Objectives: Cardiac transplant is a life-saving procedure for patients with end-stage heart failure. Preoperative pulmonary vascular resistance is indicative of intrinsic pulmonary vascular disease and correlates with posttransplant survival. However, its measurement is costly and time consuming. Therefore, simpler techniques are required. Diastolic transpulmonary gradient reportedly indicates intrinsic pulmonary vascular disease. Here, we investigated the relationship between preoperative diastolic transpulmonary gradient with preoperative pulmonary vascular resistance and 1-year and overall mortality among cardiac transplant patients.

Materials and Methods: Fifty-one patients who underwent cardiac transplant between 2006 and 2017 were included. All patients underwent preoperative right and left heart catheterization and oxygen study. Among these, diastolic transpulmonary gradient, mean transpulmonary gradient, and pulmonary vascular resistance were correlated with one another and 1st-year and overall mortality rates. Patients were grouped according to whether they received diastolic transpulmonary gradient or not, and both groups were compared with respect to 1-year and overall mortality. Binary logistic regression analysis was done to test whether diastolic transpulmonary gradient was a significant predictor of 1-year and overall mortality.

Results: Mean patient age was 45.5 ±9.8 years. The 1-year and overall mortality rates were 21.6% (11/51) and 37.3% (19/51), respectively. Diastolic transpul­monary gradient was significantly correlated with pulmonary vascular resistance, 1-year mortality, and overall mortality (P < .05) and was a significant predictor of 1-year and overall mortality (odds ratio 6.0; 95% confidence interval, 1.4-25.3; P < .05 and odds ratio 4.8; 95% CI, 1.4-17.5; P < .05, respectively). Patients with a diastolic transpulmonary gradient of ≥ 7 mm Hg had significantly higher 1-year and overall mortality (P < .05).

Conclusions: Diastolic transpulmonary gradient can be used as a promising easy-to-use parameter of intrinsic pulmonary vascular disease and a predictor of 1-year and overall mortality among patients undergoing cardiac transplant.

Key words : End-stage heart failure, Pulmonary hypertension, Pulmonary vascular disease

Introduction

Cardiac transplant is a life-saving procedure for a number of disorders, including ischemic cardio­myopathy, dilated and hypertrophic cardio­myopathy, fulminant myocarditis, and other types of cardiomyopathies.^1,2 Increased pulmonary pressures, and in turn right ventricular and right atrial pressures, before cardiac transplant increase the risk of death among cardiac transplant recipients. Although pulmonary hypertension is usually due to increased left heart pressures responsible for heart failure, several studies have suggested that increased pulmonary pressures, particularly intrinsic irrever­sible pulmonary vascular disease, also known as precapillary pulmonary hypertension, increase the risk of posttransplant right ventricular failure and death.^3-5 Thus, it is imperative to identify those with reactive pulmonary changes that are irreversible and potentially put the transplanted heart in jeopardy before transplant.

Measurement of pulmonary vascular resistance (PVR) is traditionally the criterion standard for identifying those with reactive pulmonary changes. However, conducting an oxygen study and its flow dependence sometimes makes measurement of PVR unideal. Thus, simpler and flow-independent techniques to identify intrinsic pulmonary vascular diseases are needed. Diastolic pulmonary gradient (DPG; defined as the difference between diastolic pulmonary artery pressure [DPAP] and pulmonary capillary wedge pressure [PCWP]) is a newly introduced flow-independent marker of intrinsic pulmonary vascular disease not caused by passive increases in pulmonary pressures due to elevated left-sided filling pressures.^6,7 Its use in various conditions affecting pulmonary vasculature has been tested.^8-11 A few studies have investigated its role in identifying intrinsic pulmonary vascular disease in cardiac transplant patients.^12,13 Here, we investigated associations between DPG and posttransplant 1-year and overall mortality and its relationship with PVR among patients scheduled for cardiac transplant procedures.

Materials and Methods

This was a retrospective study involving 51 adult patients who were older than 18 years and who received orthotopic heart transplant at Başkent University Faculty of Medicine, Department of Cardiology (Ankara, Turkey) between 2014 and 2016. This study was approved by our local ethics committee.

Demographic data of the patients were recorded. The preoperative right-left heart catheterization data, including right and left heart pressures (right atrial, right ventricular), systolic pulmonary artery pressure, DPAP, mean pulmonary artery pressure (MPAP), PCWP, left ventricular end-diastolic pressure, cardiac output (CO), and PVR, were recorded. Diastolic pulmonary gradient was calculated as the difference between the DPAP and mean PCWP. Mean trans­pulmonary gradient (TPG) was calculated as the difference between MPAP and mean PCWP. Pulmonary vascular resistance in Woods units (WU) was calculated by the following formula: (MPAP – mean PCWP/CO) × 80. Cardiac output was calculated by the Fick formula as follows: CO = 3 mL × weight (kg)/[Hb × 1.36 × SaO2) - (Hb × 1.36 × SpO₂] × 10, where Hb denotes hemoglobin con­centration, SaO2 denotes aortic oxygen saturation, and SpO₂ denotes pulmonary artery oxygen saturation.

