Diastolic Dysfunction

Why you need to know this disease

Left Ventricular Diastolic Dysfunction (LV DD) is a very common cause of shortness of breath (dyspnea). It is far more common than Pulmonary Arterial Hypertension which is a disease characterized by increased pulmonary artery pressures caused by increased pulmonary vascular resistance (PVR). In contrast, LVDD can cause an increased pulmonary artery pressure but frequently is present in patients with normal pulmonary vascular resistance. Of patients who have a Right Heart Catheterization (RHC) for evaluation of possible PAH, 2/3 to 4/5 of patients will be found to have diastolic dysfunction as the primary abnormality leading to increased pulmonary pressures.

This is an important reason, if not the main reason, why all patients suspected of pulmonary arterial hypertension have to have a Right Heart Catheterization to confirm the diagnosis since using PAH medications in patients with uncontrolled LV DD is frequently harmful at worst or not helpful at best.

Background

The left ventricle of the heart is a muscular pump that pumps blood through muscle contraction and then fills either as a result of left atrial contraction (normal situation) or just as a result of blood flowing downstream from the right heart and lungs (atrial fibrillation). So far as the Left Ventricle (LV) is concerned, this is a passive process as the LV doesn’t pull blood into itself. In a normal person, the LV during the diastolic or relaxation phase of the heart beat is a compliant structure that can normally be filled easily with very little driving pressure. In fact, in a normal person, a pressure as low as 5 mm Hg can be sufficient to fill the LV. This pressure can be measured directly as the Left Ventricular End Diastolic Pressure (LVEDP) during a Left Heart Catheterization or indirectly as the Pulmonary Capillary Wedge Pressure (PCWP) during a Right Heart Catheterization. This is a measurement taken while the mitral valve is open and blood has stopped flowing from the Left Atrium to the Left Ventricle but before the Left Ventricle starts to contract. As there are no valves between the pulmonary veins and the left atrium this pressures is transmitted back through the pulmonary venous system toward the pulmonary capillaries and alveoli.

Diastolic Dysfunction

In patients with diastolic dysfunction, the left ventricle is abnormally non-compliant meaning that it takes more pressure than normal to deliver a normal stroke volume into the relaxed LV. In a euvolemic patient, most would consider an LVEDP or PCWP greater than 15 mm Hg to be abnormal though in a hypovolemic patient, an LVEDP or PCWP less than 15 mm Hg could still be abnormal and be indicative of diastolic dysfunction. Non-compliance of the LV could result from hypertrophy of the LV muscle wall such as might occur from long term hypertension though it sometimes occurs due to genetic factors or some feel, even as a result of ischemia that may be small-vessel ischemia. Additionally, elevations of filling pressures and a reduction in effective LV compliance can occur with LV systolic dysfunction where the residual volume of the LV is elevated at the end of systole.

Effect on the Lungs

When the LVEDP or PCWP exceeds about 20 mm Hg most patients will begin to develop pulmonary edema as the hydrostatic pressure can cause fluid to cross the alveolar capillary membrane resulting in ventilation-perfusion mismatching and shunting in the lung and this will result in hypoxemia and dyspnea. Eventually this can progress to result in Right Ventricular failure (as evidenced by an increased Central Venous Pressure (CVP) and lead to edema elsewhere in the body even to the point of causing recurrent pleural effusions in more severe cases.

What makes LV DD worse?

Anything that increases LV muscle tone can aggravate diastolic dysfunction. The most common causes are uncontrolled systemic hypertension. Hypertension to some degree frequently occurs as a normal result of exercise and in patients with diastolic dysfunction, trivial exercise can worsen LV DD enough to raise a marginal LVEDP/PCWP into a range causing symptomatic pulmonary edema, hypoxemia, and dyspnea. Tachycardia can aggravate diastolic dysfunction as can systolic heart failure. In patients with pulmonary arterial hypertension that is severe there can be inter ventricular coupling where a grossly enlarged Right Ventricle can push the intraventricular septum into the LV thus further compromising the LV’s ability to fill. Finally it is theorized that small vessel ischemia can increase LV muscle tone. Elderly patients frequently have some degree of diastolic dysfunction as a perhaps normal part of aging. Patients with morbid obesity and particularly uncontrolled sleep apnea or end stage renal disease also frequently have significant LV diastolic dysfunction. There are likely other humoral factors at play that have yet to be fully characterized as well.

How is diastolic dysfunction diagnosed?

A heart catheterization is the gold standard but usually must be combined with doppler echocardiography to help evaluate other causes of increased LVEDP/PCWP pressures such as mitral valve disease. LV DD is suspected in patients who clinically have left heart failure with a normal or frequently increased LV ejection fraction. The presence of recurrent transudative pleural effusions may also be a sign of diastolic dysfunction as are excessive diuretic requirements in patients who do not have significant LV systolic dysfunction.

How is diastolic dysfunction treated?

There are currently no medications with FDA approved indications for treatment of LV diastolic dysfunction. That said there are things you can do. Most important is to make the diagnosis. Once this is established, hypertension must be controlled. Diuretics can help to a point but excessive diuresis tends to worsen renal function and can even cause hypotension. If the LVEDP is high it’s frequently because the LV needs this much pressure to be filled. If the LVEDP is lowered excessively in a patient who is not volume overloaded then one would expect the stroke volume to fall and the patient’s cardiac output and perhaps blood pressure to fall as well. Most physicians treating LV DD feel that avoiding excessive tachycardia is helpful by increasing LV filling time. Calcium Channel blockers and Beta Blockers have been tried to decrease LV muscle tone and this is a reasonable theory though results are of limited efficacy in practice. Treating other aggravating factors such as obstructive sleep apnea, hypoxia, and obesity can be helpful.

Future directions

There is some limited evidence that
Ranexa (Ranolazine) can help improve LV compliance and can lower the LVEDP or PCWP in patients with LV diastolic dysfunction but as yet there are no completed randomized placebo controlled human trials demonstrating significant benefit. Such therapy has to be considered both off label in that the drug is approved only for angina and experimental since there is so little human data. A Google search on “Ranolazine” and “diastolic dysfunction” will yield many links on the current state of evidence for use of Ranolazine in diastolic dysfunction. There is a single-site clinical trial staring at Boston University and another in Europe to better evaluate this potential new indication.

In our experience with off-label use of Ranolazine for LV diastolic dysfunction (based on about 40 patients treated) we have found that approximately 1/3 of patients appear to experience good improvements in exercise performance and sometimes hemodynamic parameters within 4-6 weeks of starting therapy while about 2/3 don’t see much early difference. The mechanisms of how Ranolazine may work in this disease are not totally clear and as time passes one would expect other similar agents to be developed that may be better targeted for diastolic dysfunction. It’s almost certain that LV Diastolic Dysfunction is more than one disease entity and one can theorize that there is one group with relatively fixed disease related to hypertrophied muscle while another more drug responsive group has diastolic dysfunction based on things that can change such as ischemia or hormonal / humoral factors.

Donald Elton, MD, FCCP
Lexington Pulmonary & Critical Care
Lexington, SC
http://LexingtonPulmonary.com