Left Heart Disease in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common type of pulmonary hypertension. Pulmonary hypertension due to LHD has two subgroups: isolated post-capillary PH due to left sided filling pressures, and then in long-standing cases, the pre-capillary component is added due to pulmonary vascular disease developing, which is termed post- and pre-capillary PH. These groups have differing clinical implications. We describe the hemodynamic, from left and right heart cardiac catheterization, pathophysiology, and the role of pulmonary vasodilators and studies of this up to date. We will also discuss the left heart diseases that cause PH, such as congestive heart failure and valvular heart disease. We will also discuss future areas for research in this area of PH.

1. Introduction

Right heart catheterization has been covered extensively in this book. Left heart catheterization is considered the gold-standard test for coronary artery disease diagnosis but can also provide further diagnostic and therapeutic uses.

Left heart catheterization is performed via percutaneous access of the femoral or, in preference to this, via the radial artery due to reduced complications from bleeding [1]. Through various arterial branches, access is gained to the aorta and left ventricle, where pressures can be transduced. Similarly, to intubation of the coronary arteries in which catheters can measure pressures and take images of each artery, the anatomy of the aorta and left ventricle can be delineated by aortogram and ventriculogram, respectively.

Therefore, left heart catheterization can be used to evaluate and treat coronary artery disease as well as assess valvular disease, defects, and cardiomyopathies. Aortic stenosis is typically assessed by echocardiography, but cardiac catheterization can add important information through pressure transducing. Mitral stenosis can also be assessed with gradients across the valve in stenosis assessed by left ventricular pressure readings and the pulmonary artery wedge pressure (PAWP) being taken as a surrogate for left atrial (LA) pressure, although direct LA measurements can also be taken via trans-septal puncture from the right atrium via venous access. Both aortic and mitral regurgitation can also be measured.

Right heart catheterization will produce pressure waveforms. An important measurement achieved from right heart catheterization is PAWP, also known as the pulmonary capillary wedge pressure (PCWP). This is measured by “wedging” the pulmonary arterial catheter tip into a small pulmonary artery. By measuring pressures at end-expiration at end-diastole (the p wave on the ECG), the blood flow between the pulmonary artery and left atrium is static, and therefore, the pressure represents the left ventricular end-diastolic pressure (LVEDP). Pressures are normally 6–12 mmHg, which is generally 1–5 mmHg less than pulmonary artery diastolic pressure. Pressures of more than 18 mmHg are suggestive of left heart failure.

Left heart catheterization is not performed in all patients where pulmonary artery hypertension is being assessed but should be performed where invasive right-sided heart pressures are being measured to assess for the left heart diseases mentioned [2].

2. Pulmonary hypertension secondary to left heart disease

Left heart disease is the most common cause of PH where mean pulmonary artery systolic pressure is >20 mmHg and pulmonary capillary wedge pressure > 15 mmHg during right heart catheterization [3].

Pulmonary hypertension can be defined as pre- or post-capillary according to the PCWP.

PH is defined as precapillary when PCWP measurement is <15 mmHg, as the left-sided pressure measurement is considered normal. If the pulmonary capillary wedge pressure measurement is >15 mmHg, it is defined as postcapillary pulmonary hypertension.

Pulmonary hypertension can be classified as isolated postcapillary pulmonary hypertension and combined post-and precapillary pulmonary hypertension.

Pulmonary vascular resistance, transpulmonary pressure gradient, and diastolic pressure gradient is obtained through right heart catheterization and can help to define the subtype of pulmonary hypertension caused by left heart disease.

Pulmonary vascular resistance is calculated by subtracting pulmonary capillary wedge pressure from mean pulmonary artery pressure and then dividing this by the cardiac output. A measurement of <3 wood units suggest that the left atrial pressure is raised and that the pulmonary vasculature remains normal. This is called isolated postcapillary pulmonary hypertension, as only the left atrial pressure is abnormal.

A measurement of >3 wood units indicates that there is raised left atrial pressure alongside pulmonary vascular disease. The diastolic pressure gradient is pulmonary capillary wedge pressure subtracted by diastolic pulmonary artery pressure. A low diastolic pressure gradient of <7 mmHg suggests isolated postcapillary pulmonary hypertension. Where gradients are >7 mmHg, this would suggest post-and precapillary involvement.

3. Pathophysiology of left heart disease causing pulmonary hypertension

Heart failure (both with preserved and reduced ejection fraction) and valvular heart disease can lead to an increase in left atrial pressure and volume. This can lead to reduced left atrial compliance [4]. This reduction in compliance increases the hydrostatic pressure of the pulmonary veins.

As the left atrial volume and pressure increase, the left atrium cannot act as a barrier between elevated left ventricular pressure and pulmonary vascular resistance. This passive pressure transmission to the pulmonary vascular tree results in isolated postcapillary pulmonary hypertension [5], which will gradually lead to structural abnormalities in the pulmonary vasculature. This includes intimal fibrosis and medial hypertrophy, which results in reduced vasodilator response, pulmonary vasoconstriction, and elevated pulmonary vascular resistance [3]. This is how postcapillary pulmonary hypertension can lead to combined pre- and post-capillary pulmonary hypertension. The increased hydrostatic pressure of the pulmonary veins will over time cause increased pressure of the pulmonary arteries.

Elevated pulmonary capillary wedge pressures result in a reduction in pulmonary vascular compliance for a given pulmonary resistance due to alterations of right ventricular pulsatile load. As the pulmonary circulation becomes less compliant, there is accompanying endothelial dysfunction that leads to a reduction in nitric oxide production and an increase in endothelin levels [3].

