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New Definition for Pulmonary Hypertension in Left Heart Disease: Haunted by how we measure the wedge?
“I know that character exists from the outside alone. I know that inside the body there’s just temperature.”
Background: DPG versus PVR
In 1971, the use of the pulmonary artery diastolic pressure gradient [DPG] was introduced to better refine the hemodynamic definition of pulmonary vascular disease. What is the DPG? Theoretically, why would the DPG be superior to the calculated pulmonary vascular resistance [cPVR] for evaluating the resistance to flow in the pulmonary circulation? What does this have to do with the most recent  World Symposium on Pulmonary Hypertension [WSPH] recommendations for diagnosing pulmonary hypertension in left heart disease [PH-LHD]?
In 2013 the DPG was revitalized in an intensely influential paper by Naeije et al; the DPG is the difference between the diastolic pulmonary artery pressure and the pulmonary artery occlusion pressure [often referred to as the ‘wedge pressure’]. The elegant reasoning put forth in that manuscript molded my previous musings on the DPG’s basic physiology and its application [or lack thereof] in clinical trials like SIOVAC. Simply, the cPVR may rise in response to increased left atrial filling pressure; this gives the appearance that there is increased resistance in the pulmonary vascular tree – when there may be none. The ostensible concern is that a ‘false positive’ cPVR elevation may entice clinicians to give therapies that specifically decrease pulmonary vascular resistance.
Importantly, the DPG was initially found to accurately prognosticate mortality in patients with pulmonary hypertension related to left heart disease [PH-LHD] and this inspired updates in the 2013 WSPH to include two subcategories of PH-LHD – ‘isolated post-capillary pulmonary hypertension’ [Ipc-PH] as well as ‘combined pre-and-post capillary pulmonary hypertension’ [Cpc-PH]. Originally, the differentiation between these two subtypes of PH-LHD was based on the value of the DPG; if the DPG was 6 mmHg or less, then the patient was categorized as having mere passive congestion [i.e. Ipc-PH] whereas if the DPG was abnormally elevated [i.e. 7 mmHg or more], then this was considered evidence of truly increased pre-capillary resistance. The European Respiratory Society, however, included an elevated cPVR as a part of the definition.
Updated Hemodynamic Definition: prognosis preempts physiology
Since the 5th WSPH in 2013, the ability of the DPG alone to prognosticate outcome in PH-LHD has been mixed; handfuls of studies have and have not borne out the initial predictive power of the DPG. Importantly, there has not necessarily been refutation of the physiology or the mechanisms underpinning the DPG – rather, the DPG simply hasn’t been as promising at predicting the future.
Indeed, there have been a good number of investigations demonstrating that the DPG does, in fact, reflect pre-capillary resistance. For example, patients with PH-LHD and abnormally high pre-capillary resistance [i.e. Cpc-PH, defined as a DPG of at least 7 mmHg] had the same physiological response as patients with true pulmonary arterial hypertension to a standardized fluid bolus, while those with isolated post-capillary pulmonary hypertension [i.e. Ipc-PH; DPG of 6 mmHg or less] demonstrated worsening pulmonary compliance in response to the fluid challenge – consistent with rising passive venous congestion. Interestingly, in that study, if the DPG cut-off of 7 mmHg was used as the ‘gold standard’ for diagnosing increased pulmonary vascular resistance, then a cPVR above 3 Wood Units had a 32% false positive rate [i.e. those with a normal/low DPG, but high cPVR].
In another engaging physiological investigation, the DPG accurately predicted patients with pulmonary hypertension and abnormal pulmonary arterial-right ventricular coupling. Cpc-PH was found to be present in 12% of patients with chronic heart failure and it predicted poor survival. Lastly, there is some histopathological evidence supporting the DPG as a predictor of increased pre-capillary resistance.
Nevertheless, the current guidelines suggest – under ‘careful consideration’ – that the DPG not be the primary right-heart-catheterization metric to determine pre-capillary abnormalities. While the authors declare that ‘none of the haemodynamic variables proposed to describe PH-LHD are free from limitations’, they have opted to keep cPVR as a part of the current definition:
IpcPH: Ppao >15 mmHg and mPAP >20 mmHg and cPVR<3 Wood Units
CpcPH: Ppao >15 mmHg and mPAP >20 mmHg and cPVR ⩾3 Wood Units
Ppao is pulmonary artery occlusion pressure [i.e. the ‘wedge’ pressure], mPAP is mean pulmonary artery pressure and cPVR is calculated pulmonary vascular resistance.
Haunted by the ‘wedge?’
The physiologically-appealing element of the DPG is that it occurs during cardiac diastasis. In other words, the DPG is liberated from the confounding elements of stroke volume and pulmonary arterial compliance – the ‘Windkessel’ elements of the circulatory system; the ‘step-down’ from the diastolic pulmonary artery pressure to the ‘wedge’ pressure should be closer to the truth in the pulmonary vascular tree.
The undeniably unappealing aspect of the DPG is that it is prone to measurement error. Small errors when measuring the ‘wedge’ are amplified in the DPG – consider the clinical difference between a DPG of 10 mmHg and 6 mmHg. The former patient is predicted to have high pre-capillary resistance, while the latter is suspected of having only passive venous congestion. Yet, a small error measuring the diastolic pulmonary arterial pressure and especially measuring the ‘wedge’ may be the only difference between these two values. In the best editorial I have ever read on the pulmonary artery occlusion pressure, Houston and Tedford make clear the many problems we face when we talk about this frequently misunderstood and variably measured pressure. In fact, they discuss a fascinating study that evaluated the differences in DPG that occur when the ‘wedge’ pressure is measured by an electronic mean versus an ECG-gated method. Certainly, an electronic mean 'wedge' pressure is over-estimated by large v waves [e.g. mitral regurgitation or congested left atrium] and the electronic mean is often used in atrial fibrillation when there is no a wave to estimate end-diastole. Problems measuring the ‘wedge’ pressure may account for the large proportion of studies that found a negative DPG [i.e. the ‘wedge’ is higher than the diastolic pulmonary artery pressure]. Surprisingly, 30% of studies reported a negative DPG which isn’t physiologically impossible [blood moves down an energy gradient rather than a pressure gradient] but it is highly unusual. Measurement variability and inaccuracies are undeniably one reason why the DPG under-performs the cPVR in prognostication; it’s much easier to mess up the DPG than the cPVR.
Future Directions: diagnosis and therapy
Unquestionably, there will be a rise in ultrasonographic methods to differentiate Cpc-PH from Ipc-PH – for example the ‘Echo Score' and the TAPSE/systolic pulmonary arterial pressure ratio. Nevertheless, a right heart catheterization remains the cornerstone of diagnosis, especially when trying to ascertain the presence of pre-capillary resistance problems – critical when contemplating therapy directed at the pre-capillary circulation.
‘There is still no multicentre trial that suggests targeting PH-LHD with PAH-specific drugs is beneficial. Therefore, we maintain a strong recommendation against the use of PAH therapies in group 2 PH.
In addition, a safety signal should be acknowledged: 1) the use of sildenafil in the context of PH post-valvular heart disease intervention is associated with an increased risk of clinical deterioration and death, and 2) the use of macitentan in CpcPH due to heart failure is associated with an increased risk of fluid retention.
Following the MELODY-1 trial, new standards have been proposed to explore the role of PAH-approved therapies in the context of group 2 PH. If pursued, such trials should be limited to PH due to HFpEF with CpcPH …’
Please access and digest these well-developed guidelines yourselves, found here. At the present, we cannot measure the character of PH-LHD from the outside alone; there is more inside the body than just temperature - there's an accurately-measured pulmonary artery occlusion pressure waiting to be found.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he is also the creator and author of a free hemodynamic curriculum at heart-lung.org