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Pulmonary Hypertension and Right Heart Failure in Scleroderma

Posted Nov 18 2010 2:33am

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Discuss the basic science work that the Division of Cardiology, Department of Medicine, Johns Hopkins University is doing with human tissue.

Discuss some of the pathophysiology, particularly in rheumatologic diseases.

To study physiology, mice can be genetically manipulated and there are various ways to look at them, including isolated heart-lung preparations
A right heart catheterization technique for mice to measure wedge and PA pressure, etc. in the intact-chest, spontaneously breathing mouse.

Right ventricular pressure-volume loops in animal models.

All the molecular techniques.

The physiology studied in mice needs to relate to patients. Kiche Sagawa was, essentially, the father of pressure-volume loop analysis. His approach was that we should think about individual cardiac myocytes working by themselves, how they interact within a single chamber and certainly how those chambers interact with each other.

In particular, this article will focus on the right ventricle (RV) and how that chamber interacts with the vasculature. This interaction is critical; most pulmonologists consider the heart to be a conduit by which the lungs get blood and most cardiologists consider the lungs to be the way a body holds the heart up in the chest and gives oxygen for the coronary perfusion. But, then we also want to think about how this all interacts in our patients. It is difficult to go back and forth between the two, and oftentimes find a mouse that recapitulates our human experience.
This is the JHH experience with pulmonary hypertension in patients with scleroderma. This is a mortality curve compared with idiopathic pulmonary hypertension from 2001 to 2005.

It may not surprise a lot of people that patients with scleroderma and pulmonary hypertension may die sooner, probably because their lung pressures are higher or maybe they have other problems. In reality this patient population had the same mean pulmonary artery pressure. So, despite the fact that the pulmonary circulation had the same pressure, these patients were dying quicker. This group was not limited by their comorbid state. Most of these patients actually died from RV failure or sudden cardiac death, which usually comes from the inability of the RV to promote forward flow. And most importantly, all of these patients were being treated. All of these patients were on some type of therapy, whether it was prostacyclin therapy or Bosentan or other, at-the-time-investigational drugs (mainly Sildenafil or Viagra).

Thinking differently about the disease

Although many consider pulmonary hypertension to be elevated pulmonary vascular resistance and elevated lung pressure, these patients don’t die from high lung pressure. These patients die from the failure of their heart to compensate for those pressures. Some patients survive many years with a very high mean PA pressure. Some patients have a modestly elevated PA pressure and they die relatively quickly. It may be that very little, if any, of therapy has to do with the small arterioles. A lung biopsy of a patient with pulmonary arterial hypertension prior to death, and a lung biopsy of a patient on Flolan or an endophelin blocker at the time of death don’t look different. Therapy does not have a significant impact in terms of small vessel remodeling. Patients on therapy usually live longer, but not because of small vessel remodeling. In reality, pulmonary hypertension is a condition of the heart and the lung. Because of this, Hopkins has integrated the heart-lung program to take note and try to treat the whole disease—not just the lung pressures.

Most people consider pulmonary hypertension to be a very rare disease. In fact, the prevalence for idiopathic PH is around 6 per million. But, there is a whole host of other patients that have pulmonary hypertension; particularly heart failure patients and end-stage liver disease patients. One of the main reasons why we don’t transplant patients for their heart or their liver is because of pulmonary hypertension. A huge number of patients with obstructive lung disease have subsequent pulmonary arterial hypertension. Other conditions like sarcoid and connective tissue disease can have subsequent pulmonary arterial hypertension as well.

A January 2008 article in USA Today reported that hospitalizations are on the increase for a deadly lung disease ( PH is one of the few diseases that no one cared about before there was treatment. The thinking was as follows “We are not going to do anything about it, so why even do the right heart cath?” Now, there are therapies and some of them are better than others but we are looking for PH a lot more frequently and more echocardiograms are giving the right ventricular systolic pressure.

The mean age for all pulmonary hypertension patients is almost 70 years old. This is amazing considering 30 years ago PAH was taught as a disease of young woman, in particular. In reality, pulmonary hypertension may be, in large part, a normal cardiovascular aging process.

Detection is getting better

Mean PA pressure in SSc patients 2002: 43.68 mmHg
Mean PA pressure in SSc patients 2007: 28.91 mmHg
Earlier treatment is having an impact
Pulmonary hypertension is being detected before profound right heart failure, partly as a benefit of having the Scleroderma Center. There is frequent screening for not just drop in DLCO and other PFT abnormalities, but also frequent echoes for right ventricular systolic pressures that are elevated. Patients are also cathed a lot sooner. For example, if a patient has a RVSP of 40, and they have symptoms of shortness of breath, they should be cathed because, a lot of these patients have a significant amount of pulmonary hypertension (if not at rest, certainly with exercise). Therefore, the Scleroderma Center is cathing a lot of patients with exercise and finding that they augment their mean PA pressure with a little bit of increase in flow.

Five problems

PA = All PAH drugs have a modest effect on mPAP at best

All of the PH drugs have a modest effect on mean pulmonary artery pressure at best. In the Sildenafil trial (80 mg dose of Sildenafil taken 3 times a day) the average lung pressure at the beginning of therapy was 54 mm/Hg. The average lung pressure at the end of the treatment was 52 mm/Hg. There was very little impact on mean PA pressure, which is important. Developing new ways to look at echo as well as other diagnostic tools to try to be able to say if PAH drugs are effective is a critical next step.

RV=Difficult to measure given interdependence with pulmonary circulation

Right ventricular function is often difficult to measure. In the past it has been difficult to measure, given that it is ejecting into a pulmonary circuit. Because of this, how the heart interacts with the lung and the pulmonary vasculature is important.

The RV may not hold on while attempting to reverse remodeling of the pulmonary circulation

Even though RV dysfunction can be recognized, it may not be able to hold on while waiting for reverse remodeling of the pulmonary circulation to occur. It is going to be many years before we know if treating a patient with a mean PA pressure of 25 and a relatively normal preserved cardiac index (but with some evidence of pulmonary vascular remodeling) will reverse remodel with therapy. Part of the reason this is something not seen now is because patients die too quickly.

There is a need to develop techniques to study RV-PA Coupling

Because of these three factors, there has been a dire need to develop new techniques to study not just right ventricular function, but how the right ventricle interacts with the pulmonary circuit.

There is a need to move away from the “looks OK to me” mentality

In the past, there has been a “looks OK to me” mentality about PA, and it is crucial to move away from this to develop new study techniques. Clinicians need to be a little bit more quantitative and a little bit more scientific during assessment.


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