Participants

Individuals (n = 321) in a PH registry were reviewed for consideration of being approached for the study based on inclusion/exclusion criteria, and availability of individuals for frequent study visits and calls over 6 months. Thirty patients were consented and randomized, 10 in each study group (Figure 1). Baseline characteristics are summarized in Table 1 and detailed PAH-specific therapy in Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.95240DS1 Participants assigned to the dose-escalating carvedilol group were randomly older compared with the placebo group and the low-fixed-dose group (age [years]: dose-escalating group 53 ± 9; placebo group 38 ± 14; low-fixed-dose group 42 ± 6; P = 0.006) (Table 1). A cohort of 12 healthy controls was enrolled in parallel for baseline comparison with the PH subjects. Baseline characteristics are shown in Table 1. Controls had similar age, height, gender, and race distribution as PH participants (Supplemental Table 2). Controls had lower weight compared with the PH participants (P = 0.002). As expected, the PH group had worse right atrial and ventricular functions as determined by echocardiography and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) as compared with healthy controls (Supplemental Table 2). The PH group had higher heart rates, supportive of catecholamine overload. PH individuals also had higher glucose uptake as measured by 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the right ventricle (23–25). These findings are in support of the well-recognized RV dysfunction and glycolytic shift with pathologic activation of hypoxia pathways in PH (23, 24, 26–29).

Table 1 Demographics and baseline characteristics

Outcomes

Safety and tolerability of carvedilol. All 30 participants tolerated the 1-week run-in low-dose carvedilol with no significant changes in heart rate (baseline, 78 ± 7; 1-week, 77 ± 8; P = 0.3) and a slight decrease in systolic blood pressure (baseline, 119 ± 17; 1-week, 112 ± 13; P = 0.003). Of the 30 enrolled participants, 29 completed the 6-month study. One participant exited the study at 4 months because of pregnancy. Five participants had dose de-escalation: 4 were in the dose-escalating carvedilol group (final dose 12.5 mg [n = 3] and 3.125 mg [n = 1]) and 1 in the low-fixed-dose carvedilol group (final dose 0 mg). Two participants stopped taking the study drug before their last visit (2 months and 3 months prior to last study visit); 1 in the placebo group and 1 in the carvedilol dose-escalating group. Fifteen adverse events were identified and reported to the IRB (Supplemental Table 3). Thus, although some participants required dose de-escalation due to minor adverse effects, carvedilol was safe and well tolerated throughout the study in all participants.

NT-proBNP levels were similar among the 3 groups at all study visits (P > 0.1) and did not change significantly over the time of the study in any of the study groups. This indicates that carvedilol therapy did not worsen heart failure.

Effects of carvedilol on heart rate, blood pressure, oxygen saturation, and temperature

Heart rate decreased with carvedilol therapy (Table 2). Even after adjusting for age, the dose-escalating carvedilol group tended to have lower heart rates than the placebo group at the 1-month and 3-month visits (P = 0.05 and 0.07, respectively). Heart rate correlated strongly with pill dosage (mg carvedilol) at the 1-month and 3-month visits (R = –0.5, P = 0.006 and R = –0.4, P = 0.04, respectively).

Table 2 Differences in clinical outcomes measured among the 3 study groups at baseline, 1-month, 3-month, and 6-month visits

Systolic blood pressure tended to drop in the dose-escalating group at both the 1-month and 3-month visits (systolic blood pressure [mmHg]: baseline 122 ± 17; 1-month visit 114 ± 16 [P = 0.04]; 3-month visit 112 ± 19 [P = 0.08]). Diastolic blood pressure dropped at the 1-week and 3-month visits compared with baseline in the low-fixed-dose group (diastolic blood pressure [mmHg]: baseline 81 ± 12; 1-week visit 71 ± 11 [P = 0.05]; 3-month visit 73 ± 15 [P = 0.03]).

