Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction

Abbreviations

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

mPAP

mean pulmonary arterial pressure

PA

pulmonary arterial/artery

PCWP

pulmonary capillary wedge pressure

PH

pulmonary hypertension

PVR

pulmonary vascular resistance

RV

right ventricle / right ventricular

TAPSE

tricuspid annular plane systolic excursion

Case Study

A 66-year-old woman with long-standing systemic hypertension, obstructive sleep apnea, coronary artery disease, atrial fibrillation, and chronic kidney disease is referred for evaluation. She had a pulmonary vein isolation procedure 10 years prior but had recurrent atrial fibrillation and 5 years ago underwent surgical maze at the time of coronary artery bypass grafting. She presents now with a 12-month history of progressive dyspnea, lower extremity edema, and weight gain. She has functional Class III symptoms of exertional dyspnea. She denies chest pain, palpitations, or syncope.

On physical examination her pulse is 80 bpm and irregular, blood pressure (BP) is 108/70 mmHg, respiration rate is 20/min, body weight is 131 kg, body mass index (BMI) is 52 kg/m ² , and O ₂ saturation at rest is 90%. Her cardiovascular exam is remarkable for an elevation in her jugular venous pressure to the angle of the jaw and an accentuated pulmonic component of S ₂ and III/VI holosystolic murmur best heard at the lower left sternal border. Her abdomen is obese and nontender. There is marked bilateral edema. Laboratory tests: creatinine (Cr) = 2.5 mg/dL. Transthoracic echocardiogram was obtained and representative images are shown ( Videos 33.1, 33.2, 33.3, and 33.4 ; Figs. 33.1, 33.2, and 33.3 ).

The patient is prescribed a low sodium diet, nocturnal positive airway pressure (PAP) therapy with O ₂ supplementation, furosemide 80 mg twice daily, and leg wraps and abdominal massage three times a week at the lymphedema clinic. However, over the following 3 weeks despite increasing her furosemide to 160 mg twice daily she becomes wheelchair bound with functional Class IV dyspnea, her weight rises to 136.8 kg, and her creatinine increases from 2.5 to 2.8 mg/dL.

She is referred for a right heart catheterization. Her hemodynamics are as follows:

Mean right atrial (RA) pressure: 21 mmHg
Pulmonary artery pressures (S/D/m): 71/30/49 mmHg
Pulmonary capillary wedge pressure (PCWP): 29/38/24 mmHg
Cardiac output: 5 L/min
Pulmonary arteriolar resistance: 5 Wood units (WU)

Definition and Classification of PH

Pulmonary hypertension (PH) is not in of itself a diagnosis or disease but a syndrome characterized by an elevation in pulmonary arterial (PA) pressure, traditionally defined as a mean PA pressure (mPAP) assessed by right heart catheterization, of 25 mmHg or higher. Pulmonary pressure can be further classified based on the PCWP. The PH is precapillary if the PCWP is less than or equal to 15 mmHg and postcapillary when the PCWP is greater than 15 mmHg ( Fig. 33.4 ). Pulmonary vascular resistance (PVR) is defined as the (mPAP – PCWP) divided by the cardiac output. Put simply, a PVR less than 3 Wood units (WU) is consistent with postcapillary PH, and a PVR of 3 WU or greater is consistent with precapillary PH. PH is most often due to left-sided heart disease; however, many patients with left heart disease have PH, an elevated PCWP, and an elevated PVR. This condition has been variably described as “out-of-proportion PH” or “mixed PH.” The proposed mechanism is that a chronic elevation in pulmonary venous pressure leads to pulmonary vascular vasoconstriction or pulmonary vascular remodeling. Other measures to characterize this mixed PH syndrome include PH with a high transpulmonary gradient (i.e., a difference between the mPAP and the PCWP of ≥10–12 mmHg). The 2015 guidelines preferred the use of the diastolic pressure gradient (the absolute difference between the PCWP and the diastolic PAP). A diastolic pressure gradient of less than 7 mmHg and a PVR less than 3 WU in the setting of a PCWP over 15 mmHg and an mPAP of 25 mmHg and above characterizes an isolated postcapillary PH. Whereas PH is defined as mixed or combined precapillary and postcapillary when the PCWP is greater than 15 mmHg, and the diastolic pressure gradient is 7 mmHg and above and the PVR over 3 WU. However, in isolation the diastolic pressure gradient is imprecise, and the clinician should factor in the PCWP, the diastolic pressure gradient, and the PVR.

