Diastolic Filling in Patients After Heart Transplantation Is Impaired Due to an Altered Geometrical Relationship Between the Left Atrium and Ventricle

Abstract

Background

The geometrical relationship between atrial and ventricular short‐axis cross‐sectional area determines the hydraulic forces acting on intracardiac blood. This is important for diastolic filling. In patients undergoing heart transplantation (HTx), the left atrium is often enlarged as a result of the standard surgical technique. We hypothesized that diastolic filling in HTx patients is affected by the surgery altering the geometrical relationship between atrium and ventricle.

Methods and Results

This retrospective, cross‐sectional study included 25 HTx patients (median age, 52 [range, 25–70] years), 15 patients with heart failure with reduced ejection fraction (median age, 63 [range, 52–75] years), 15 patients with heart failure with preserved ejection fraction (median age, 74 [range, 56–82] years), and 15 healthy controls (median age, 64 [range, 58–67] years) who underwent cardiac magnetic resonance imaging. Left ventricular, atrial, and total heart volumes (THV) were obtained. Atrioventricular area difference at end diastole and end systole was calculated as the largest ventricular short‐axis area minus the largest atrial short‐axis area. Left atrial minimum volume normalized for THV (LA_min/THV) was larger in HTx patients (median, 0.13 [range, 0.07–0.19]) compared with controls (median, 0.05 [range, 0.03–0.08], P <0.001), whereas left ventricular volume normalized for THV (left ventricular end‐diastolic volume/THV) was similar between HTx and controls (median, 0.19 [range, 0.12–0.24] and median, 0.22 [range, 0.20–0.25], respectively). At end diastole, when atrioventricular area difference reached its largest positive value in controls, 11 HTx patients (44%) had a negative atrioventricular area difference, indicating impaired diastolic filling.

Conclusions

Diastolic filling is impaired in HTx patients due to an altered geometrical relationship between the left atrium and ventricle. When performing cardiac transplantation, a surgical technique that creates a smaller left atrium may improve diastolic filling by aiding hydraulic forces.

Nonstandard Abbreviations and Acronyms

AVAD

atrioventricular area difference

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

HTx

heart transplantation

PAWP

pulmonary artery wedge pressure

RER

respiratory exchange ratio

THV

total heart volume

VO₂peak

peak oxygen uptake

Clinical Perspective.

What Is New?

• The geometrical relationship between the left atrium and left ventricle is of importance for diastolic filling.

• A disproportionally large left atrium, as often seen after heart transplantation, impairs diastolic filling.

What Are the Clinical Implications?

• It is important to keep the balance between the left atrial volume and ventricle as normal as possible at transplantation.

Choice of surgical technique for orthotopic heart transplantation (HTx) affects geometry, ¹ contractility and electrophysiology of the atrium, and consequently also diastolic function. ² The bicaval technique has been suggested as the preferred alternative because it best preserves atrial geometry and function. ³ , ⁴ However, preservation of anatomy may be of higher importance than previously known.

Pressure from atrial and ventricular blood pool exerts a hydraulic force directed perpendicular to the myocardial wall at each location. These forces can be resolved into components acting in the longitudinal apex‐base direction and radial direction. ⁵ The longitudinal forces are especially interesting for diastolic function in HTx patients, as illustrated in Figure 1. As originally shown by Maksuti et al, ⁵ diastolic function is affected by the geometrical relationship between the left atrium and left ventricle. ⁵ , ⁶ When the atrial short‐axis area is smaller than the ventricular short‐axis area, a hydraulic force contributes to the upward movement of the atrioventricular plane, ⁵ , ⁶ and thus to diastolic filling. ⁵ However, the net hydraulic force may instead impair filling if the atrial short‐axis area is larger than the ventricular short‐axis area. ⁶ The left atrium is often enlarged in HTx patients because the left atrium of the donor's heart is sutured to the remnant back wall of the recipient's left atrium containing the pulmonary veins (Figure 2), and thus the geometrical relationship between atrium and ventricle is affected.

Figure 1. Visualization of the concept of longitudinal hydraulic forces in normal hearts compared with transplanted hearts.

