Kussmaul’s Sign in Pulmonary Hypertension Corresponds with Severe Pulmonary Vascular Pathology rather than Right Ventricular Diastolic Dysfunction

Kussmaul’s sign is the paradoxical rise in right atrial pressure (RAP) during inspiration. Normally, RAP declines with inspiration, despite increased venous return, thought due to right ventricular (RV) compliance. Kussmaul’s sign is observed in cases of reduced RV compliance such as constrictive pericarditis, restrictive cardiomyopathy, and heart failure. In pulmonary hypertension (PH), Kussmaul’s sign is also thought due to RV diastolic dysfunction¹. However, heart failure patients with Kussmaul’s sign (K+) have higher pulmonary vascular resistance (PVR) and, interestingly, increased RV failure and mortality post-heart transplant, even after excision of the native RV². If Kussmaul physiology were specifically due to RV non-compliance, a pre-transplant Kussmaul’s should not necessarily predict post-transplant outcomes. These findings suggest a potential role for pulmonary vascular disease, independent of RV dysfunction, in the development of Kussmaul physiology. Therefore, we sought to investigate whether Kussmaul’s sign in PH patients is associated primarily with pulmonary vascular or RV diastolic pathology.

We prospectively assessed 26 PH subjects referred for right heart catheterization (RHC) at our center from 2012–2015. The protocol was approved by the Hopkins Institutional Review Board and informed consent obtained for all. Data available upon reasonable request. The full protocol is previously described³. Briefly, subjects underwent cardiac magnetic resonance imaging, resting and supine bicycle exercise RHC, and concomitant RV pressure-volume (PV) loop measurements (CD-Leycom,Netherlands). Kussmaul’s sign was prospectively defined in this study as a clear inspiratory increase in mean RAP tracing during resting RHC. Data presented as mean±SD unless otherwise specified. Comparisons made using Student’s t-tests in StataSE-15 (StataCorp,TX,USA); graphs created using Prism (GraphPad,CA,USA). P-value <0.05 considered significant.

Of the 26 study subjects, 21 had World Health Organization (WHO) Group-1 pulmonary arterial hypertension (PAH), with 10/21 associated with connective tissue disease, while 5 had secondary PH (WHO Group-3, n=3; Group-2, n=2). Mean age was 55.6±12.7 years and 22/26 (85%) were female. K+ was present in 12/26 (46%) subjects. Kussmaul positive and negative groups were similar with respect to age (54.9±13.5 vs. 56.2±12.5 years), female sex (83% vs. 86%), and proportion of PAH (79% vs. 75%). Group-2 and 3 PH were evenly represented as well.

Comparing resting hemodynamics, K+ subjects had lower PA compliance (PAC) and cardiac output (CO). Resting pulmonary vascular resistance (PVR) and effective arterial elastance (Ea) were higher, but these differences did not meet statistical significance. RV-PA coupling was reduced, but not statistically so (Ees/Ea 0.72±0.48 vs. 1.00±0.51; p=0.16). RV end-systolic elastance (Ees) was similar (0.71±0.42 vs. 0.74±0.47 mmHg/ml; p=0.88), as were mean PA and wedge pressure. Exercise unmasked disproportionate pulmonary vascular pathology in K+ subjects. Specifically, at peak exercise they had significantly higher PVR, higher Ea, lower CO, and lower CO reserve; ventilatory efficiency (Ve/VCO₂) was also worse (Figure).

Pulmonary hypertension (PH) patients with a positive Kussmaul’s sign (measured during right heart catheterization) have disproportionately elevated pulmonary vascular resistance (PVR), effective arterial elastance (Ea), reduced peak cardiac output (CO), exercise CO reserve, and ventilatory efficiency (Ve/VCO₂) when compared to those without Kussmaul’s sign. These differences are particularly manifest at peak exercise. On the other hand, measures of right ventricular (RV) diastolic dysfunction were similar between Kussmaul groups, both at rest and peak exercise. mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; RVEDP, RV end-diastolic pressure; RVEDV, RV end-diastolic volume; τ_suga, diastolic relaxation time constant; dP/dt_min, maximal rate of RV isovolumic relaxation; β-coefficient, stiffness coefficient of end-diastolic pressure-volume relationship; RVEF, RV ejection fraction; RA, right atrial; RAP, right atrial pressure. Data graphically depicted as mean±SEM * denotes p<0.05.

On the other hand, no differences in RV diastology were detected between Kussmaul groups (Figure). There were no resting nor peak differences with respect to RA physiology, RV end-diastolic pressure (RVEDP) and volume (RVEDV), and RV ejection fraction (RVEF) (Figure). PV measures of RV lusitropy, namely the relaxation time constant (τ_suga), β-coefficient of stiffness⁴, and maximum rate of isovolumetric relaxation (dP/dt_min), were also similar. Lastly, all comparisons remained unchanged in a PAH-subgroup sensitivity analysis.

Signs of RV dysfunction are paramount in the assessment of PH, and Kussmaul’s sign is used as one such marker¹. This is based on classical understanding of Kussmaul physiology as a manifestation of RV stiffness leading to poor preload accommodation⁴. However, Nadir and colleagues found in a prospective study of 90 advanced cardiomyopathy patients that K+ patients, when compared to those without, had higher resting PVR, lower CO, and, intriguingly, increased risk of post-transplant RV failure and mortality². The present study finds that severe pulmonary vascular pathology in PH leads to severely elevated exercise PVR, RV afterload, and reduced CO reserve, which is sufficient to elicit Kussmaul physiology. Our findings suggest a plausible mechanism for the observations of Nadir and colleagues². Moreover, this is the first report to our knowledge that shows Kussmaul’s in PH corresponds more strongly with severe pulmonary vascular disease than RV diastolic dysfunction.

We also show that Kussmaul’s sign is associated with significantly increased Ve/VCO₂. Ventilatory efficiency is known to be particularly abnormal in pre-capillary PH and was recently shown to correlate well with RV afterload (indexed by Ea)⁵. Together, these insights suggest Kussmaul’s may serve as a useful sign of RV afterload and ventilatory inefficiency in PH.

Poor RV compliance is certainly sufficient to result in Kussmaul physiology¹. However, the present study argues that severe pulmonary vascular pathology, independent of RV diastolic dysfunction, is also sufficient to elicit Kussmaul’s by way of reducing pulmonary vascular reserve. As a corollary, these results argue that normal venous return depends upon interrelated and adequate compliance of both the RV and pulmonary vasculature. Future studies will hopefully further explore the mechanism and clinical utility of Kussmaul’s sign in PH.