Fig. 33.1, Case study: Echo Doppler data from patient.

Fig. 33.2, Case study: Echo Doppler data from patient.

Fig. 33.3, Case study: Still 2-D image of the very dilated inferior vena cava from the patient’s echo.

Fig. 33.4, Types of pulmonary hypertension.

Recently guidelines addressing PH in left heart disease were published as part of the Sixth World Symposium on Pulmonary Hypertension. The panel reviewed the evidence concerning patient populations with isolated postcapillary PH (IpcPH) and those with combined postcapillary and precapillary PH (CpcPH). While discussing the value of various hemodynamic variables, including PVR, transpulmonary gradient, and the diastolic pressure gradient, they recognized that no one variable accurately characterizes a particular phenotype and all have potential limitations. They also underscored the importance of an accurate PCWP measurement.

Epidemiology

Heart failure with preserved left ventricular (LV) ejection fraction (HFpEF), defined as symptomatic left heart failure occur in the setting of a LV EF that is normal (≥50%), is responsible for close to half of all HF hospitalizations and is a significant cause for postcapillary, or group 2, PH. The diagnosis of postcapillary PH is usually straightforward. Discerning the etiology of PH occurring in the context of severe left-sided valvular disease or a dilated left ventricle with reduced EF is typically not challenging. However, the patient with PH and HFpEF may be harder to assess clinically. Typically these patients may not have marked pulmonary congestion, at least at rest, and have features of right heart failure and left-sided abnormalities that may be underappreciated on imaging. Many of these patients may have normal or borderline LV filling pressures at rest making even the hemodynamic catheterization difficult. A high clinical index of suspicion is required to ensure that these patients are not misclassified as having pulmonary arterial hypertension (PAH).

PH in the setting of HFpEF is common and is associated with worse exercise capacity and worse clinical outcomes. However, the true prevalence of PH in HFpEF is challenging as studies vary based on differences in severities of HFpEF, the definition of PH used, the mechanism of PAP measurement (right heart catheterization or echocardiography), and the recognition that variations within patients of PAP hour-to-hour and day-to-day are common due to changes in volume status, stress, and systemic BP. Studies have demonstrated the presence of PH in HFpEF to be between 35% and 80% ( Table 33.1 ). In a community-based study of 244 patients with HFpEF, Lam et al. identified PH as defined by an echo-derived PA systolic pressure over 35 mmHg, to be present in 83% of patients. In comparison, PH was present in only 8% of hypertensive controls. An E/e′ ratio and a PA systolic pressure were the best echo parameters for the diagnosis of heart failure, with PA systolic pressure elevation being the best predictive measure on receiver operating characteristic curve analysis.

Table 33.1

Epidemiology of Heart Failure With Preserved Ejection Fraction and Pulmonary Hypertension

	Prevalence of PH in HFpEF		EF	PA pressure	Other
Lam et al.	83%	Echo	≥50%	PASP >35 mmHg	Elevated E/e′ ratio
Shah et al.	36%	Echo	≥45%	TR velocity >2.9 m/sec	Heart failure history
Vanhercke et al.	51%	Echo	≥50%	TR velocity >2.75 m/sec	≥75 years
Benza et al.	47%	RHC	≥40%	PAmP ≥25 mmHg
Leung et al.	53%	RHC	≥50%	PAmP >25 mmHg	PAWP ≥15
Hurdman et al.	62%	RHC	≥45%	PAmP >25 mmHg	PAWP ≥15
Gerges et al.	54%	RHC	≥40%	PAmP ≥25 mmHg
Borlaug et al.	88%	RHC	≥50%	PAmP ≥30 mmHg with exercise	PAWP ≥15 at rest PAWP ≥25 with exercise

E′, Early diastolic annular tissue velocity; E/e′, the ratio of the peak early diastolic mitral inflow velocity to E’; EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction, PAmP, pulmonary artery mean pressure; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; RHC, right heart catheterization; TR, tricuspid regurgitant Doppler.

