QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension
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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2019, Journal of ElectrocardiologyCitation Excerpt :Thus, RVH may serve as a marker of severity of the LV dysfunction or HF, or it may directly contribute to the development of HF due to impaired RV filling [2]. Finally, a dilated hypertrophied RV may act as a substrate for malignant arrhythmias [27,28]. ECG pattern resulting from RVH is variable and depends on intrinsic and extrinsic factors such as the hemodynamic pattern of RV load, severity of LVH, coexistence of branch block, heart rotation and changes in lung volumes altering diaphragm position [29].