDH cases are included (2). Conversely, 0.3% of infants requiring surgery for CHD have associated CDH (3).

Forty-two percent of infants with CDH and CHD are considered to have critical lesions, rather than simple shunts (ventricular and atrial septal defects, patent ductus arteriosus). The commonest associated cardiac lesions are, in order of frequency, ventricular and atrial septal defects, hypoplastic left heart syndrome (HLHS), coarctation of the aorta or aortic hypoplasia, tetralogy of Fallot and double outlet right ventricle (2, 4).

The relationship between measures of CDH severity (e.g., defect size, abdominal organ position, fetal lung size) and CHD incidence is as not yet understood. Similarly, the potential shared mechanisms, including genetic and environmental factors, contributing to CDH and associated CHD remain unclear, but may involve disruption of common pathways in cardiac and diaphragmatic development (5, 6). An increasing number of genetic mutations have been identified in CDH, however, the frequency of these is not affected by the presence or absence of associated anomalies including CHD (7, 8). Of note, HLHS and aortic anomalies may represent one end of a spectrum of left heart hypoplasia in CDH that is distinct from other mechanisms of CHD, as discussed in more detail below.

The presence of any CHD significantly affects surgical management of the diaphragmatic hernia. Systematic review indicates that CDH repair rates are lower (72% vs. 85%), patch repair more frequent (45% vs. 30%), and minimally invasive approaches are employed less often (5% vs. 17%). CDH repair typically precedes any cardiac intervention, and notably only 10% of affected cases received a cardiac intervention during the neonatal period (2). ECMO use is similar between CHD and non-CHD groups (9). The commonest cardiac surgeries performed in CDH cases are hybrid procedures, coarctation and aortic arch repair, VSD repair and pulmonary artery banding (3).

Importantly, any CHD confers lower survival rates in CDH, which approach 50% overall and as low as 30% for infants with critical cardiac lesions, and 1–5% for infants with CDH and HLHS (2, 3, 9, 10). Conversely, the presence of CDH also confers higher overall and peri-operative mortality when compared to all CHD, as well as increased rates of post-op complications and longer length of stay after cardiac surgery in both high and low risk cardiac lesions (3, 4).

Though no formal guidelines exist for management of CHD in CDH, an algorithmic, team approach has been advocated to assist in complex decision-making for critical lesions (11).

The remainder of this review will now focus on abnormalities of cardiac structure and function distinct from classical CHD, and which appear to be specific to CDH pathophysiology.

Hypoplasia of the developing heart in CDH is an established finding, observed first in post-mortem studies and confirmed by echocardiography analyses, Table 1 (12–14).

In fetuses with left-sided CDH ventricular hypoplasia appears to predominantly affect the left ventricle (LV), characterized by reduced ventricular width and associated reductions in LV area and mass, together with reduced aortic valve diameter (14, 15). Right ventricular (RV) dimensions may also be reduced at earlier gestation but appear to increase, along with pulmonary artery diameter, at later gestation (16, 17). Accordingly, ratios of left to right cardiac dimensions in left-sided CDH are lowest at later gestations (18–20). Conversely, in right-sided CDH the limited available data indicate reduced fetal right ventricular and pulmonary arterial dimensions combined and less severe LV hypoplasia than in left-sided CDH (14, 21).

Multiple mechanisms of fetal cardiac hypoplasia have been proposed, though the relative contribution and timing of these remains uncertain (Figure 1):

Prenatal cohort studies of myocardial function have not to date demonstrated significant fetal cardiac dysfunction (25–29). Theoretically, the fetal circulation may mitigate against cardiac dysfunction in utero; the presence of a patent ductus and low resistance placenta protecting the RV from excessive afterload (despite increased resistance in the pulmonary vasculature) and ensure that the non-dominant, hypoplastic LV remains untaxed by excessive preload or afterload, Figure 1. Prospective studies throughout gestation are needed to understand the natural history and clinical significance of fetal cardiac function.

The relationship between fetal cardiac hypoplasia and clinical outcome remains unresolved. In single center cohorts of left-sided CDH left heart dimensions, notably LV width, mitral and aortic valve diameters, and ratios of left to right-sided dimensions have been associated with adverse outcome including higher neonatal mortality, higher ECMO use, increased inhaled nitric oxide use, and prolonged length of stay (18, 19, 30–33).

However, these findings have not been replicated in other series. VanderWall did not observe any association between fetal ventricular dimensions and outcome, though small cohort size may have been a factor (17). Vogel et al. observed mild to moderate fetal LV hypoplasia in a cohort of 125 CDH cases. LV fetal dimensions, expressed as z-scores, were not associated with postnatal survival when analyzed as continuous data, but were on categorical analysis (15). In the same cohort, there was a trend toward normalization of LV dimensions on paired postnatal, post-CDH repair, echocardiograms. This may suggest that reduced LV volumes are recruitable in response to postnatal hemodynamics.

