1. Would you please summarize your findings for our readers.
   
   Although it is clear that patients with combined post- and pre-capillary pulmonary hypertension (CpcPH) due to left heart disease (PH-LHD) have worse prognosis compared with isolated post-capillary, how to best hemodynamically distinguish these two groups remains controversial. The diastolic pulmonary gradient (DPG), defined as diastolic pulmonary artery pressure (dPAP) minus pulmonary artery wedge pressure (PAWP)) may be less affected by left heart failure-induced changes in vascular compliance than the transpulmonary gradient (TPG). Based on this rationale and a study that showed an elevated DPG (≥ 7mmHg) in setting of an elevated TPG (≥ 12 mmHg) was associated with a worse prognosis than a low DPG and elevated TPG¹, the Fifth World Symposium on Pulmonary Hypertension proposed that a DPG ≥ 7 mmHg alone should define CpcPH². We studied a cohort of 1236 patients evaluated at Johns Hopkins Hospital for unexplained cardiomyopathy with a right heart catheterization and endomyocardial biopsy (467 had PH-LHD) to assess the ability of DPG to predict mortality (median follow up 4.4 years). Although both an elevated TPG and pulmonary vasculature resistance (PVR) predicted mortality, DPG failed to do so. It also failed to further risk stratify patients with an elevated TPG or PVR in our cohort. In fact, high DPG in the setting of an elevated PVR had an inverse relation with mortality, most likely identifying a sicker population with higher PCWP and more severe left heart failure.


2. As you know, diastolic pressure gradient has been proposed in the Nice documents as part of new terminology for PH due to left heart disease. You have found that the DPG does not predict mortality in PH from left heart disease. Is it still a useful marker or should we readdress whether or not to use it to distinguish '"isolated post-capillary PH" from "post-capillary PH with a pre-capillary component," as suggested by the Nice meeting?
   
   Although DPG has limited prognostic value, this does not necessarily preclude the possibility that it may be diagnostically useful to identify patients with true pulmonary vascular disease. However, several factors warrant further consideration. First, dPAP when measured with fluid-filled catheters may be particularly prone to measurement error. Given the low absolute value of DPG, even minor inaccuracies in dPAP, or in the PAWP measurement, can have a significant effect on DPG. These factors likely account for the negative values observed in our study and others (30.2% of all patients and 36% of patients with PH-LHD)³. Finally, the DPG is known to be heart rate dependent⁴ and may also be affected by other factors including hypoxemia, acidosis, and positive pressure ventilation^5-7. The heart rate dependence of DPG suggests the parameter will be misleading in acute heart failure. While those with a markedly elevated DPG (15 to 20mmHg) may have clear pulmonary vascular disease, these patients are quite rare in HF and are also likely to have a significantly elevated TPG and PVR (similar to pulmonary arterial hypertension). In this group, the diagnosis of pulmonary vascular disease is not in doubt. In the more borderline patient with a DPG of 4-12mmHg, where many with a 'pre-capillary component' will fall, the lack of precision of the DPG may result in significant misclassification if used alone. We believe this imprecision, coupled with the heart rate dependence of DPG, will likely limit its diagnostic value. Therefore, when defining a 'precapillary component,' if DPG is used, it should only be considered in conjunction with an elevated PVR and TPG and after careful evaluation of the limitations discussed above.


3. If DPG does not predict mortality in Group 2 PH, then what do you suggest we should use to risk stratify these patients?
   
   Right ventricular (RV) function is a well-established predictor of prognosis in patients with heart failure⁸. Since DPG only accounts for a small percentage of RV load, it does not necessarily correlate with significant RV dysfunction. PVR which includes flow assessment, is a better predictor of mortality in individuals with PH-LHD, but may also incompletely describe total RV load. Pulmonary artery compliance (PAC, defined as stroke volume divided by [systolic PAP (sPAP) minus dPAP]) is a more robust measure of total RV load, reflecting both resistive and pulsatile components. It has inversely correlated with mortality in several recent studies of left heart failure patients^9-11, even in those patients with normal PVR. RV effective arterial elastance (Ea), defined in PH patients as sPAP divided by stroke volume – is another lumped parameter of total RV load and may have prognostic value¹².

References

1. Gerges C, Gerges M, Lang MB et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in "out-of-proportion" pulmonary hypertension. Chest 2013;143:758-66.
2. Vachiery JL, Adir Y, Barbera JA et al. Pulmonary hypertension due to left heart diseases. Journal of the Am J Cardiol 2013;62:D100-8.
3. Harvey RM, Enson Y, Ferrer MI. A reconsideration of the origins of pulmonary hypertension. Chest 1971;59:82-94.
4. Enson Y, Wood JA, Mantaras NB, Harvey RM. The influence of heart rate on pulmonary arterial-left ventricular pressure relationships at end-diastole. Circulation 1977;56:533-9.
5. Zapol WM, Snider MT. Pulmonary hypertension in severe acute respiratory failure. N Engl J Med 1977;296:476-80.
6. Marland AM, Glauser FL. Significance of the pulmonary artery diastolic-pulmonary wedge pressure gradient in sepsis. Critical care medicine 1982;10:658-61.
7. Wrobel JP, Thompson BR, Stuart-Andrews CR et al. Intermittent positive pressure ventilation increases diastolic pulmonary arterial pressure in advanced COPD. Heart & lung : the journal of critical care 2015;44:50-6.
8. Ghio S, Gavazzi A, Campana C et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. Journal of the Am J Cardiol 2001;37:183-8.
9. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart failure 2013;1:290-9.
10. Dupont M, Mullens W, Skouri HN et al. Prognostic role of pulmonary arterial capacitance in advanced heart failure. Circulation Heart failure 2012;5:778-85.
11. Pellegrini P, Rossi A, Pasotti M et al. Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure. Chest 2014;145:1064-70.
12. Tampakakis E, Kelemen BW, Shpigel A et al. Right ventricular effective arterial elastance is a novel predictor of mortality in pulmonary hypertension due to left heart disease. AHA Scientific Sessions 2014, Abstract 16651

Keywords: Acidosis, Biopsy, Blood Pressure, Capillaries, Cardiac Catheterization, Cardiomyopathies, Follow-Up Studies, Heart Failure, Heart Rate, Humans, Hypertension, Hypertension, Pulmonary, Positive-Pressure Respiration, Prognosis, Pulmonary Artery, Pulmonary Wedge Pressure, Stroke Volume, Systole, Vascular Diseases, Ventricular Dysfunction, Right

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