Nitric oxide is an important pulmonary vasodilator because as the levels reduce, the pulmonary vascular resistance increases. Endothelin is a vasoconstrictor and proliferative cytokine, so increased levels further increase the pulmonary vascular resistance. This increase in pulmonary vascular resistance will cause an increase in right ventricular afterload and result in right ventricular dysfunction/heart failure.

4. Clinical classifications

There are 5 broad pulmonary hypertension clinical categories that focus on the underlying cause of abnormal pulmonary artery pressure. The table below illustrates these, with the prevalence showing left heart disease (group two) is the most prevalent subtype (Figure 1) [6].

Figure 1.

Clinical classifications of pulmonary hypertension [6].

The most common left heart disease causing pulmonary hypertension is left ventricular dysfunction, where systolic contraction is impaired [7].

It is important to note that while there are vasodilator therapies available to treat pulmonary arterial hypertension with robust evidence to support their use, there are no specific treatments for managing pulmonary hypertension due to left heart disease apart from optimization of the underlying etiology [8]. The treatments for individual left heart diseases are broad and varied. Ensuring accurate diagnosis and confirmation of the cause of pulmonary hypertension is therefore important so the correct treatment can be offered.

5. Treatment

Multiple pharmacological therapies for pulmonary artery hypertension include prostanoids, endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylate cyclase stimulators. Trials using these therapies in pulmonary hypertension with left heart disease have not yet shown enough evidence to promote their use, and at the 6th World Symposium on Pulmonary Hypertension, these therapies were strongly recommended against use for this group [9].

Treatments for left heart disease are dependent on the specific disease itself. Left ventricular systolic dysfunction or heart failure, which is the most common cause of PH, has pharmacological and surgical treatment. Coronary artery disease is treated medically or by percutaneous coronary intervention or coronary artery bypass grafting. Pharmacological treatment of heart failure follows a strong evidence base of prognostic medications such as ace-inhibitors, angiotensin-2 receptor blockers, aldosterone antagonists, cardioselective beta-blockers, aldosterone receptor antagonists, angiotensin receptor neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors and digoxin which is a cardiac aminoglycoside. Although diuretics are not prognostic in left ventricular systolic dysfunction, they form the cornerstone of symptomatic benefit. Surgical or rather procedural treatment of left ventricular systolic dysfunction is by the placement of biventricular pacemakers, also known as cardiac resynchronization therapy. Here, pacing leads are placed in the right ventricle and a branch of the coronary sinus to improve cardiac function and contractility, where patients fulfill various guidelines, the main one being the electrocardiogram criterion of the left bundle-branch block.

Aortic and mitral regurgitation are initially treated with ace-inhibitors or angiotensin-2 receptor blockers, but ultimately, the treatment is percutaneous or surgical. Aortic and mitral stenosis are both only treated by percutaneous or surgical replacement of the valves. Similarly, shunts such as atrial septal defects and ventricular defects can be treated percutaneously or surgically. Cardiomyopathies encompass a huge spectrum of diseases, each with specific and varied treatments, as do the rarer causes of left heart disease that cause PH.

6. Trials

Previous clinical trials have often grouped both post-capillary with combined pre-and postcapillary pulmonary hypertension, which may have contributed to the results not showing significant benefits. Many clinical trials are now focusing on these subtypes separately, as the previous trials of drugs described above could have conflicting results due to differing results on each subtype.

In the CHAMPION study, an implantable sensor called CardioMEMS™ was used and provided for the funding [10]. The study enrolled patients with symptomatic heart failure irrespective of left ventricular ejection fraction in 64 centers across the USA. The sensor allowed a home measurement of pulmonary arterial pressure as a surrogate of pulmonary capillary wedge pressure. Diuretics were used significantly more in the intervention group due to these readings, and there was a lower composite outcome of death and all-cause hospital admissions over a 31-month follow-up for the intervention group. The addition of pulmonary artery pressure information to signs and symptoms allowed for much-improved heart failure management.

The REDUCE LAP-HF II trial was a prospective randomized controlled trial with an intervention group treated with an interatrial shunt device. [10] 626 patients with heart failure with preserved ejection fraction with isolated post-capillary pulmonary hypertension were treated with the device or placebo for up to 24 months. The study showed no significant effects of the device on the primary composite outcomes, which included cardiovascular deaths. The trial was analysed further to discriminate patients with latent pulmonary vascular disease by using the measurement of peak exercise pulmonary vascular resistance. The patients with no evidence of latent pulmonary vascular disease showed clinical benefit from the device. This is also a possible area for research in future trials.

7. Future areas of research

Two therapies that are being studied currently for pulmonary hypertension with left heart disease are sodium-glucose cotransporter 2 inhibitors such as empagliflozin, and angiotensin receptor neprilysin inhibitors such as sacubitril/valsartan. Some studies have shown significant improvements in pulmonary artery pressures; however, these studies have been small and, therefore, need repeating on a much larger scale.

8. Conclusion

Pulmonary hypertension due to left heart disease is an important but complex disease process. Identifying the cause of pulmonary hypertension through use of right and left heart catheterization is vital to ensure appropriate treatment can be started. Current guidelines for treatment are limited due to multiple studies showing poor evidence for use of traditional pulmonary hypertension treatments in this subgroup. Treating the left heart disease is currently the best treatment option, however through ongoing research additional treatments will hopefully be discovered.