Further investigation is a priority to determine which, if any, fetal cardiac dimensions have the greatest prognostic utility, when and how these should be measured, and the mechanisms by which these might directly influence postnatal LV dimensions, function, and outcome.

Whether structural changes in the fetal heart in CDH are associated with primary or secondary abnormalities at a genetic, epigenetic, cellular or metabolic level remains largely unknown. Cardiac hypoplasia in nitrofen rat models of CDH is associated with reduced expression of insulin-like growth factor-1, epidermal growth factor, basic fibroblast growth factor and platelet derived growth factor, Table 2 (34, 35). Zhaourigetu et al. also recently observed abnormal cardiomyocyte structure associated with reduced expression of mitochondrial and fatty acid biogenesis genes in this CDH model (36).

A single post-mortem study of hearts from human CDH fetuses also demonstrated dis-homogenous growth factor expression (37). In the same study fetal CDH hearts had abnormal thickening and proliferation of intra-myocardial vessels, particularly in the inter-ventricular septum. This raises the hypothesis that intra-cardiac vasculature in CDH might demonstrate developmental abnormalities analogous to those in the pulmonary vasculature (18).

In fetal rabbit models of CDH, though not lamb models, cardiac hypoplasia is associated with decreased ventricular wall thickness and increased septal thickness (38, 39). Ventricular wall thickening, due to cardiomyocyte hyperplasia, is also observed in hypoplastic left heart syndrome (HLHS), potentially pointing to common mechanisms of cardiac dysgenesis in these two conditions (40).

In limited cohort studies fetal tracheal occlusion (FETO), the principal prenatal therapy attempted for CDH, does not appear to significantly affect fetal cardiac dimensions or function in CDH (16, 18). Of note, the recent larger multicenter TOTAL trials of FETO did not include assessment of cardiac dimensions or function FETO (41).

A variety of pre-natal pharmacotherapies aimed at modulating pulmonary vascular development have been investigated in pre-clinical CDH models (42). Sildenafil, a phosphodiesterase 5 inhibitor partially reverses pulmonary vascular abnormalities and lowering pulmonary vascular resistance and reducing RV hypertrophy in animal models (43–45). However, adverse events associated with of prenatal administration in non-CDH patients have prevented clinical trials in diaphragmatic hernia (46). Maternal hyperoxygenation may be an alternative therapeutic approach which in congenital heart disease has been observed to increase pulmonary blood flow, and could potentially increase left ventricular flow and size in turn (47, 48). Further investigation is required of the impact of prenatal therapies on cardiac development and postnatal function in CDH.

Dysfunction in the RV, in conjunction with ventricular dilatation and hypertrophy, has been demonstrated from the first days of life in CDH (49). These are considered to result from pathological increases in RV afterload as a result of the structural and functional pulmonary vascular abnormalities characteristic of CDH (50). Increased RV pressure, and a concomitant reduced systemic pressure, may also reduce coronary artery flow gradient, leading to RV ischemia and dysfunction. Whilst recognized in other pulmonary hypertensive disease this mechanism has not been studied directly in CDH (51).

Early RV dysfunction in CDH is characterized by both impaired systolic function and, notably early diastolic dysfunction, demonstrated by reduced diastolic myocardial velocities and shortened diastolic duration in the RV (52–55).

Right ventricle dysfunction, when present, likely contributes to early clinical instability via a number of mechanisms. First, the failing RV may become “uncoupled” from the pulmonary circulation, unable to maintain adequate pulmonary blood flow, contributing to impaired oxygenation, and reduced LV filling and output (56). Second, RV dysfunction negatively impacts LV performance via mechanisms of ventricular interdependence including shared myocardial fibers, disruption of normal systolic and diastolic time intervals, and septal displacement reducing LV volume (40). Through these mechanisms RV dysfunction may be a key mediator of adverse effects of pulmonary hypertension in CDH (57, 58).

In cohort studies early RV dysfunction is associated with prolonged duration of respiratory support, increased mortality and ECMO use (49, 59–61). In a recent large multi-center registry analysis of cardiac function in the first 48 h of life RV dysfunction was present in 34% of CDH cases either in isolation in combination with LV dysfunction, and was associated with increased mortality and ECMO use (62).

The potential for postnatal left ventricular dysfunction in newborns with CDH has been long-recognized by experienced clinicians, and more recently quantified using functional echocardiographic techniques (52, 55, 63). Its importance as a component of CDH pathophysiology was highlighted by recent multi-center analysis demonstrating that LV dysfunction, in isolation or combined with RV dysfunction, independently predicted death and ECMO use (62).

