Introduction

Heart transplant (HTx) is a therapeutic option in selected patients with advanced heart failure. In 2018, HTx in Colombia corresponded to 6.6% of all transplants¹.

Colombian National Transplant Network divides national territory into six regions, of which five have HTx centers. Our hospital belongs to region 1, which is the largest in extension. All HTx centers in region 1 are located in Bogotá D.C city situated at 2,640 m above sea level (masl), being the city with the highest altitude in the world where this procedure is performed². Region 1 encompasses territories at altitudes from 0 masl and some populations located at more than 3,000 masl. Some of the transplanted patients in this region live at low altitudes and move to Bogota for transplant surgery, remaining the first 3 months of the post-operative period (POP) in the city. The majority of transplanted patients live in the city or in near localities, and remains at high altitudes (> 2,500 masl) before, during and after HTx.

Clinical trials have shown the effect of height on cardiovascular and pulmonary systems. Changes start from 1500 masl and are accentuated at higher altitudes. In general, high altitudes lead to pulmonary vasoconstriction and as a consequence, increase in pulmonary pressures and decrease in oxygen supply, favoring cardiovascular performance changes³. In HTx candidates, pulmonary hypertension (PH) is a poor prognostic factor, which carries an increased mortality risk and heart dysfunction⁴.

Due to effects of altitude on pulmonary physiology, it is presumed that transplant patients residing at higher altitudes may have a poor outcome after HTx, possibly by greater right ventricle (RV) dysfunction. Nowadays, no data have been published describing the hemodynamic behavior of RV in HTx patients at more than 2,500 masl.

The purpose of this study is to describe the RV pressures and systolic function, asses by transthoracic echocardiogram (TTE) in a historical cohort of HTx patients in our hospital. The measurements analyzed correspond to the immediate POP (Days 1-7 post-HTx), 3, 6, 12, and 24 months after HTx, both in patients living at an altitude of 2,640 masl, and in those living at a lower altitude.

Methods

Results

Echocardiographic post-operative features

Echocardiographic results were available in 37 patients (40.6%) (Table 4). Some degree of RV dysfunction was evidenced in the immediate post-operative period in 95% of HTx-patients (Mild 27%, moderate 43%, and severe 24%). There was a progressive reduction in the percentage of patients with RV systolic dysfunction: about 41% at 3^th month (Reclassify as mild in 3% of the patients and, as moderate in 38%), 31% at 6^th month (Reclassify as mild in the 3%, and as moderate in 29%), and 17% at 24^th month (Reclassify as mild in 7%, and moderate in 10%). After the 3^rd month, none of the patients presented severe RV dysfunction (Figure 1A). The analysis of RV systolic dysfunction after the 3^rd month of HTx is shown in (Figure 1B).

Table 4 Echocardiographic characteristics 

	Inmediate POP	3 Months POP	6 Months POP	12 Months POP	24 Months POP	p-value
Culitative Evaluation	n = 37	n = 32	n = 31	n = 30	n = 29	0,0001
Mild RV Disfunction, n (%)	10 (27)	12 (37.5)	9 (29)	5 (16.7)	2 (6.9)
Moderate RV Disfunction, n (%)	16 (43.2)	1 (3.1)	1 (3.2)	2 (6.7)	3 (10.3)
Severe RV Disfunction, n (%)	9 (24.3)	0 (0)	0 (0)	0 (0)	0 (0)
Normal RV Function, n (%)	2 (5.4)	19 (59.4)	21 (67.7)	23 (76.7)	24 (82.7)
Cuantitative Evaluation
TAPSE (mm) mean ± SD	8.9 ± 4.9	15.1 ± 3.6	13.5 ± 4.2	14.9 ± 2.8	15.8 ± 4.9	0,02
sPAP (mmHg) mean ± SD	39.8 ± 8.2	33.8 ± 7.7	31.1 ± 6.2	30.2 ± 6.4	31.0 ± 5.0	0,04
IVC dilation (> 2,1 cms) n (%)	11 (29.7)	2 (6.2)	0 (0)	0 (0)	0 (0)	NS
LVEF % mean ± SD	ND	59.2 (6.7)	57.8 (6.5)	57.5 (5.1)	58.5 (4.6)	0,56
Tricuspid Regurgitation						0,005
Mild, n (%)	19 (51.3)	17 (53.1)	16 (51.6)	18 (60)	18 (62)
Moderate, n (%)	8 (21.6)	0 (0)	0 (0)	0 (0)	0 (0)
Severe, n (%)	3 (8.1)	0 (0)	0 (0)	0 (0)	0 (0)
Normal, n (%)	7 (19.8)	15 (46.9)	15 (48.4)	12 (40)	11 (38)

sPAP: systolic pulmonary artery pressure; TAPSE: Tricuspid annular plane systolic excursion; LVEF: Left ventricular ejection fraction; IVC: inferior vena cava; RV: right ventricle; n: number; %: percentage; IQR: Interquartile range; SD: standard deviation.

Figure 1 A: RV systolic function evaluation in different POP-HTx periods. B: RV systolic function evaluation in different POP-HTx periods in patients living at more than 2,500 masl and less than 2,500 masl. M-POP: months POP; RV: right ventricle. 

The mean TAPSE in the immediate postoperative period was 8.9 ± 4.9 mm. There was a significant improvement at the 3^rd month post-transplant (15.1 ± 3.6 mm), which was maintained during follow-up. At the 24^th month TAPSE approached to a normal value (15.8 ± 4.9 mm) (Fig. 2A).

Figure 2 A: tricuspid annular plane systolic excursion (TAPSE) evaluation. B: systolic pulmonary artery pressure (sPAP) evaluation. 

Some degree of tricuspid regurgitation (TR) was present in 81% of HTx-patients in the immediate postoperative period. The highest sPAP value was registered in the immediate postoperative period (39.2 ± 8.2 mmHg), with a 33% decrease in the 6^th month (31.1 ± 6.2 mmHg), having then a stable behavior during follow-up (Fig. 2B).

Abnormal inferior vena cava dilation was identified in 29.7% of the patients in the immediate post-operative period. At the 3^rd month post-transplant, abnormal dilation was present in only 6.2% of patients and was then normal, during the follow-up (Table 4).

A total of 24 TTE were available for the second evaluation of patients transplanted between January 2018 and May 2019. All patients lived at more than 2500 masl before and after HTx. The results of the second evaluation showed a high concordance with respect to the following registered variables: sPAP (r = 0.98), TR-severity (r = 0.87), and TAPSE (r = 0.69) (Table 5).

Table 5 TTE parameters correlation between historical data and a second observer in HTx patients in 2018-2019 

Characteristic	Historical record	Observer 2	Differences test	Interobserver concordance (r)
TAPSE	14.5 ± 4.6	14.7 ± 4.1	0.78	0.69
sPAP	40.2 ± 11.6	39.6 ± 12.9	0	0.98
Tricuspid insufficiency	34.8	34.8	0.75	0,87
Normal, n. (%)	39.1	43.5	0.88
Mild, n. (%)	13	4.3	0.22
Moderate, n. (%)	13	17.4	0.01
Severe, n. (%)	-	-	0.07

sPAP: systolic pulmonary artery pressure; TAPSE: tricuspid annular plane systolic excursion; n: number, %: percentage.

A measurement of the RVFAC and the basal diameter of the RV was performed. The results showed RV dysfunction and dilation in the immediate POP period: FAC: 38.5% (23-52%) and RV basal diameter: 43.5 mm (42-48), respectively. However, all patients presented recovery of these parameters at the 3^rd month after POP, with a FAC of 47% (41-50%) and a basal diameter of 35mm (34-37), remaining so until the 1^st year of follow-up (Figs. 3A and B). LVEF of transplanted patients was normal throughout the follow-up (Table 4).

Figure 3 A: RV Fractional Area Change (FAC). B: basal diameter in four post-operative momentum of HTx patients in 2018-2019. 

Discussion

A total of 91 patients underwent HTx in our hospital, during the past 14 years. Echocardiographic results were available in 37 patients (40.6%), 95% presented RV dysfunction in the immediate postoperative period, which was predominantly moderate (43%). After the 3^rd post-operative month, improvement in RV function was observed. Patients with moderate disfunction decrease from 43% to 3%. These data are similar to the one reported by Mastouri et al.⁶ in a study carried out in Indianapolis (A city located at 218 masl) where RV dysfunction was observed in 100% of transplants in the immediate POP period, 41% with severe dysfunction and 59% with moderate dysfunction. These results suggest a high incidence of RV dysfunction in the immediate POP period of HTx patients, possibly due to sudden increase in the RV afterload, secondary to residual pulmonary receptor hypertension, significant TR, and time prolonged ischemia⁷. There are no published data on the relationship with the recipient’s residence altitude.

At 12^th and 24^th months, two thirds of our patients (77-83%) were classified as normal RV function. The rest of the patients were classified as having mild dysfunction, and only 7%-10% were classified as having moderate dysfunction. This trend in improvement was greater than reported in the Indianapolis study, where after the first POP year, only 55% of patients showed improvement in RV function⁶.

Other studies have reported lower incidence of RV dysfunction with values close to 30%⁸, suggesting influence of additional factors not considered in this study, such as immediate POP care protocols, surgical technique, ischemia time, monitoring and care in the medium and long term, donor’s, and recipient’s pulmonary pressure, among others.

Taking in account that there is some RV dysfunction in the immediate POP, guidelines for assessment of post-HTx patients recommend the use of the 6^th month POP-ETT as a reference, expecting a peak function recovery in the 1^st year POP⁷, as we documented in our study.

A few years ago, cardiologists made a qualitative estimate of the size of the RV, comparing it with the left ventricle⁹. The evaluation of RV systolic function was also qualitative (“eye-ball” estimation)¹⁰, with only a few quantitative parameters available (TAPSE and tissue Doppler velocity of the tricuspid annulus), as in our study. However, RV quantification guidelines are now available⁵. At present, a multiparametric strategy is recommended for the classification of RV dysfunction¹¹.

RVFAC and 3D echocardiography volume and function evaluation have a good correlation with cardiac magnetic resonance imaging (cMRI). However, methods such as 3D evaluation are not yet widely available. When possible, cMRI should be the method of choice as it is considered the “gold standard” for size and function ventricles evaluation.

Studies comparing subjective RV evaluation by TTE against cMRI have shown moderate correlation in volume estimation and low correlation in systolic function¹⁰. RV quantitative values obtained by 2D ETT compared with cMRI in patients undergoing HTx showed FAC as the value with the best correlation (r = 0.747, p < 0.001). FAC value ≤ 48.5% has a sensitivity and specificity of 90.5% to predict a reduce RV ejection fraction (< 50%) estimated by cMRI (AUC: 0.96; 95% CI, 0.908-1.013)¹². This RVFAC cutoff point is higher than the previously of 35%, described as normal in the ASE guidelines⁵. We should keep in mind that populations are different, and the value of 48.5% specifically refers to post-HTx patients. A small group of patients with PH analyzed by López-Candales et al.¹³, established a cutoff point of 40.9% as a normal value. Larger trials with different population groups are needed to establish better “normal” values.

In the patients in whom the RVFAC was measured in the second evaluation (transplanted patients between 2018 and 2019), the immediate POP values showed RV dysfunction according to the cutoff point defined by the ASE (< 35%)⁵. However, these values showed an improvement from the 3^rd month, with levels close to those established in the literature, as normal, for patients with HTx (40-48%)¹²,¹³. These results showed the same behavior as other qualitative and quantitative parameters found in the medical records (Fig. 3A)

Another quantitative parameter available in most of our population was TAPSE and its behavior showed a similar trend to the qualitative evaluation of RV systolic function. TAPSE decreased markedly, but increased from the 3^rd month of POP, and remained that way at follow-up. Values almost reach the normal range after month 24 (Table 4 and Fig. 2A). The non-return to normality in the quantitative parameters of RV evaluation has been previously described in the literature⁶,⁷.

PHT after HTx is a risk factor that increases postoperative mortality¹⁴,¹⁵. In our study, the majority of patients showed a progressive decrease in sPAP. After 24 months, none patients had PHT. The 33% reduction in sPAP estimated by TTE in the first 6 months was similar to that described in a cohort from Coimbra, Portugal (Located at 499 masl), in which sPAP decreased from 46 mmHg to 31 mmHg¹⁶.

Regardless PHT etiology, it was expected that living at more than >2,500 masl could have a deleterious effect; however, it seems that it does not. At altitudes > 2,500 masl, the oxygen partial pressure is decreased by 20%, which cause a constrictive pulmonary vascular response that guarantee blood flow to a better ventilated alveolus. In addition, there is a 20-30% decrease in cardiac output compared to cardiac output at sea level. These changes occur within hours after exposure to altitude and in chronic exposures can lead to adaptive changes³. Patients with pulmonary comorbidity (Chronic obstructive pulmonary disease) expose to moderate altitudes (1780 masl) have an increase in mPAP values compared to those living at lower altitudes. However, this apparent overload does not seem to affect systolic function and performance of RV which suggests adaptation processes¹⁷.

In our cohort, 30% of the patients returned to cities located < 2500 m above sea level, 3 months after HTx. Comparative analysis of RV hemodynamic behavior and sPAP does not seem to produce significant differences. However, because the follow-up time is highly variable among study subjects and it is a retrospective study, it is not possible to make comparisons that allow evaluating the effect of confounding variables.

Data from HTx in patients living at more than 2500 masl have not been published. To the best of our knowledge, Bogota-Colombia is the world’s highest city where HTx is currently performed.

General characteristics of the population described in this study specially, recipient age, donor age, body mass index, kidney function, and 5-year survival, were similar to data published by ISHLT for 2019¹⁸. Heart failure etiology was mainly non-ischemic cardiomyopathy, mostly idiopathic dilated cardiomyopathy and chagasic cardiomyopathy, the latter because Colombia is an endemic area for Chagas disease. In general, distribution pattern by etiology was similar to the one that has been described worldwide¹⁸.

Comorbidities were identified in < 25% of the population, which can explain lower complication rates.

In the recipient evaluation, our population had slightly higher pulmonary vascular resistances than average values described by ISHLT in adult population¹⁸. This could be related to altitude. Some studies have shown that at higher altitudes there is a slight increase in mean pulmonary artery pressure and in pulmonary vascular resistance¹⁹,²⁰.

Regarding the PRA I and II, the ISHLT reported a positive value (> 10%) in 13.4%-22% of patients (both, PRA I and II) between 2001 and 2018¹⁸. In our cohort, positive values (> 10%) were present in 18% of patients (PRAI: 16% and PRAII: 18%). PRA positivity have impact on early or more severe organ rejection incidence, especially when the positivity level of these antibodies is > 10% with an impact in survival reduction at values > 25%²¹.

Adequate gender and weight concordance are important to prevent rejection and major complications. The previous studies have shown that gender incompatibility (donor woman/recipient man) increases rejection risk in more than 3 times²². According to ISHLT gender mismatch was presented in 16.1% of HTx patients between 2010 and 2018¹⁸. In our cohort, gender mismatch occurred in 11% of patients, being less than worldwide reports.

Weight mismatch, defined as a donor weight < 70% of recipient’s weight, has also been associated with mortality increased in short and long term. This association is lost with obese donors (BMI ≥ 30)²³. In the present study, weight mismatch was not documented.

Conclusions

HTx population in our center is similar to patients transplanted in different centers around the world. This may correspond to a uniformity in criteria and treatment applied in these patients.

After HTx, the majority of patients presented moderate to severe right ventricular dysfunction probably due to the recipient’s PH, which improved rapidly in the 3^rd month after HTx.

Despite high altitude physiological changes in cardiovascular and pulmonary systems, HTx at 2640 masl and subsequent stay of patients at this altitude seems to have no significant impact on sPAP and RV systolic function evaluated by TTE in the immediate POP and in medium and long-term follow-up. This is probably related to a fast-onset adaptation phenomenon, adequate patient selection, and optimal post-transplant treatment.