We recorded 1-year and overall mortality rates and transplant rejection data, obtained from pathologic examinations of the serial endomyocardial biopsy samples.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21, IBM Corporation, Armonk, NY, USA). The 1-year and overall mortality rates were compared between patients with and without DPG ≥ 7 mm Hg. Diastolic and mean transpulmonary gradients were correlated with PVR and 1-year and overall mortality rates using Pearson correlation analysis. A binary logistic regression analysis was performed to determine whether DPG ≥ 7 mm Hg contributed to 1-year and overall mortality. Kaplan-Meier survival curves with log-rank tests were used to observe the effects of DPG ≥ 7 mm Hg on 1-year and overall mortality.

Results

Table 1 shows the demographics properties of the study population. The study population had a mean age of 45.5 ± 9.8 years at transplant. Of the 51 included patients, 40 (78.4%) were male. The causes of heart failure included ischemic dilated cardi­omyopathy in 22 patients (43.1%), nonischemic (idiopathic, alcoholic, diabetic, hypertensive, familial, valvular) cardiomyopathy in 23 patients (45.1%), acute myocarditis in 5 patients (9.8%), and hypertrophic cardiomyopathy in 1 patient (1.9%).

Table 2 shows the preoperative right-left heart catheterization results of the study population. There was a strong correlation between DPG and PVR (r = 0.525, P < .01). However, TPG and PVR were only marginally significantly correlated (r = 0.288, P = .040). The 1-year mortality rate was 21.6% (11/51), and the overall mortality rate was 37.3% (19/51). We found that 1-year mortality was significantly correlated with DPG (r = 0.303, P < .05) and PVR (r = 0.334, P < .05) but not TPG (P > .05) or the number of rejection episodes (P > .05). There were 16 patients with DPG ≥ 7 mm Hg (n = 16) and 35 with DPG < 7 mm Hg; those with ≥ 7 mm Hg DPG had significantly higher 1-year mortality rate (43.7%) than those with DPG < 7 mm Hg (11.4%; P < .05). The overall death rate was 37.3% (19/51). There was a significant correlation between overall mortality and DPG (r = 0.297, P < .05), number of rejection episodes (r = 0.282, P < .05), and PVR (r = 0.417, P < .05), but not TPG. The overall mortality rate of patients with DPG ≥ 7 mm Hg (10/16; 62.5%) was significantly higher than that of patients with DPG < 7 mm Hg (9/35; 25.7%) (P < .05). In a multivariate analysis, DPG ≥ 7 mm Hg was associated with a significantly greater 1-year mortality rate (OR = 6.0; 95% CI, 1.4-25.3; P < .05) and a significantly greater overall mortality rate (OR = 4.8; 95% CI, 1.4-17.5; P < .05). A Kaplan-Meier analysis showed a significant survival advantage of patients with DPG < 7 mm Hg compared with those with DPG ≥ 7 mm Hg (P < .01) (Figure 1).

Discussion

Our study demonstrated that DPG was significantly associated with PVR and that both DPG and PVR were significantly associated with 1-year and overall mortality. In addition, DPG was also a significant predictor of 1-year and overall mortality in multivariate analysis. In contrast, TPG was not significantly correlated with mortality and only borderline significantly correlated with PVR. Our results suggest that, among patients scheduled for cardiac transplant, DPG is closely correlated with PVR and thus may be a surrogate marker of PVR and that DPG may successfully predict mortality both at 1 year and anytime after cardiac transplant. Diastolic pulmonary gradient has the advantage of not necessitating an oxygen study or CO measurements, thus reducing radiation exposure and right and left heart catheterization time, cost, equipment, and staff. This simple parameter could therefore be utilized to make decisions regarding performance of cardiac transplant, perhaps without the need for measuring PVR.