Early postnatal LV dysfunction is frequent. In registry analysis of over 1100 CDH cases from 59 centers LV dysfunction was reported in 24% of CDH cases (62). However, this may be an underestimate; In smaller cohort studies utilizing sensitive, quantitative strain analysis of myocardial function LV dysfunction was observed in 56% of cases (63).

Postnatal LV dysfunction is characterized by both global systolic and diastolic dysfunction affecting longitudinal, circumferential and radial function, and dyssynchrony of myocardial segments (60, 63, 64). Postnatal LV volumes may also be reduced possibly due to compressive actions of a dilated RV and the herniated organs, combined with the legacy of fetal LV hypoplasia.

Left ventricle dysfunction is frequently observed in combination with RV dysfunction and may therefore be a secondary consequence via mechanisms of ventricular interdependence, as discussed above (64). However primary LV dysfunction may occur in the absence of, or disproportionate to, RV dysfunction (62). Multiple factors are hypothesized to contribute to primary postnatal LV dysfunction in the transitional period (1, 65):

Left ventricle dysfunction likely contributes to adverse clinical outcome via reduced LV output and systemic blood flow, resulting in impaired tissue oxygenation and a viscous cycle of worsening hypoxia and acidosis (66). Accordingly, the systemic hypotension frequently observed in early CDH is likely to be a consequence of impaired cardiac function and cardiac output, rather than hypovolemia or low systemic vascular resistance.

Early LV dysfunction is associated with other markers of CDH severity, including smaller fetal lung volumes, larger diaphragmatic defect size, and liver herniation (62, 63). However, Dao et al. have observed that LV dysfunction may also occur in “lower risk” CDH cases with smaller defects (67).

Of note, LV dysfunction appears to be a transitional phenomenon, apparently present from soon after birth but with the potential to improve rapidly over the first week of life (68, 69). This may have important consequences for individualized management strategies, including ECMO, as discussed below.

Left ventricle dysfunction leading to increased end diastolic, left atrial and pulmonary venous pressures is well-recognized as a mechanism of increased pulmonary vascular resistance in adult heart disease (70). There is increasing recognition that similar mechanisms may occur in CDH in the setting of early, transition LV dysfunction, contributing to a post-capillary increase in pulmonary venous resistance, distinct from pre-capillary changes in pulmonary arterial resistance (1). This may have important implications for targeted management strategies in CDH, including the suitability of pulmonary vasodilators, as discussed below.

The complex interplay of ventriculo-arterial, inter-ventricular, and cardio-respiratory interactions in CDH results in dynamic hemodynamic phenotypes with variable RV and LV function and dysfunction. As discussed later, this concept may be important in targeted, individualized therapeutic strategies.

Atrial shunting patterns may help define these phenotypes in the clinical setting. As recently highlighted by Wehrmann et al., the frequent presence of left-to-right atrial shunting in CDH, despite elevated pulmonary artery pressures, should prompt a closer examination of the left ventricular size and function (71).

Current models of CDH are based on three key inter-related pathophysiologies; pulmonary hypertension, pulmonary hypoplasia, and cardiac dysfunction (65). However, the severity of each of these may be variable and disproportionate. Although severe cardiac dysfunction is associated with larger diaphragmatic defects, smaller lung volumes, and more severe pulmonary hypertension, it may also be observed in patients with smaller diaphragmatic defects and milder respiratory compromise (62, 63, 67). Improved recognition and characterization of individual clinical phenotypes may be an important concept in CDH, and potentially inform more effective, targeted therapies.

Recent animal and human feasibility studies have explored the use of physiologically based strategies for managing the transition at birth, combining lung recruitment with delayed cord clamping. These have demonstrated short-term improvements in pulmonary blood flow, pulmonary artery pressure and systemic blood pressure, though the impact on cardiac function per se has not been directly investigated (98–100). Randomized trials are in progress, but do not include cardiac function as a key outcome measure (101, 102).

Hemodynamic pharmacotherapy in CDH remains a challenging and unresolved issue. Historical approaches focused on maintaining systemic blood pressure and promoting pulmonary arterial vasodilation. The list of possible pharmacological therapies is ever-increasing, but with limited and often contradictory evidence leading to clinical confusion and risk of inappropriate use (103).

The current use of pulmonary vasodilators exemplifies this. Inhaled nitric oxide and sildenafil (in oral and intravenous formulations) are widely used in CDH patients with the intention of reducing pulmonary vascular resistance via endogenous nitric oxide pathways (104). However, only a minority of recipients demonstrate improved oxygenation, historic RCTs did not demonstrate improved outcomes, and recent registry analysis has suggested that iNO may be associated with increased mortality (105, 106).

Improved understanding of cardiac dysfunction may help address the uncertainty and anxiety around the use of these agents. The presence of LV dysfunction appears to be associated with non-response to iNO and sildenafil (107, 108). Possible mechanisms may be post-capillary hypertension secondary to LV dysfunction unresponsive to pre-capillary vasodilatation, or increased pulmonary blood flow exacerbating LV dysfunction (109).