Oxygen saturation did not vary over the course of the study among the different groups or within each individual study group (all P > 0.1). There were no differences in temperature among the 3 study groups at baseline or at any of the study visits. Temperature did not change significantly within any of the study groups over time (all P > 0.1). Similarly, weight did not vary over the course of the study among the different groups or within each individual study group (all P > 0.1). The drops in heart rate and blood pressure with carvedilol therapy were well tolerated and did not lead to dose de-escalation.

Pulmonary function during carvedilol therapy

Spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured at initial visit and at 3 and 6 months after randomization. Lung functions were similar among the groups at all visits (Table 3). However, within all study groups, airflow (forced expiratory volume during first second [FEV 1 ]) decreased at the 3-month visit (change in FEV 1 compared with baseline [L] at 3 months: placebo group –0.08 ± 0.1; P = 0.02; low-fixed-dose group –0.09 ± 0.14; P = 0.06; dose-escalating group –0.17 ± 0.14; P = 0.005). FEV 1 % was 5% lower than baseline in the dose-escalating group at 3 months (P = 0.002). FEV 1 and FEV 1 % decreased at the 6-month visit only in the low-dose group (change in FEV 1 [L]: –0.17 ± 0.16; P = 0.009 and 3% drop in FEV 1 %: 5 ± 5; P = 0.01). Forced vital capacity (FVC) was not different among the 3 study groups over the different visits (all P > 0.1). FVC and FVC% dropped slightly at the 3-month visit in the dose-escalating group (P < 0.001). At the 6-month visit, FVC and FVC% decreased in the low-dose group (P = 0.03). The FEV 1 /FVC ratio did not vary within the study groups over time (all P > 0.1). DLCO and DLCO corrected for alveolar volume (DLCO/VA) were similar among the 3 study groups at all visits (all P > 0.1) (Table 3). Altogether, these findings show that carvedilol therapy did not substantially affect lung functions over a 6-month time period in PAH individuals. Clinical signs of airflow deterioration were not observed. The small but significant decreases in FVC and FEV 1 did not require dose adjustment.

Table 3 Lung functions over course of PAHTCH

Six-minute walk test and heart rate recovery with carvedilol therapy

One of the main reasons for the relative contraindication of β-blockade in PAH is an observed decrease in functional capacity, such as 6-minute walk distance, with its use. Here, 6-minute walk was performed at baseline, after the 1-week run-in visit, and at the 3-month and 6-month visits. There were no significant differences in the distance walked among the 3 groups at any visit (all P > 0.1). The changes in the distance walked over time were not different among the study groups, and there were no significant changes in distance walked within any of the groups (all P > 0.1) (Table 2). Oxygen saturation during the walk was similar among the groups at all visits without significant changes within the groups (all P > 0.1) (Table 2).

On the other hand, heart rates at peak exercise (6 minute) and 1 minute after exercise were lower in the carvedilol dose-escalating group. Heart rate at rest was lower in the dose-escalating carvedilol group at the 3-month and 6-month visits (Figure 2). After 3 months of carvedilol, the maximal heart rate at the end of the 6-minute walk was lower in the dose-escalating group (heart rate at 6-minute walk [beats/min]: baseline 122 ± 13; 3-month visit 105 ± 17; P = 0.008) (Table 2). Heart rate at 1 minute after the walk was lower in the dose-escalating group at the 3-month and 6-month visits (heart rate at 1 minute after walk [beats/min]: baseline 100 ± 17; 3-month visit 78 ± 13; P = 0.002; 6-month visit 82 16; P = 0.02) (Table 2). The change in heart rate at 1 minute after walk correlated with carvedilol dose at the 3-month visit (R = –0.4, P = 0.03).