Top row shows a schematic view of the left atrium and left ventricle. Black horizontal lines indicate the maximal diameter (and area) of the left atrium (d _A) and left ventricle (d _V), and red arrows show the direction of the net hydraulic force. Bottom row shows examples of cardiac magnetic resonance images in the 2‐chamber view for a healthy control with normal geometry and a HTx patient with enlarged atrium. Note how the red arrows indicating the net hydraulic force differ in direction between the 2 subjects. HTx indicates heart transplantation.

Figure 2. Connection points using the bicaval technique shown as a graphical illustration (A) and in a cardiac magnetic resonance (CMR) image (B).

A, The donor heart is connected to the remnant back wall of the left atrium with the recipient's pulmonary veins. Incision lines indicated by red dashed lines. B, CMR 2‐chamber view where the white arrow indicates the suture line in the left atrium to the donor's heart. Adapted from Annika Ingvarsson thesis 2021, Lund University, Sweden, with permission. LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle.

An enlarged left atrium after HTx may also disturb the close relationship between exercise capacity peak oxygen uptake (VO₂peak) and total heart volume (THV) seen in healthy subjects, ⁷ , ⁸ which can be used to differentiate between an athlete's heart and dilated cardiomyopathy. ⁹ , ¹⁰ Whether this relationship and thus the index VO₂peak/THV can be useful for early detection of graft failure in HTx patients is unknown.

In the current study, cardiovascular magnetic resonance (CMR) imaging was used to investigate the hypothesis that the current bicaval surgery technique affects the relationship between the left atrium and ventricle, determined as atrioventricular area difference (AVAD). The specific aims of the study were (1) to assess diastolic function determined as AVAD in patients after HTx and in patients with heart failure with or without reduced ejection fraction in relation to healthy controls, and (2) to assess the relationship between THV and VO₂peak in patients after HTx, and in healthy controls.

METHODS

The Regional Ethical Review Board in Lund, Sweden, approved the study (permit 2004/741 and 2018/948). The study followed the Declaration of Helsinki and written consent was obtained from all subjects before data acquisition. Results are presented according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies. ¹¹ Author KSE had full access to all the data in the study and takes responsibility for its integrity and data analysis. All research participants were included at Skåne University Hospital, Lund, Sweden, between 2020 and 2021. Because of the sensitive nature of the data collected for this study, requests to access the data set from qualified researchers trained in human subject confidentiality protocols may be sent to Cardiac MR Group in Lund at cmr-lund@med.lu.se.

Study Design

Patients after HTx with bicaval technique (n=25) who had undergone CMR as part of clinical follow‐up were compared with patients with HFpEF (n=15, ejection fraction >50%) or HFrEF (n=15, ejection fraction <40%) and healthy controls (n=15) in this retrospective, cross‐sectional study. Sample size was chosen based on previous work showing that a sample size of n=12 is sufficient to detect significant differences in cardiac volumes. ¹²

Figure 3 shows a flow chart of all examinations. For 10 HTx patients, right heart catheterization was performed with patients in the supine position at rest in a dedicated hemodynamic laboratory as a part of the clinical 1‐year follow‐up after HTx. All subjects underwent CMR, echocardiography, and cardiopulmonary exercise testing. CMR, echocardiography, and cardiopulmonary exercise testing were performed on median 2.5 years (range, 1–26) after HTx.

Figure 3. Flow chart of examinations.

CMR indicates cardiac magnetic resonance imaging; CPET, cardiopulmonary exercise test; Echo, echocardiography; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HTx, heart transplanted patients; and Right heart cath, right heart catheterization.

Hemodynamic Assessment

Hemodynamic assessment with a right heart catheterization was performed as a part of the 1‐year clinical follow‐up in 10 HTx patients. The time delay between CMR and hemodynamic assessment in the 10 HTx patients was median 3 days: however, with 3 subjects waiting 7, 16, and 33 days, respectively. A Swan Ganz catheter (Edwards Life Science, Irvine, CA) was inserted via the internal jugular vein. Pressures in the right atria, right ventricle, and pulmonary artery wedge pressure (PAWP [mm Hg]) were recorded as mean over several heartbeats during free breathing. Cardiac output was calculated by thermodilution. Data were acquired and stored in Sensis VC12M (Siemens Healthcare, Erlangen, Germany).

