QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension

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Abstract

Background

In rodent models of pulmonary hypertension (PH) and right ventricular hypertrophy (RVH), the QTc interval is prolonged, reflecting downregulation of repolarizing Kv channels in RV myocytes. The significance of QTc prolongation in human PH is unknown. We hypothesized that QTc prolongation occurs in human PH, is associated with RVH and decreased RV function, and predicts adverse prognosis.

Methods

Patients receiving a PAH-specific therapy (a prostanoid, endothelin-receptor antagonist and/or a phosphodiesterase-5 inhibitor), who had a 12-lead electrocardiogram (ECG) (n = 202) were compared to age- and sex-matched controls (n = 100). The duration of QTc on ECG was correlated with invasive hemodynamics (n = 156) and with the status of the RV, as measured by Brain Natriuretic Peptide (NT-proBNP, n = 145) and magnetic resonance imaging (n = 24). Survival of the entire PH cohort and a subgroup with WHO Groups 1 and 4 PAH was prospectively determined from the Social Security Death Index.

Results

QTc intervals were longer in PH vs. controls (454.8 ± 29 ms vs. 429.8 ± 18 ms, p < 0.001) and did not differ based on PAH-specific therapy. NT-proBNP increased proportionately with QTc and was higher for those in the upper quintile (QTc  480 ms) vs. those with QTc < 480 ms (4004 ± 6682 pg/mL vs. 1501 ± 1822 pg/mL, p < 0.001). The QTc interval also correlated directly with increasing RV end-diastolic volume (r = .67, p < 0.001) and mass (r = .0.51, p < 0.05), and inversely with RV ejection fraction (r = −.49, p < 0.05). In the entire PH cohort and WHO Groups 1 and 4 subgroup, QTc  480 ms and cardiac index were independent predictors of mortality.

Conclusions

QTc prolongation in PH patients reflects the status of the RV and is an independent predictor of mortality.

Introduction

Pulmonary arterial hypertension (PAH) has an annual incident mortality rate of 15%, with most deaths occurring due to right ventricular (RV) failure [1], [2], [3]. It is increasingly recognized that prognosis in PAH is best predicted by RV function [4], [5]. Simple screening tests for RV failure and hypertrophy include N-Terminal pro Brain Natriuretic Peptide (NT-proBNP) and echocardiography; however, early detection of RVH is difficult and patients with severe PAH and dyspnea have a mean delay to diagnosis of > 1 year [6]. Although the surface electrocardiogram (ECG) is specific for RVH, its sensitivity is quite low [7], [8]. Recent studies of experimental PAH and RVH demonstrate that there are additional electrophysiologic changes in the RV that might offer insights into the status of the RV, notably prolongation of the duration of the QTc interval on the surface ECG [9].

In rodent models of RVH, whether accompanied by PAH (monocrotaline) or not (pulmonary artery banding), there is prolongation of the RV monophasic action potential duration and the QTc interval on the surface ECG [9]. Mechanistically, this reflects downregulation of repolarizing voltage-gated potassium channels in RV myocytes, including Kv1.5 and Kv4.2 [9]. The QTc prolongation observed in these rodents with RVH was reversed with agents that regressed PAH and RVH, notably the pyruvate dehydrogenase kinase inhibitor, dichloroacetate, and these electrical changes were associated with improved RV function [9].

Few studies have examined whether humans with PAH manifest prolongation of the QTc interval or increased QRS duration and no studies have assessed whether QTc prolongation or increased QRS duration in patients with PAH is associated with indices of RV size and function or predicts clinical outcomes [10], [11].

We thus performed the current study to determine:

  • a)

    whether PAH is associated with QTc prolongation or increased QRS duration.

  • b)

    whether such ECG abnormalities correlate with established indices of RV dysfunction.

  • c)

    whether such ECG abnormalities predict worse clinical outcomes.

Section snippets

Patient selection

The institutional review board at the University of Chicago Medical Center approved the conduct of this study. We initially performed a retrospective chart review of patients diagnosed at the University of Chicago with pulmonary hypertension (PH) between January 2004 and February 2010. The following inclusion criteria were applied:

  • a)

    Presence of PH, defined as a mean pulmonary artery pressure (PAP) ≥ 25 mm Hg and an elevated pulmonary vascular resistance (PVR), measured during cardiac

Results

Patient demographic, electrocardiographic, clinical, laboratory, and invasive hemodynamic data can be seen in Table 1. There was no difference in age (54 ± 14 years vs. 52 ± 15 years, p = 0.48) or sex (79% female vs. 74% female, p = 0.31) between PH subjects and controls, reflecting the effective case matching. However, subjects with PH had a significantly longer QTc interval (454.8 ± 29 ms vs. 429.8 ± 18 ms, p < 0.001) and QRS duration (96.5 ± 16 ms vs. 84.4 ± 8 ms, p < 0.001), as compared to controls (Fig. 1A–B).

Given

Discussion

In the present study, we found that both the QTc interval and QRS duration are prolonged in patients with PH. Moreover, increasing QTc predicts increasing NT-pro BNP levels, suggesting a dose–effect of QTc on an important biomarker of RV function (Fig. 3). Also, both prolonged QTc interval and increased QRS duration are associated with accepted indices of RV dysfunction in PH, including increased RV mass and depressed systolic function, as measured by CMR. Finally, a severely prolonged QTc

Limitations

The present study is not without limitations. First, this was a retrospective cohort study and is thus subject to potential selection and information bias. However, we prospectively followed the patients in our PH cohort for clinical outcomes which may minimize biases. Second, the PAH-specific treatments were not randomly or prospectively assigned but rather prescribed at the discretion of the PH specialist; thus, we cannot assess the effects (beneficial or deleterious) on the QTc interval.

Conclusions

In conclusion, both QTc interval and QRS duration are prolonged in patients with PH and this reflects the status of the RV. We show for the first time that a QTc interval ≥ 480 ms is an independent predictor of worse clinical outcomes. If confirmed by others, the present work identifies an inexpensive and readily detectable abnormality on the surface ECG that can be potentially used to risk stratify PH patients. Whether effective treatment of the underlying PH would shorten the QTc interval and

Acknowledgments

This work is supported by the National Institute of Health [NIH-RO1-HL071115, 1RC1HL099462-01, UL1RR024999]; the American Heart Association (AHA); and the Roche Foundation for Anemia Research. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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