Figure 2 Heart rate reduction with dose-escalation carvedilol therapy. Carvedilol therapy reduced heart rate over the 6-month period in the dose-escalating group (n = 10 at each time point). The effect was more pronounced at rest and during recovery at 1 minute after a 6-minute walk test. The drop in heart rate was not accompanied by a worsening of functional capacity as measured by 6-minute walk distance (not shown in figure). Horizontal lines represent the mean. The gray lines represent control heart rate mean and SEM. Paired t test with Bonferroni-adjusted significance level 0.025 used to adjust for comparisons to each of 3 and 6 months.

Heart rate recovery was faster in the low-fixed-dose compared with the placebo group at the 3-month visit (heart rate recovery [beats/min]: placebo group 12 ± 23; low-fixed-dose group 36 ± 19; dose-escalating group 27 ± 15; P = 0.03). This difference remained significant after adjusting for age (P = 0.01). Heart rate recovery tended to be faster in the dose-escalating carvedilol group at the 6-month visit compared with baseline (heart rate recovery [beats/min]: baseline 22 ± 16; 6-month visit 30 ± 11; P = 0.06). Overall, carvedilol therapy reduced heart rate at rest and at 1-minute postwalk recovery more than at peak exercise. The reduction in heart rate did not affect exercise capacity as measured by 6-minute walk distance.

Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)

The CAMPHOR questionnaire is a PH-specific measure and is made up of 3 main scales that assess symptoms, functioning, and quality of life (30, 31). The symptom dimension is made up of 25 symptoms divided into 3 subscales: energy, breathlessness, and mood. The activity scale has 15 items. The quality-of-life scale has 25 items, with focus on socialization, role, acceptance, self-esteem, independence, and security. Scores for quality of life and symptoms range from 0–25, with higher scores indicating worse quality of life. Activity scores range from 0–30, with higher scores indicating greater physical limitation. CAMPHOR was completed at baseline, after the 1-week run-in, 3-month, and 6-month visits. There were no significant differences in the scores among the groups at any visit. There was a small but significant drop in CAMPHOR score in the low-fixed-dose and placebo groups at the 6-month visit (both P = 0.04). Thus, carvedilol therapy did not adversely affect CAMPHOR scores over a 6-month time period in PH individuals.

Echocardiographic assessment of cardiovascular function

Echocardiography was performed at baseline and at the 3-month and 6-month visits. The LV parameters, including LV end-diastolic diameter, LV end-systolic diameter, and LV ejection fraction, were similar among the study groups and did not vary over time (Table 4). Left atrial area was greater in the dose-escalating group compared with other groups at the 3-month and 6-month visits but did not significantly change within any of the groups over the course of the study (Table 4). Right atrial pressure did not change within groups over the time of the study. Other parameters of RV function and size, including RV end-diastolic diameter and RV end-systolic diameter, RV Tei, and tricuspid annular plane systolic excursion (TAPSE), did not change significantly over the time of the study within groups. However, RV systolic pressure (RVSP) at the 3-month visit tended to be higher in the placebo group as compared with carvedilol groups (RVSP [mmHg]: placebo group 78 ± 21; P = 0.02; low-fixed-dose group 59 ± 18; P = 0.06; dose-escalating group 54 ± 24; P = 0.05) (Table 4). RVSP inversely correlated with carvedilol pill dose at 3 months (R = –0.4; P = 0.01). RV fractional area change (RVFAC) was higher at the 3-month visit in the dose-escalating group and the low-fixed-dose group compared with placebo (Table 4). RV global strain was not different among the study groups (Table 4). Stroke volume tended to increase at the 3-month and 6-month visits compared with baseline in the dose-escalating group (change in stroke volume compared with baseline: 3-month visit 13 ± 16; P = 0.03 and 6-month visit 12 ± 19; P = 0.08) (Table 4). Cardiac output (LV CO) was not different among the 3 study groups at any visit and did not vary significantly within any of the study groups over the course of the study (all P > 0.1) (Table 4). Altogether, carvedilol therapy was not associated with deterioration in cardiac parameters measured by echocardiography. In fact, RV function improved in the dose-escalating group in parallel with an increase in LV stroke volume. These changes could be a reflection of carvedilol direct effect on the RV or on afterload reduction or even a compensatory mechanism to maintain CO in the face of a reduction in heart rate.

Table 4 Differences in echocardiographic measurements among the three study groups at baseline, 3-month, and 6-month visits

Assessment of hypoxia signaling: cardiac glucose uptake by PET scan and erythropoietin level

Erythropoietin was measured at baseline and 1-month, 3-month, and 6-month visits. Erythropoietin levels were similar among the PH study groups and did not vary over the time of the study (all P > 0.1).

FDG-PET scan was performed at baseline and at the 6-month visit. LV, RV, and septum FDG uptake were measured as maximal standardized uptake values (SUVs) in the LV and RV free walls and septal wall in images acquired 90 minutes after injection in the fasting state. The LV FDG uptakes were similar among study groups and did not change over the course of the study. The RV/LV FDG-uptake ratio was used to assess relative differences in RV FDG uptake among groups and among individuals over time. RV/LV FDG uptake was not different among the groups at baseline or at the 6-month follow up visit (both P > 0.1). However, RV/LV FDG uptake decreased in the dose-escalating carvedilol group at the 6-month visit (RV/LV FDG uptake median [25%, 75%]: baseline 0.9 (0.5, 1.5), 6-month visit 0.7 (0.4, 1.0); log-transformed values: baseline –0.2 (–1.0, 0.6), 6-month visit –0.5 (–1.2, –0.08); paired t test P = 0.04) (Figure 3 and Table 5). RV/LV FDG uptake correlated with heart rate at 1 minute after the 6-minute walk (R = 0.4; P = 0.03) and with RVSP (R = 0.5; P = 0.002) at 6-month visit (Figure 4). The baseline RV/LV FDG uptake correlated to echocardiographic measurements at baseline as recently published (24). The relationship of FDG uptake with heart rate, a correlate of the β-blocker efficaciousness, suggests the decrease in glucose uptake is related to carvedilol therapy. Overall, carvedilol therapy over a 6-month period led to reduced RV/LV uptake of glucose, suggesting that carvedilol improved RV function.

Figure 3 Right ventricle (RV) uptake of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) relative to left ventricle (LV) with dose-escalating carvedilol. Individuals treated with dose-escalating carvedilol had a reduction in RV FDG uptake as measured by the ratio of RV to LV standardized uptake values (RV/LV SUV). n = 10 at each time point; paired t-test analysis using log-transformed values. Horizontal lines represent means. Values of SUV are shown plotted on a logarithmic y axis.

Figure 4 Association of RV/LV glucose uptake to heart rate and RV systolic pressure (RVSP). The ratio of right ventricular to left ventricular FDG-uptake (RV/LV SUV) was associated with heart rate at 1-minute recovery after a 6-minute walk, and RVSP. Pearson correlations are based on values at the 6-month visit and include all participants (n = 30).

Table 5 Differences in biological outcomes measured among the 3 study groups at baseline, 1-month, 3-month, and 6-month visits

βAR expression

Flow cytometry with alprenolol binding was used to quantify βAR density on circulating white blood cells. βAR density was similar among groups at baseline and 6 months (Table 5). However, the change in βAR density relative to baseline was dose-dependently related to the carvedilol dose (0 mg, –0.11 ± 0.26; 3.125 mg, 0.004 ± 0.237; 12.5 mg, 0.025 ± 0.198; 25 mg, 0.110 ± 0.250; R = 0.3; P = 0.02) (Figure 5). The greatest increase in βAR density was found in those individuals on the highest dose of carvedilol (P = 0.02).

Figure 5 Carvedilol therapy recovers β-adrenergic receptor density as determined by alprenolol binding. Carvedilol dose was correlated with an increase in β-adrenergic receptor density relative to baseline levels (Pearson P = 0.02; n = 53).

Urinary cAMP

βAR activation in cardiac muscles is associated with increased cAMP as downstream signaling. Urinary cAMP/creatinine is a measure of βAR function (32), and was used to assess βAR recovery with carvedilol. Urinary cAMP/creatinine was highest in the placebo group at baseline but did not change over time in the placebo group (Table 5). In contrast, urinary cAMP/creatinine tended to increase in the low-fixed-dose carvedilol group (P = 0.07) and the dose-escalating carvedilol group over time (P = 0.04) (Figure 6).

Figure 6 Carvedilol therapy recovers β-adrenergic receptor function as determined by change in urinary cAMP/creatinine. Carvedilol treated groups had a tendency to increase urinary cAMP/creatinine relative to baseline, though not statistically significant when corrected for multiple comparisons (*P = 0.07 for the low-fixed-dose carvedilol group, and *P = 0.04 for the dose-escalating carvedilol group; Bonferroni-adjusted significance level required P < 0.017; n = 10 in each group at each time point).

Carvedilol effects compared with placebo based on heart rate

To further evaluate the effect of carvedilol, all participants receiving carvedilol, either low-fixed-dose or dose-escalating, were compared with those participants receiving placebo. At 3-month visit, heart rate at rest was lower in the carvedilol group compared with placebo (heart rate [beats/min]: placebo group 78 ± 10, carvedilol group 70 ± 10; P = 0.04). Heart rate at the end of walk at 6 minutes was similar among the 2 groups (P = 0.3), but heart rate at 1 minute after walk decreased at the 3-month visit in the treatment group (heart rate 1 minute after walk: baseline 98 ± 16, 3-month visit 83 ± 12; P < 0.001), but not in the placebo group (heart rate 1 minute after walk: baseline 97 ± 14, 3-month visit 91 ± 22; P = 0.2). Heart rate recovery was fastest in the carvedilol group at the 3-month visit (P = 0.05) and significantly faster than in the placebo group (heart rate recovery [beats/min]: carvedilol group 32 ± 17, placebo group 12 ± 22; P = 0.01). At the 6-month visit, heart rate differences could not be appreciated (all P > 0.1).

Next, to adjust for dose de-escalation, variable adherence, and/or drop out, heart rate at rest was used as a physiologic surrogate of carvedilol effect among the population at 6 months. Heart rate correlated with parameters of right heart dysfunction by echocardiography, including with RVSP (R = 0.5; P < 0.001) and inversely with RVFAC (R = 0.5; P < 0.001). Heart rate correlated with cardiac RV/LV FDG uptake (R = 0.4; P = 0.002). These findings suggest that higher heart rates are associated with disease severity and dosing of carvedilol to achieve heart rate reductions may be of benefit to PAH. However, as the increased heart rate in this population is presumably a compensation for reduced stroke volume, introducing carvedilol should be performed under close observation to monitor for any decompensation.

Changes in heart rate and RV metabolism excluding non–group 1 PAH

The study cohort included 4 non–group 1 PH patients. To evaluate if non–group 1 PAH patient data influenced the findings, the data were also analyzed after excluding the 4 non–group 1 subjects. Similar to the entire cohort, dose-escalating carvedilol therapy decreased heart rate at rest (P = 0.007) and 1 minute after recovery (P = 0.01) without affecting heart rate at the end of the walk at 6 minutes (P = 0.1). Similarly, RV glucose uptake decreased in the dose-escalating group 1 patients at 6-month visit compared with baseline (RV/LV FDG uptake median [25%, 75%]: baseline 0.9 [0.5, 1.5], 6-month visit 0.7 [0.4, 1.0]; log-transformed values: baseline –0.2 [–1.0, 0.6], 6-month visit –0.5 [–1.2, –0.08]; paired t test P = 0.01). There were no significant changes in NT-proBNP or 6-minute walk distance over the time of the study in group 1 PAH patients participating in any of the study arms (all P > 0.05).

The findings support the effect of carvedilol on cardiac metabolism and heart rate in RV dysfunction regardless of the PH group.