The actions of other cardiovascular therapies which have been directly investigated in CDH are summarized in Table 5. Milrinone, a phospho-diesterase 3 inhibitor acting on the endogenous prostacyclin pathway appears well suited to treat both RV and LV dysfunction in CDH, for its inotropic, lusitropic and pulmonary vasodilating effects (110). In a case series of infants with pre-existent RV dysfunction milrinone use was associated with improved oxygenation and RV diastolic function (111). However, a recent retrospective analysis in mild to moderate CDH observed no effect on oxygenation or LV dimensions (112). An RCT of early milrinone use in CDH is ongoing but does not include cardiac dysfunction as an enrollment parameter (113).

Levosimendan a calcium-sensitizing drug is commonly used in infants with congenital heart defects in the setting of low cardiac output syndrome (114). There is preliminary evidence that levosimendan is also associated with improvement of right and left ventricular dysfunction and a decrease in the Vasopressor-Inotropic Score in CDH (115).

Vasopressin use in CDH has also been associated with improved blood pressure, and reduced pulmonary:systemic blood pressure ratio, though the specific impact on LV function remains unstudied (116). The utility of systemic vasoconstrictors in CDH is unclear, and may depend on individual patient pathophysiology. In the setting of severe LV dysfunction increasing afterload may exacerbate ventricular failure (117). However, if LV function is preserved and RV function impaired there may be theoretical benefits to increasing systemic vascular resistance; to improve RV coronary blood flow, augment LV function via the eponymous Anrep effect, and restore septal positioning (51, 118, 119). Further investigation is required to understand which patient phenotypes are likely to benefit, and which of these potential mechanisms are beneficial in the clinical setting.

Prostaglandin E1 (PGE₁) use been proposed in early cardiovascular management in CDH to maintain ductal patency, as well as for its pulmonary vasodilating properties. In the setting of supra-systemic pulmonary hypertension a patent ductus permits right-to-left shunting, reducing the effective afterload on the RV, and supporting systemic blood flow, with theoretical benefits in the setting of both RV and/or LV dysfunction. Case series have demonstrated improvements in pulmonary artery pressure, oxygenation and LV function with PGE₁ use, however the optimal timing, dosing and duration remains undefined (120–122).

From the investigations described here it has become clear that there is no universally effective single agent for treating cardiac function and pulmonary hypertension in CDH. However, that does not necessarily mean that current therapies are ineffective. Instead new therapeutic strategies may be required, based on characterization of individual patient phenotype, including the relative contributions of RV and LV dysfunction, pre and postcapillary PVR, and ductal patency. This will allow investigation of the efficacy of targeted, pathophysiology-based therapeutic approaches, rather than indiscriminate use of single agents.

Hydrocortisone is also frequently used in the management of infants with CDH as an adjunct treatment for hypotensive cardiovascular compromise, and appears to elicit useful increases in both systemic vascular resistance and cardiac output (123, 124). Up to two thirds of CDH cases may have biochemical evidence of adrenal insufficiency in the immediate pre and post-operative periods, as observed by Kamath et al. (125). Low cortisol levels were associated with need for higher levels of cardio-respiratory support including ECMO, but not survival.

Early ventricular dysfunction is predictive of extra-corporeal membrane oxygenation (ECMO) use in CDH, and ECMO may be an important means of mechanically supporting the failing heart (62). However, there is minimal published data on longitudinal changes of ventricular function during the ECMO therapy. Additionally, decision-making regarding the relative benefits of venoarterial or venovenous ECMO based on the severity of concomitant ventricular dysfunction is at present supported only by clinician experience and opinion and not by published data (126). Bo et al. recently observed that ventricular function improves rapidly over the first days of life on ECMO support and may be monitored using biomarkers including NT-pro BNP (69).

Although cardiac dysfunction is commonly observed before and immediately after commencement of ECMO, it is rarely the cause of failure to wean support. As discussed above, severe LV dysfunction is a transient phenomenon and typically resolves in a matter of days. Nevertheless, ongoing right ventricular dysfunction after ECMO has been described, associated with persistent elevation of pulmonary artery pressure (61).

The two principal phenotypes responsible for ECMO weaning failure are first severe ventilation failure secondary to pulmonary hypoplasia, and second severe ongoing pulmonary hypertension. The latter may be due to irreversible developmental anomalies of pulmonary vasculature structure and function, decruitment of lung, or other factors such as ongoing infection.

Improved understanding of the relative contribution of cardiac dysfunction to individual pathophysiology before and during ECMO may be important for improved ECMO management strategies and help resolve ongoing uncertainties and controversies (127, 128).

To achieve effective use of these and other cardiovascular therapies in CDH future priorities should include: