Common misconceptions and mistakes
- •
Believing that the most common cause of pulmonary hypertension (PH) in patients with severe lung disease is group 3
- •
Obtaining an nonexpert right-sided heart catheterization (RHC) to rule out World Health Organization (WHO) group 2 disease
- •
Believing that WHO group 2 patients with “out-of-proportion PH” require pulmonary vasodilator/antiremodeling therapy
- •
Thinking that chronic thromboembolic pulmonary hypertension (CTEPH) represents the accumulation of multiple untreated pulmonary emboli over time
- •
Believing that patients with isolated right-sided heart failure (RHF) are not safe to diurese to euvolemia because of preload-dependent physiology
Pulmonary hypertension
- •
PH is defined as a mean pulmonary artery pressure (mPAP) > 25 mm Hg and is grouped by cause/category
- •
The diagnosis of PH is most commonly suggested by an elevated pulmonary artery systolic (PAS) pressure, as estimated by transthoracic echocardiogram
- •
Requires tricuspid regurgitation, which is common when the pulmonary artery (PA) is high
- •
PAS pressure is estimated from the maximum velocity of the tricuspid regurgitant jet
- •
- •
Echocardiography may overestimate, underestimate, or entirely miss PH
- •
- •
A definitive diagnosis of PH and an accurate severity assessment requires an RHC, with direct measurement of PA pressure and an assessment of cardiac output and pulmonary vascular resistance
- •
Pulmonary vascular resistance is superior to mPAP in the assessment of pulmonary vascular disease because as right ventricular cardiac output (RV CO) decreases, mPAP goes down
- •
Pulmonary vascular resistance, on the other hand, increases (by taking CO into account), reflecting the worsening pulmonary vascular disease (despite a lower mPAP)
- •
- •
Pulmonary vascular resistance (in dyn-sec-cm − 5 ) = (mPAP – left-ventricular end-diastolic pressure [LVEDP])/cardiac output × 80
- •
Because pulmonary capillary wedge pressure (PCWP) systematically underestimates LVEDP, LVEDP may need to be measured directly by left-sided heart catheterization
- •
- •
This invasive approach should be reserved for patients with proven or strongly suspected group 1 disease (eg, idiopathic pulmonary arterial hypertension [IPAH])
- •
PCWP measurement (even in expert hands) is a poor predictor of LVEDP, making RHC generally unhelpful in excluding left-sided heart failure (LHF) as the etiology of PH (ie, group 2)
- •
Most PH (> 90%) can be easily attributed to LHF or underlying lung disease based on clinical assessment using the patient history, physical examination, imaging, pulmonary function testing (PFT), echocardiogram, and response to diuresis
- •
The evaluation of PH hinges on an approach that presumes (and thus works hard to exclude) LHF (group 2 disease) as the etiology, because this is the cause the vast majority of the time ( Fig. 7.1 )
Fig. 7.1
Flow diagram outlining the evaluation of suspected pulmonary hypertension (ie, elevated PAS pressure suggested by an echocardiogram). Approach hinges on excluding left-sided heart failure by diuresis to euvolemia. Pulmonary function testing (PFT) and a ventilation-perfusion (VQ) scan should be done relatively early for individuals without obvious left-sided heart failure. Diuresis to euvolemia is indicated in both decompensated isolated right-sided heart failure and biventricular heart failure. In cases of isolated right-sided heart failure, diuresis will improve CO (via improved starling forces) but will not significantly reduce pulmonary artery (PA) pressures. In cases of biventricular heart failure, diuresis to euvolemia will significantly improve or resolve the pulmonary hypertension (PH) (pathognomonic for group 2 disease).
- •
Sudden severe PH, without shock from acute RHF ( Fig. 7.2 ) , and intermittent PH ( Fig. 7.3 ) are common in individuals with LHF and rare or unheard of in individuals with primary pulmonary vascular disease (eg, chronic thromboembolic pulmonary hypertension [CTEPH], idiopathic pulmonary arterial hypertension [IPAH]), or PH related to lung disease
Fig. 7.2
Encapsulated case illustrating pulmonary hypertension (PH) secondary to overt or obvious left-sided heart failure. At the point the patient is admitted with volume overload (decompensated heart failure with preserved ejection fraction [HFpEF]), he has 7 years of echocardiograms showing the gradual development of HFpEF: echo 1, LVH; echo 2, diastolic filling abnormality; echo 3, left atrial enlargement; and finally echo 4, severe PH. Even without serial echocardiograms, the patient’s PH and volume overload can be confidently attributed to biventricular heart failure from the presence of bilateral pleural effusion and left atrial enlargement, seen on the echocardiogram that prompted the pulmonary consult. Ruling out pulmonary embolism should only have been pursued if the patient had failed to improve with euvolemia.
Fig. 7.3
Panel A shows the encapsulated case of an obese woman with severe chronic obstructive pulmonary disease (COPD) presenting with heart failure with preserved ejection fraction (despite no obvious thoracic fluid) illustrating the point that pulmonary hypertension (PH) and peripheral edema may be the only objective signs of biventricular heart failure. This occurs in individuals whose left ventricular end-diastolic pressure (LVEDP) remains in the 16 to 17 mm Hg range (not high enough to cause interstitial edema, which is required for pleural effusion formation). Panel B shows the same individual demonstrating intermittent pulmonary hypertension over several years, occurring with repeated episodes of decompensated LHF Resolving and remitting PH is only seen with group 2 disease. Note how unhelpful assessment of inferior vena cava (IVC) collapse is with regard to determination of total body volume status.
Pathophysiology, evaluation, and treatment of pulmonary hypertension by group ( Table 7.1 ):
- •
Step 1: rule out group 2 disease
- •
Exclude (or more likely confirm) LHF by reassessment after diuresis to euvolemia
- •
- •
PH secondary to LHF (WHO group 2):
- •
The vast majority of PH is group 2, related to the biventricular heart failure reflex, because LHF is a very common disease
- •
Many group 2 patients have overt LHF (most commonly heart failure with reduced ejection fraction [HFrEF]) and pose no diagnostic challenge
- •
Others have occult or “missed” LHF (most commonly heart failure with preserved ejection fraction [HFpEF]), often leading to needless subspecialty referral, invasive advance testing, and erroneous administration of contraindicated medications (ie, pulmonary vasodilators)
- •
LHF causes PH via the biventricular heart failure reflex:
- •
Where elevated LVEDP causes increased PVP via back pressure, and
- •
Increased PVP triggers an increase in PAP, via a neurohormonal reflex ( not backpressure)
- •
- •
Ensuring that PAP is always greater then PVP
- •
This pressure gradient is required to maintain forward flow through the pulmonary vasculature (waterfall/reservoir mechanism)
- •
- •
Enormous individual variability exists in the biventricular heart failure reflex (ie, an LVEDP of 25 may trigger a PAS pressure anywhere from 35 to 99 mm Hg [see CH 6 ])
- •
Unfortunately, group 2 has been further subdivided (descriptively/deceptively) into three (misleading) categories based on the magnitude of the biventricular heart failure reflex (ie, comparing the magnitude of the mPAP elevation to the LVEDP elevation)
- •
Passive PH is defined as an mPAP-LVEDP ≤ 12
- •
Reactive PH is defined as an mPAP-LVEDP ≥ 12
- •
Out-of-proportion PH is defined as an mPAP-LVEDP ≥ 12 and LVEDP ≤ 25
- •
- •
The terms are misconstrued such that “passive” is interpreted as back pressure and “out of proportion” is interpreted as a remodeled vasculature requiring pulmonary vasodilator/antiremodeling therapy
- •
Instead the terms are descriptive only and have no physiologic basis or implications with regard to management
- •
Out-of-proportion PH is the most dangerous because it suggests the need for pulmonary vasodilator therapy in individuals with known LVEDP elevation, which is a contraindication
- •
These patients are typically referred for PH or exercise limitation thought to be “out of proportion” to the perceived degree of left-sided dysfunction, or a RHC showing an mPAP-PCWP ≥ 12 and PCWP ≤ 25
- •
- •
The cornerstone of management of these patients is euvolemia and optimization of LHF (eg, treatment of HFpEF provocative factors)
- •
Worsening PH in these patients is an indication of increasing LVEDP, not progressive vascular remodeling
- •
Group 2 disease should be the presumed cause of PH in:
- •
Individuals with systolic dysfunction, increased left atrial (LA) size (without mitral valve disease), pulmonary edema, and/or pleural effusion
- •
Because these conditions are virtually pathognomonic for LHF
- •
- •
Edematous patients with risk factors for HFpEF, such as chronic kidney disease (CKD), hypertension (HTN), obesity, obstructive sleep apnea (OSA), diabetes mellitus (DM), and age > 65 years
- •
Because these are the most common conditions associated with occult LHF, a very common disease
- •
- •
- •
Traditional teaching suggests that group 2 PH should be differentiated from group 1 via RHC with PCWP (a.k.a. pulmonary artery occlusion pressure) measurement, demonstrating an mPAP > 25 mm Hg occurring with a PCWP < 15 mm Hg
- •
This approach fails for two reasons:
- 1.
PCWP is a poor predictor of LVEDP (mischaracterizing PH 50%–85% of the time, depending on the expertise of the RHC operator)
- 2.
Intermittent LVEDP elevations may lead to sustained elevations in mPAP (such that a single, resting pressure measurement is not adequate at ruling out the clinical syndrome of HFpEF)
- 1.
- •
- •
A more robust, practical strategy involves a reassessment of PA pressure after diuresis to euvolemia
- •
PH that improves significantly (or resolves) with diuresis is pathognomonic for group 2 disease (ie, secondary to LHF)
- •
- •
Diuresis to euvolemia is critical to the management of both group 2 and group 1 disease, making this the obvious approach
- •
Even though longstanding elevations of LVEDP may cause areas of IPAH-like remodeling, there is almost no role for pulmonary vasodilators /antiremodeling agents in these patients
- •
Pulmonary vasodilators should only be considered in patients with LHF who:
- •
Demonstrate the ability to maintain outpatient euvolemia for months to years:
- •
No pleural effusion, no peripheral edema
and
- •
- •
Still have an exercise limitation believed to be secondary to RV afterload from a remodeled vasculature, from previous longstanding LVEDP elevation
- •
- •
Theses patients may be trialed on a phosphodiesterase 5 inhibitor with significant risk/benefit counseling regarding possible worsening LVEDP physiology
- •
Endothelin receptor antagonists and prostacyclins are contraindicated because they may dramatically worsen left-sided heart failure, causing arrhythmia; flash pulmonary edema and death
- •
Use of these medications with known LHF requires referral to an IPAH center of excellence (and likely LVEDP measurement by left-sided heart catheterization) before initiation
- •
- •
- •
- •
- •
Step 2: rule out group 3 disease
- •
Individuals without obvious signs of LHF or risk factors for HFpEF, or individuals whose PH does not improve/resolve with diuresis, should have PFTs obtained (flows, volumes, and diffusion capacity of the lungs for carbon monoxide [DLCO]) to rule out group 3 disease
- •
- •
PH secondary to end-stage parenchymal lung disease and severe OSA/obesity hypoventilation syndrome (OHS) (WHO group 3):
- •
Group 3 represents the next largest category because lung disease and sleep-disordered breathing/hypoventilation are common
- •
Group 3 PH, from severe parenchymal lung disease, occurs in patients with:
- •
Emphysema, diffuse parenchymal lung disease (DPLD), and/or combined pulmonary fibrosis and emphysema (CPFE)—a.k.a. mixed obstructive restrictive disease
- •
Usually obvious from the patient history, physical examination, imaging, and PFTs
- •
- •
PH secondary to end-stage parenchymal lung disease is caused by parenchymal destruction, with its accompanying loss of small–medium sized blood vessels
- •
Decreasing the cross-sectional area available to receive RV CO, increasing pulmonary arterial resistance
- •
- •
Normally the DLCO needs to be ≤ 50% predicted (ie, over half of the vasculature destroyed) to cause PH at rest
- •
If the DLCO is ≤ 50%, the forced expiratory volume 1 (FEV 1 )/forced vital capacity (FVC) ratio is < 70%, FEV 1 is ≤ 50%, and the total lung capacity (TLC) is ≥ 80%, a diagnosis of cor pulmonale, secondary to emphysema (the most common cause), may be considered if diuresis to euvolemia fails to resolve the PH
- •
If the DLCO is ≤ 50%, but either the the TLC is < 80%, or the FEV1/FVC ratio is > 70, then the differential diagnosis becomes group 4 disease (CTEPH) vs group 3 PH secondary to severe mixed obstructive restrictive disease (eg, CPFE ), or MUCH less likely group 1 disease (eg, IPAH)
- •
Individuals with CPFE may demonstrate pseudonormalization of air flows (from restricted areas) and volumes (from obstructive areas) leading to an apparent ‘isolated low DLCO’ on PFT testing
- •
However, the physical examination and chest imaging are not subtle for severe mixed obstructive restrictive disease, often making the distinction easy
- •
Patients with mixed obstructive restrictive disease (eg, CPFE) often warrant a ventilation-perfusion (VQ) scan because disease severity may be more challenging to establish, potentially allowing severe PH to be erroneously attributed to moderate mixed disease (missing concomitant CTEPH, a relatively common comorbid condition)
- •
- •
Group 2 PH is more common in patients with end-stage lung disease than group 3
- •
Lung disease, with its associated tachycardia and hypoxemia, is a common provocateur of LHF, causing diastolic dysfunction, leading to concomitant HFpEF
- •
- •
Because of this, edematous patients with severe parenchymal lung disease should have concomitant group 2 PH excluded by a trial of euvolemia before a diagnosis of cor pulmonale is made ( Fig. 7.4 )
- •
Euvolemia is also indicated in group 3 disease to maintain optimal RV starling forces and myocardial perfusion (both jeopardized by RV overdistension), making this the obvious approach
- •
- •
- •