Pulmonary hypertension and intrinsic pulmonary vascular diseases are adverse prognostic signs for patients undergoing cardiac transplant procedures. Because patients undergoing cardiac transplant are predominantly affected by conditions affecting the left heart, namely, ischemic cardiac disease, hypertrophic and idiopathic and other dilated cardiomyopathies, and aortic and mitral valve diseases, and because pulmonary hypertension is commonly associated with left-sided heart disease (PH-LHD),^14,15 pulmonary hypertension in cardiac transplant candidates commonly originates from left heart disorders, mainly heart failure due to reduced ejection fraction. Pulmonary hypertension associated with left heart disease is defined as a resting MPAP ≥ 25 mm Hg plus a mean PCWP > 15 mm Hg on right heart catheterization.^16,17 An increase in left-sided filling pressures causes an initial passive increase in PAP, which is called isolated postcapillary or passive PH-LHD. In this condition, MPAP is thought to return to normal whenever PCWP is normalized. This stage is characterized by normal TPG and PVR (TPG < 12-15 mm Hg and PVR < 2.5-3 WU).18 However, when sufficiently prolonged, PH-LHD can be complicated by increased intrinsic pulmonary vascular disease or precapillary disease characterized by pulmonary vasoconstriction and alveolar wall injury, ultimately resulting in small resistance pulmonary artery remodeling.^19,20 This add-on precapillary component increases the MPAP out of proportion of the PCWP increase, resulting in elevated TPG (≥ 12-15 mm Hg) and PVR (≥ 2.5-3 WU). This condition is termed as mixed, reactive, or combined postcapillary and precapillary pulmonary hypertension, and it does not normalize with acute interventions aimed at reducing left-sided filling pressures.¹⁸

When fixed at the precapillary level, pulmonary hypertension is detrimental before cardiac transplant and deteriorates right-sided cardiac function after transplant if unnoticed Hence, hemodynamic dif­ferentiation of isolated postcapillary PH-LHD from combined post- and precapillary PH-LHD is of utmost importance.^21,22 Traditionally, the presence of a TPG > 12 to 15 mm Hg or a PVR > 2.5 to 3 WU has been used to pick patients with a precapillary pulmonary hypertension component.¹⁸ However, it is known that TPG and PVR are flow dependent and influenced by changes in left-sided filling pressures and CO6 and thus may not accurately reflect precapillary pulmonary arteriolar remodeling. Recently, DPG has been introduced as a flow-independent, accurate marker of precapillary pulmonary hypertension.^6,7 This is because, normally, pulmonary blood flow is maximal during systole and minimal at end-diastole, and the DPAP is approximately equal to the PCWP with a DPG of 1 to 3 mm Hg.²³ Thus far, DPG has been used in a number of disorders, namely sepsis, post-coronary artery bypass grafting,8 respiratory distress syndrome,⁹ acidosis,¹⁰ and hypoxia.¹¹ Gerges and associates reported that, among patients with PH-LHD, those with a DPG ≥ 7 mm Hg had an increased proportion of small pulmonary vessel medial hypertrophy, intimal and adventitial fibrosis, luminal occlusion with angioproliferative lesions, and more myocytes per vessel wall.7 In their retrospective study of 3107 patients with heart failure with reduced ejection fraction, Gerges and colleagues demonstrated that, in patients with postcapillary pulmonary hypertension and TPG > 12 mm Hg, a DPG ≥ 7 mm Hg predicted a worse median survival compared with those with DPG < 7 mm Hg (78 vs 101 mo; P = .010).⁷

So far, DPG has not been effective in predicting mortality after cardiac transplant.^12,13 However, we demonstrated that DPG was significantly correlated with PVR and that both DPG and PVR were significantly correlated with 1-year and overall mortality. We also found that DPG was a significant predictor of 1-year and overall mortality in multivariate analysis. Our results suggest that DPG should be prospectively studied to investigate its prognostic significance in cardiac transplant patients. Because an accurate measurement of PVR needs an oxygen study, thus requiring more time, radiation exposure, equipment, cost, and staff, and because a CO measurement is also necessary, requiring knowledge about hemoglobin and patient weight, the calculation of PVR is more problematic. However, DPG is a simple parameter calculated only by subtracting an intracardiac pressure from another, thus saving time, cost, staff expenditure, and most importantly radiation exposure. Therefore, this method allows a simple prediction of precapillary pulmonary hypertension and death at posttransplant follow-up. These points should be clarified in large-scale prospective studies.

Limitations
This study has some limitations. First, this was a retrospective study, with a small number of patients. Second, a DPG measurement is prone to significant errors. Catheter motion artifacts can lead to errors in DPAP measurement. Inaccurate wedging of the catheter can result in overestimation of PCWP, whereas the recording of mean PCWP measurements averaged throughout the respiratory cycle, rather than those measured at end expiration, can result in underestimation of PCWP.²⁴ Small errors in the measurement of either variable will have a major impact on DPG due to its relatively low absolute value. In addition, the DPG has been shown to increase with heart rate in a linear fashion,²⁵ thereby potentially limiting its utility.

Conclusion

This study showed that diastolic transpulmonary gradient, an easy-to-calculate parameter, is closely related to invasively derived pretransplant pulmonary vascular resistance and 1-year and overall mortality among cardiac transplant recipients. Further prospective trials with larger sample sizes are needed to verify the findings of this study.

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