Cardiac Imaging, Analysis, and Calculation of AVAD

Standard long‐axis images in the 2‐chamber, 3‐chamber, and 4‐chamber view and short‐axis images covering the atria and ventricles were acquired using CMR. All image analysis was performed in the software Segment 4.0 (http://segment.heiberg.se) ¹³ by an experienced observer with 17 years of CMR experience. Any uncertainties in delineations were discussed with a second observer with 25 years of CMR experience to reach consensus. Epicardial and endocardial contours of the left ventricle were manually delineated at end diastole and end systole. ¹⁴ Due to the thin walls of the left atrium, only the endocardial border was delineated, both at ventricular end diastole and end systole, with the atrial appendage included.

Total heart volume was defined as the volume of all structures within the pericardium at end diastole and manually delineated in short‐axis images by planimetry. ¹⁵

AVAD was obtained as previously described. ⁶ In short, the largest endocardial ventricular and atrial short‐axis areas at ventricular end diastole and end systole were identified and used to calculate AVAD for the respective time frames, as shown in the following calculation:

$$\begin{array}{c}\text{AVAD}\left({\mathrm{cm}}^2\right)=\text{ventricular short}-\text{axis area}\left({\mathrm{cm}}^2\right)\hfill \\ -\text{atrial short}-\text{axis area}\left({\mathrm{cm}}^2\right)\hfill \end{array}$$

In 4 subjects, AVAD was determined over the full cardiac cycle to illustrate the dynamic interplay between the atrium and ventricle.

Since force is equal to pressure×area, the same pressure applied over different areas will generate different forces. A force transmitted through a liquid such as blood is referred to as a hydraulic force. The magnitude of the hydraulic force generated by AVAD was calculated in a subgroup of 10 HTx patients at mid‐diastasis, when the mitral valve is open, and left atrial and ventricular pressure can be assumed to be equal. For this subgroup of HTx patients, invasive hemodynamic measurements of PAWP (mm Hg) had been obtained within 7 days of CMR in 7 patients (median 0 days, range 0–7) and for 3 patients CMR was performed on day 10, 16, and 27 after hemodynamic measurements. After conversion to appropriate units where 1 mm Hg=133.32 N/m² and 1 cm²=0.0001 m², the hydraulic force was calculated as:

$$\begin{array}{c}\text{Force}\left(\mathrm{N}\right)=\text{pulmonary artery wedge pressure}\left(\mathrm{N}/{\mathrm{m}}^2\right)\hfill \\ \times \text{difference in endocardial area}\left({\mathrm{m}}^2\right)\hfill \end{array}$$

Echocardiography

For nontransplanted patients, transthoracic 2‐dimensional echocardiographic assessments were performed using Acuson S3000 (Siemens Healthcare, Erlangen, Germany) with a 1.75‐ to 4‐Mhz transducer (4v1c), while HTx patients were examined using an iE33 platform equipped with a S5‐1 transducer (Philips Healthcare, Eindhoven, the Netherlands). All echocardiographic images were analyzed using Intellispace Cardiovascular (Philips Healthcare, Best, the Netherlands). Image acquisition and analysis were performed by 4 experienced sonographers (6–13 years of experience) and according to guidelines, ¹⁶ with the observer blinded to clinical data.

Cardiopulmonary Exercise Test

Exercise tests were performed using a ramp‐protocol adapted to age, sex, and perceived fitness to yield an exercise duration of 10 to 12 minutes. ¹⁷ Peak oxygen uptake was obtained by calculating the average of all breaths over a 10‐second period. However, for patients with heart failure with ventilatory oscillations during exercise, ¹⁸ up to 30 seconds was used to obtain a representative value. To ensure maximal exercise was obtained, respiratory exchange ratio >1.05 and heart rate >85% of predicted was used together with clinical evaluation of exhaustion done by the physician. Peak oxygen uptake is presented as absolute value (mL/min) and as percentage of expected value based on age and sex. ¹⁹ Values >75% of the reference material are considered normal.

Statistical Analysis

Statistical analysis was performed in GraphPad Prism 9.0.2 (GraphPad Software Inc, San Diego, CA). For AVAD, homoscedasticity was not assumed and Welch's ANOVA with Dunnett's T3 multiple comparisons test assessed differences between the 3 patient groups versus data from controls. For non‐normally distributed variables, Kruskal–Wallis nonparametric test was used to assess differences among the 3 patient groups versus data from controls. Results are presented as mean±SD or median (range) as appropriate. Linear regression analysis assessed the relationship between total heart volume and VO₂. When data were missing for a participant, this subject was excluded from the specific analysis. Interobserver variation for LA_min, LA_max, left ventricular end‐diastolic volume, and left ventricular mass was assessed in 5 randomly selected HTx patients. A P value <0.05 was considered to indicate statistical significance.