While common in HFpEF, PH has various phenotypes. This spans HFpEF patients with earlier stages of disease without any evidence of PH or those that display abnormal pulmonary vasodilatation only with exercise, and some developing PH with exercise. Then there are those with PH at rest but due solely to passive elevation in downstream left heart filling pressures and then those displaying features of coexisting pulmonary vascular disease, potentially sharing some pathophysiologic overlap with pulmonary arterial hypertension ( Fig. 33.5 ).

$Fig. 33.5, Pulmonary hypertension in heart failure with preserved ejection fraction (HFpEF) .$

Prognosis of PH in HFpEF

A consistent finding in the literature is that the presence of PH in the setting of patients with HFpEF is associated with increased all-cause mortality. Rates of death in HFpEF patients with PH are in a similar range to those patients with heart failure with a reduced ejection fraction (HFrEF) and PH. Whether PH is an independent marker of poor prognosis is unclear as it may simply be a marker of the degree of elevation in LV filling pressures. An impairment in diffusion capacity on pulmonary function testing, likely a marker of pulmonary vascular disease, is firmly associated with mortality in patients with HFpEF and PH. An elevation in pulmonary pressures is also typically associated with the degree of right ventricular (RV) dysfunction. The contribution of the RV dysfunction to prognosis is also likely significant. Whether it is genuinely the elevation in pulmonary pressure, in isolation of the RV dysfunction, that conveys higher risk is not well established. Likely measures of the degree of RV-PA uncoupling may better reflect the severity of disease and prognosis in these patients, with measures such as PA capacitance being predictive, as is seen in pulmonary arterial hypertension.

Pathophysiology

The pathophysiology of PH in patients with HFpEF is complex. The hallmark of group 2 PH is an elevation in left atrial (LA) pressure leading to pulmonary venous hypertension and pulmonary venous congestion. However, many patients, in addition, develop significant functional and structural abnormalities of the pulmonary vasculature. In principle, when the PH is solely due to passive pulmonary venous hypertension, the hemodynamic profile is one of an elevated PCWP and a proportional increase in PAP. Typically in these cases the transpulmonary gradient and PVR are both normal. In these patients, a reduction in LA pressure should bring about a proportional reduction and normalization of mPAP. However, likely brought about by increased severity and chronicity of pulmonary venous hypertension, but also perhaps other clinical or genetic characteristics, some patients develop PAP elevation out of proportion to the pulmonary venous pressures, due to pulmonary vasoconstriction and pulmonary artery remodeling. These patients represent a significant proportion of HF patients who undergo invasive hemodynamic catheterization. One also recognizes that an increase in pulmonary vascular stiffness and pulmonary artery pressure occurs with age, even in the absence of an elevation in LV filling pressure.

It has long been demonstrated that pressure elevations in the pulmonary capillary beds lead to disturbance of the alveolar and endothelial cell membranes and over time to thickening and weakening of the extracellular matrix. In response to the chronic elevations in hemodynamic pressure there is progressive remodeling of the vascular wall with vessel hypertrophy and fibrosis, indeed, structural changes that bear similarities to those that occur in pulmonary arteriopathies. In a detailed histopathologic study of patients with heart failure, PH was associated with global pulmonary vascular remodeling. The severity of PH most strongly correlated with intimal thickening of small vessels. Patients with group 2 PH similarly develop significant endothelial dysfunction. As with patients with pulmonary arterial hypertension, there is a relative deficiency in the production of nitric oxide as well as elevated levels of the pulmonary vasoconstrictor endothelin. Deficiencies in nitric oxide and elevations in endothelin have been demonstrated to cause hypertrophy by inducing the growth of pulmonary vascular smooth muscle cells analogous to that seen in pulmonary arterial hypertension. These may also be pathogenic in the development of pulmonary vascular remodeling in patients with PH and HFpEF. These similarities of the pulmonary vascular bed have led to attempts at targeting these pathways in patients with group 2 PH, with variable results (see Management section later in the chapter).

In addition to pulmonary vascular changes, the impact on RV structure and systolic function is also an area of intense investigation. In response to PA pressure elevation, the RV hypertrophies and dilates. However, changes in the RV systolic function frequently do not track in tandem with increases in pulmonary vascular load ( Fig. 33.6 ). This PA-RV uncoupling correlates with impaired exercise capacity, right heart failure, and prognosis.

$Fig. 33.6, Pathophysiology of pulmonary hypertension in heart failure with preserved ejection fraction (HFpEF) .$

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