RESULTS

Subject characteristics are described in Table 1. Cardiac volumes, mass, and function obtained from CMR imaging and echocardiography are presented in Tables 2 and 3. Medications for HTx patients are shown in Table 4.

Table 1.

Subject Characteristics

	Controls	HFrEF	HFpEF	Transplantation
n (female)	15 (11)	15 (3)	15 (7)	25 (9)
Age, y	64 (58–67)	63 (52–75)	74 (56–82)	52 (25–70)
Height, cm	166 (158–186)	175 (158–190)	173 (155–193)	175 (161–194)
Weight, kg	69 (58–100)	85 (57–107)*	79 (52–121)	87 (55–110)
BMI, kg/m2	24.6 (20.9–40.1)	27.6 (21.7–38.9)	28.8 (21.0–38.2)	26.3 (20.8–36.4)
BSA, m2	1.77 (1.63–2.10)	2.06 (1.60–2.38)*	1.96 (1.50–2.45)	2.07 (1.57–2.35)*
SBP, mm Hg	116 (97–143)	123 (85–156)	130 (99–154)	130 (75–160)
DBP, mm Hg	73 (57–94)	75 (50–105)	67 (52–93)	75 (60–95)
VO2peak, L/min	1.87 (1.23–3.30)	1.75 (1.09–2.62)	1.37 (0.92–2.29)*	1.53 (0.88–2.79)
VO2peak, % of expected	122 (82–149)	83 (55–123)*	90 (65–108)*	69 (51–97)*

Data are presented as median (range). Missing data for systolic blood pressure: 2 controls, 1 transplanted patient. Missing data for diastolic blood pressure: 2 controls, 3 transplanted patients. Body surface area was calculated using Mosteller's formula. BMI indicates body mass index; BSA, body surface area; DBP, diastolic blood pressure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and SBP, systolic blood pressure. *P<0.05 compared with the control group, calculated by Kruskal–Wallis nonparametric test.

Table 2.

Measurements of Cardiac Volumes, Mass, and Function Obtained from Cardiac Magnetic Resonance Imaging

	Controls	HFrEF	HFpEF	HTx
	n=15	n=15	n=15	n=25
HR rest, BPM	61 (47–79)	66 (51–90)	56 (46–96)	81 (50–87)*
LVEDV, mL	138 (107–193)	309 (131–591)*	191 (90–253)	151 (109–228)
LVESV, mL	58 (43–93)	220 (88–512)*	74 (24–114)	63 (41–112)
LVSV, mL	89 (62–112)	86 (43–129)	102 (46–139)	89 (55–139)
LVM, g	83 (52–120)	152 (70–234)*	104 (67–178)	105 (63–151)*
LVEF, %	61 (52–68)	30 (13–38)*	56 (50–76)	57 (47–69)
CO, L/min	5.2 (3.9–6.6)	6.0 (3.4–8.7)	6.1 (2.3–7.6)	7.0 (3.8–9.7)*
CI, L/min per m2	2.8 (2.3–3.6)	2.7 (1.9–4.3)	3.0 (1.2–4.0)	3.6 (1.9–5.1)*
LA max, mL	88 (45–111)	112 (69–242)*	114 (64–163)	131 (72–249)*
LA min, mL	36 (17–49)	85 (36–216)*	64 (28–132)*	97 (45–209)*
AVAD ed	12.8±3.6	22.4±10.0**	9.0±8.0	1.0±7.6***
AVAD es	−8.0±3.6	2.3±7.7***	−9.5±7.0	−13.8±6.7**

Data are presented as median (range), except for atrioventricular area difference at end diastole (ed) and atrioventricular area difference at end systole (es), which were normally distributed and thus presented as mean±SD. Heart rate was obtained during the cardiac magnetic resonance examination using ECG. BPM indicates beats per minute; CI, cardiac index; CO, cardiac output; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; HTx, heart transplantation; LA, left atrium; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end‐systolic volume; LVM, left ventricular mass; LVSV, left ventricular stroke volume. *P<0.05, **P<0.01, ***P<0.001 compared with the control group, calculated by Kruskal–Wallis nonparametric test for all but AVAD for which Welch's ANOVA with Dunnett's T3 multiple comparisons was applied as homoscedasticity was not assumed.

Table 3.

Echocardiographic Variables

	Controls	HFrEF	HFpEF	HTx
	n=15	n=10	n=15	n=25
Average E/e′	7.1 (4.5–8.8)	8.9 (3.4–14.9)	8.8 (4.7–13.0)	8.2 (5.7–14.7)
Septal e′ velocity, cm/s	9.1 (7.0–13.3)	6.9 (4.5–11.1)*	6.9 (4.5–10.7)*	6.8 (1.9–14.4)*
Lateral e′ velocity, cm/s	11.7 (10.3–14.0)	8.4 (5.6–13.9)*	8.8 (6.2–13.0)*	12.3 (4.7–20.9)
LA maximum volume index, mL/m2	24 (15–33)	39 (22–67)*	35 (14–64)*	41 (18–73)*
Tricuspid regurgitation, m/s	2.3 (1.9–2.7)	2.5 (2.0–3.1)	2.5 (2.2–3.5)	2.4 (1.9–2.9)

Data are presented as median (range). Note that only 10 patients with HFrEF underwent echocardiography in conjunction with the cardiac magnetic resonance examination. Of the patients included with echocardiography, there are missing data for E/e′ in n=1 HFpEF group and n=2 transplantation group, for septal e′ velocity in n=1 HFpEF group and n=3 transplantation group, for lateral e′ velocity n=1 HFpEF group and n=2 transplantation group, for LA maximum volume index n=1 control group and n=2 HFpEF group, and for tricuspid regurgitation n=3 control group, n=1 HFrEF group, n=1 HFpEF group, and n=5 transplantation group. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HTx, heart transplantation; and LA, left atrium. *P<0.05 compared with the control group, as calculated by Kruskal–Wallis nonparametric test.

Table 4.

Medications Prescribed for HTx Patients

Medications for HTx patients	N/%
Acetylsalicylic acid	20/80%
β‐blocker	5/20%
Ivabradine	0/0%
Calcium channel blocker	13/52%
ACE inhibitor/angiotensin receptor blockers	11/44%
Diuretics	5/20%
Statins	25/100%
Proton pump antagonists	15/60%
Oral anticoagulants	3/12%
Mineralocorticoid receptor antagonists	4/16%
Insulin	2/8%

ACE indicates angiotensin‐converting enzyme; and HTx, heart transplantation.

Cardiac Volumes

Total heart volume was larger in all patient groups compared with controls (Figure 4A). However, the volumes indexed to THV differed between patients, where HTx patients had the smallest left ventricular end‐diastolic volume/THV but the largest left atrial maximum volume (LA_max)/THV and left atrial minimum volume (LA_min)/THV (Figure 4B through 4D). There was no correlation between time from when HTx was performed and LA_max/THV (R²=0.48, P=0.29) or time from HTx and LA_min/THV (R²=0.03, P=0.044).

Figure 4. Total heart volume (THV) (A), left ventricular end diastolic volume normalized for THV (B), left atrial maximal volume (LA_max) normalized for THV (C), and left atrial minimum volume (LA_min) normalized for THV (D).

Patients after HTx had significantly larger LA_max/THV and LA_min/THV and thus, the larger THV seen in HTx patients compared with controls is likely explained by the large atrial volume. This contrasts with HFrEF patients where the larger THV is explained by a larger end‐diastolic volume, as seen in (B). Solid lines denote median values. P values were calculated by Kruskal–Wallis nonparametric test. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and HTx, heart transplanted patients.

Atrioventricular Area Difference

At end diastole, the mean value for all groups was above zero, indicating that on a group level the net hydraulic force was directed towards the base, aiding diastolic filling (Figure 5A). Three patients (20%) diagnosed with HFpEF had AVAD values just below zero and thus the net hydraulic force was instead directed towards the apex, impairing diastolic filling. Noticeably, this was also seen in 11 HTx patients (44%) with AVAD ranging from −2.1 to −16.8 cm², where more negative values correspond to a larger net hydraulic force impeding diastolic filling.

Figure 5. Atrioventricular area difference at end diastole and end systole.

Values above zero indicates a net direction of the hydraulic force going towards the base, aiding diastolic filling. A, At end diastole, when the net hydraulic force aiding filling is at its largest in healthy controls, 11 transplantation patients instead have a negative AVAD, indicating a net hydraulic force acting towards the apex, thereby impeding diastolic filling. B, End systole, which also can be thought of as the beginning of diastole. Note that the majority of patients in the HFrEF group have a value above zero already at diastolic onset, which will help diastolic filling throughout diastole and in part compensate for lack of elastic recoil of the myocardium during the early filling phase. Error bars denote mean±SD. P values were calculated using Welch's ANOVA with Dunnett's T3 multiple comparisons test, as homoscedasticity was not assumed. AVAD indicates atrioventricular area difference; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and HTx, heart transplantation.

At end systole, atrial short‐axis area in healthy subjects, HFpEF, and HTx patients were larger than ventricular short‐axis area and the net hydraulic force was directed towards the apex, impairing diastolic filling. However, 11 patients with HFrEF (73%) had larger ventricular areas also at end systole and thus AVAD was above zero. For these patients with HFrEF, diastolic filling after mitral valve opening is immediately aided by the net hydraulic force as it is directed towards the base (Figure 5B). Time from HTx did not determine AVAD at end diastole (P=0.67), nor AVAD at end systole (P=0.97).

Figure 6 shows the dynamic interaction between atrial and ventricular area over the cardiac cycle in a healthy subject (Figure 6A), in a HTx patient with enlarged atrium (Figure 6B), in a patient with HFpEF with enlarged atrium (Figure 6C), and in a patient with HFrEF with an enlarged ventricle (Figure 6D).

Figure 6. Change of atrial and ventricular short‐axis areas over a cardiac cycle in a healthy control (A), HTx patient (B), HFpEF patient (C), and HFrEF patient (D).

Note that for the HTx patient (B), the left atrial area is always larger than the ventricular area, and AVAD is negative. This means that the net hydraulic force is directed towards the apex throughout the cardiac cycle, impairing filling during diastole. The same pattern can be seen for HFpEF (C). On the contrary, in the HFrEF patient (D), the ventricular area is always larger than the atrial area, AVAD is positive, and the net hydraulic force is directed towards the base, aiding diastolic filling. Thus, all 4 subjects display different patterns of AVAD due to the different geometrical relationship between the left atrium and ventricle. AVAD indicates atrioventricular area difference; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and HTx, heart transplantation.

There was no correlation between AVAD at end diastole and standard clinical measures of diastolic dysfunction such as E/e′ and PAWP (Figure 7).

Figure 7. Atrioventricular area difference (AVAD) in relation to E/e′ measured from echocardiography (A) and invasively obtained pulmonary artery wedge pressure (PAWP, B).

There was no correlation between E/e′ and AVAD at end diastole in HTx patients with follow‐up times between 1 and 26 years. Furthermore, there was no correlation between PAWP and AVAD in 10 HTx patients who underwent CMR and hemodynamic assessment at their 1‐year follow‐up. CMR indicates cardiac magnetic resonance; and HTx, heart transplantation.

Hydraulic Force at Mid‐Diastasis

Hydraulic force was quantified in 10 HTx patients, whereof 7 had positive AVAD at mid‐diastasis favoring filling, and 3 had negative AVAD, impairing filling. The median filling pressure estimated from right heart catheterization PAWP was 8 mm Hg (range, 2–12) in these 10 HTx patients. For patients with positive AVAD, the median hydraulic force was 0.25 N (range, 0.17–1.2) at mid‐diastasis and for the 3 HTx patients with negative AVAD, the median hydraulic force was −0.39 N, −0.27 N, and −0.17 N, respectively. The 3 patients with negative AVAD underwent hemodynamic measurements within 2 days of CMR and thus time between CMR and invasive pressure measurements was not the defining factor for these results.

A simplistic computational model for calculating hydraulic force has been added as Data S1.

Exercise Capacity

Results from cardiopulmonary exercise testing were available in all controls, HFrEF, and HTx patients, whereas 2 patients with HFpEF did not undergo cardiopulmonary exercise testing. VO₂peak was within the normal range for all controls, 9 HFrEF (60%), 8 HFpEF (53%), and 11 HTx patients (44%).

Figure 8 shows that there was a strong relationship between THV and VO₂peak in healthy controls (R²=0.67, P<0.001), indicating that ≈70% of the exercise capacity can be explained by THV in healthy hearts. Correspondingly, THV explains ≈20% of VO₂peak in HTx patients (R²=0.21, P<0.05). However, this was not shown for HFrEF (R²=0.13, P=0.19) or HFpEF (R²=0.26, P=0.08).

Figure 8. Relationships between total heart volume (THV) and peak oxygen uptake (VO₂peak).

A, Relationships for all 4 groups. In healthy controls, THV is closely related to peak oxygen uptake, whereas in patients with heart failure there is no relation between THV and VO₂peak. For HTx patients the variations in VO₂peak for a given heart volume are larger, and the relation is weaker. B, Only healthy controls and HTx patients shown for better visualization. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and HTx, heart transplantation.

Intra‐Observer Variability

Mean±SD intra‐observer variability for LA_min was 0±8 mL (0±6%), LA_max 4±6 mL (3±4%), left ventricular end‐diastolic volume −2±2 mL (−1±1%), and left ventricular mass 2±2 g (2±2%).

DISCUSSION

The results of the current study show that the larger left atrium in HTx patients alters the geometric relationship between the atrium and ventricle in a way that impairs diastolic filling. In addition, the disproportionately large atrium in HTx patients increases THV and contributes to the distortion of the close relationship between THV and VO₂peak seen in healthy controls.

Effects of Atrial and Ventricular Geometry on Hydraulic Forces

Maksuti et al ⁵ were first to introduce AVAD as an additional mechanism of diastolic filling to be considered in conjunction with active relaxation, ²⁰ restoring forces generated by elastic energy stored in the myocardium ²¹ , ²² and atrial contraction. Diastolic dysfunction is commonly related to increased filling pressures. ²³ However, just like atrial fibrillation impairs cardiac filling mechanics by affecting the atrial kick, the findings in the current study show that an altered geometrical relationship between the left atrium and ventricle in patients after HTx could constitute the pathophysiological basis for diastolic dysfunction. An altered geometrical relationship between atrium and ventricle could lead to a reversed direction of the net hydraulic force and thus impair filling, irrespective of filling pressures.

Quantification of the hydraulic force in HTx patients showed values corresponding to 25% of the hydraulic force of 1.0±0.2 N previously presented in a healthy population by Maksuti et al. ⁵ Both the previous and the current study measured AVAD at mid‐diastasis, and filling pressures were comparable between the current HTx population (8 mm Hg) and estimated by Maksuti et al to be 10 mm Hg in the healthy population. Thus, it is likely not the filling pressure itself that explains the differences in hydraulic forces between HTx patients in the current study and the previously presented healthy population. Instead, this difference between populations illustrates the importance of the geometrical relationship between atrium and ventricle (the AVAD) in aiding diastolic filling.

The altered geometry and its effects on diastolic filling may shed some light on findings from previous studies showing an unexplained association between increased left atrial volumes and decreased exercise capacity. ²⁴ Changes in AVAD affect diastolic filling and consequently cardiac output and exercise capacity. We therefore suggest that a potential mechanism behind this negative relationship in HTx patients is due to the altered geometrical relationship between the left atrium and ventricle, which in turn is directly related to the surgical technique.

Surgical Technique

The findings in the present study may have significant implications for choice of surgical technique. There was no correlation between left atrial volumes nor AVAD and time from HTx. This suggests that it is the surgical technique itself that affects the geometrical relationship between the atrium and ventricle and thereby diastolic function measured as AVAD. Furthermore, with time the transplanted patient may also develop an increasingly restrictive left ventricle. ²⁵ , ²⁶ , ²⁷ Increased atrial pressure may also lead to a further enlarged atrium, whereas the left ventricle remains unchanged in volume. It may therefore be advantageous to keep the balance between the left atrial volume and ventricle as normal as possible at transplantation.

It can be noted that in contrast to other patient populations, left atrial volume does not correlate to cardiovascular adverse events in HTx patients. ²⁸ , ²⁹ This may partly be explained by the fact that HTx patients undergo electrical isolation of the pulmonary veins (cf maze procedure) and cardiac denervation in conjunction with the transplantation, which have been shown to be protective against cardiovascular events. ³⁰ Although the risk of arrhythmic events associated with increased atrial size may be low, the decreased AVAD showing decreased diastolic filling should be taken into consideration in choice of surgical technique.

Long‐Term Consequences and Follow‐Up

As discussed above, the net hydraulic force in HTx patients in the current study was −0.27 to 1.2 N and has been shown previously to be 1.0±0.2 N in healthy subjects. ⁵ This can be compared with estimated peak driving force during left ventricular rapid filling in healthy subjects of 5 to 10 N. ⁵ Thus, the hydraulic force generated by AVAD represents a vital part of the peak driving force for diastolic filling.

The importance of the geometric relationship between the atrium and ventricle in HTx patients suggests that a smaller left atrium after transplantation would be of great benefit to HTx patients. From a surgical point of view, it can be challenging to further reduce the recipient atrium when performing a bicaval anastomosis, because the size of the donor atrium is usually a limiting factor. However, the results of this study suggest that the use of a technique where the pulmonary veins are anastomosed as a cuff on the right or left side together with the bicaval technique could be beneficial. ³¹ This technique is more time‐consuming and can be technically more challenging, which is why it has not been widely adopted. With current new ex vivo preservation techniques, ³² , ³³ where the impact of ischemia is significantly reduced, this may open up the possibility to improve and evaluate new surgical techniques in HTx, so as to avoid negative effects on diastolic filling. In addition to surgical technique, medications that affect preload or afterload may affect atrial and ventricular volumes and thereby AVAD and the direction of the net hydraulic force. For example, medications lowering heart rate, providing more time for diastolic filling of the ventricle, may be beneficial because it will act both through the Frank‐Starling mechanism and through a larger ventricular area. By increasing ventricular area, AVAD is increased and consequently the net hydraulic force aiding diastolic filling. Thus, optimal surgical technique together with well‐adjusted medication can provide patients with the best conditions for diastolic filling.

Because AVAD can be obtained noninvasively using CMR, this may also be a useful marker to follow HTx patients' cardiac function over time. Indeed, it was recently shown by Soundappan et al ³⁴ in a HFpEF population that a decrease in AVAD, determined from echocardiographic images, is independently associated with poorer survival.

Heart Volume and Exercise Capacity

Total heart volume and VO₂peak are normally closely correlated. ⁷ , ³⁵ , ³⁶ An index of VO₂peak/THV discriminates between healthy hearts and heart failure ⁸ and is a recommended tool for challenging cases such as when differentiating the athlete's heart from pathological dilatation. ⁹ , ¹⁰ Because atrial volume affects THV, we expected the relationship between THV and VO₂peak in HTx patients to be affected; however, the variation in the population was larger than anticipated. There was a large variance in the HTx population for THV at a given VO₂peak and a large variance in VO₂peak at a given THV (Figure 7). The THV is inherently affected by the donor's body size and the surgical technique, whereas the VO₂peak is affected by THV, maximum heart rate, and peripheral factors such as skeletal muscle fiber type, and mitochondrial function. As both central and peripheral factors differ widely in HTx populations, it is not possible to identify a VO₂peak/THV cut‐off value to identify early signs of heart failure in HTx patients.

Limitations

The study population is small and all transplantations were performed using bicaval anastomotic technique performed at Skåne University Hospital Lund, Sweden. Thus, conclusions are drawn on the effect of this surgical technique performed by surgeons at 1 hospital. However, because the direction of the net hydraulic force is determined by the laws of physics, any surgical technique disrupting the geometrical relationship between the left atrial short‐axis are and left ventricular short‐axis area will affect the hydraulic force.

Only 10 of the HTx patients had undergone hemodynamic assessment to obtain PAWP in close conjunction with CMR. A larger sample with both CMR and invasive measurements the same day may be useful to further understand the actual forces at play during diastolic filling after HTx.

CONCLUSIONS

HTx surgery using the standard bicaval technique can lead to a large atrial volume where a negative AVAD contributes to impaired diastolic filling. This increased understanding of the effects of atrial size and AVAD's role in diastolic filling may have future implications for the surgical technique, where the results of the current study suggest that the surgeon should re‐create the left atrium as close to normal size as possible, such as by using bi‐pulmonary vein anastomosis.

Furthermore, the close relationship between THV and VO₂peak seen in healthy subjects is altered in HTx patients due to the large left atrium.

Sources of Funding

This study was funded by Swedish Governmental Funding of Clinical Research (ALF), Swedish Heart‐ and Lung Foundation grants 20220640 and 20220218, Lund University Medical Faculty, and the Foundation in Memory of Ulla Ekdahl.

Disclosures

None.

Supporting information

Data S1