Diagnostic Dilemmas: Diastolic Heart Failure Causing Pulmonary Hypertension and Pulmonary Hypertension Causing Diastolic Dysfunction

Left heart disease can cause pulmonary hypertension via multiple mechanisms. In the past, a normal ejection fraction and the absence of left-sided valve disease or congenital heart disease provided reassurance that pulmonary hypertension was not related to left-sided heart disease. However, it is now recognized that patients with clinical heart failure commonly have a normal ejection fraction, a syndrome referred to as diastolic heart failure or heart failure with normal ejection fraction.12 As reviewed below, the pathophysiologic mechanisms present in patients with diastolic heart failure may be heterogeneous. Although pulmonary hypertension has been reported in patients with diastolic heart failure, its prevalence and severity remain poorly defined.Idiopathic pulmonary arterial hypertension (IPAH) has been characterized as a disease of children and young adults,34 yet increasingly the diagnosis is made in elderly persons.56 This raises concern that some patients with dyspnea, unexplained pulmonary hypertension, and a normal ejection fraction could have diastolic heart failure with secondary pulmonary hypertension related to chronic pulmonary venous hypertension. However, as reviewed below, chronic right ventricular pressure overload can cause left ventricular diastolic dysfunction. Thus, a diagnostic dilemma arises in elderly dyspneic patients with otherwise unexplained pulmonary hypertension and a normal ejection fraction or when patients with a presumptive diagnosis of IPAH undergo right heart catheterization and are found to have an elevated pulmonary capillary wedge pressure (PCWP). Do these patients have diastolic heart failure with secondary pulmonary hypertension or is it IPAH causing left ventricular diastolic dysfunction and elevated PCWP?In this review, illustrative cases of both scenarios outlined above are presented, followed by a discussion of diastolic heart failure, novel concepts relevant to diastolic dysfunction and secondary pulmonary hypertension, and the phenomenon of left ventricular diastolic dysfunction related to chronic right ventricular pressure overload. Lastly, potential diagnostic strategies and implications for therapy are discussed.CASE 1: A 79-year-old woman presented with acutely decompensated heart failure after starting bosentan for pulmonary hypertension. She had a history of paroxysmal atrial fibrillation that began in 1986 and underwent a surgical MAZE procedure in 1996 because of worsening tachypalpitations. Atrial fibrillation recurred and an atrioventricular node ablation with pace-maker implantation was performed later that year. In 1998 the patient developed symptoms of dyspnea and peripheral edema and was found to have pulmonary vascular congestion on chest radiography. Echocardiography revealed Doppler evidence of severe diastolic dysfunction, no mitral regurgitation and a normal ejection fraction. A diagnosis of diastolic heart failure was made and she was treated with diuretics. In 2000 she had worsening dyspnea and peripheral edema and a repeat echocardiogram demonstrated a normal ejection fraction, severe diastolic dysfunction, and a right ventricular systolic pressure of 56 mmHg. The following year, her condition once again clinically deteriorated. Repeat echocardiography was unchanged with the exception of the right ventricular systolic pressure, which had increased to 75 mmHg. She then underwent a work-up for other secondary causes of pulmonary hypertension, but none were identified and she was referred to the pulmonary hypertension clinic. A right heart catheterization was performed that revealed a pulmonary artery pressure of 73/25 mmHg and a PCWP of 26 mmHg (Figure 1) with very prominent V waves in the PCWP wave form. Treatment was started with bosentan, an endothelin receptor antagonist, but she experienced a rapid increase in edema and dyspnea and had pulmonary edema on examination and chest radiography.The question arises whether or not this patient had lateonset IPAH with concomitant or secondary diastolic dysfunction or diastolic heart failure with secondary pulmonary hypertension. Atrial fibrillation is extremely common among patients with diastolic dysfunction7 and more common among patients with left heart disease than right heart disease. Demographic, clinical, and echocardiographic information seemed to favor a diagnosis of longstanding diastolic heart failure and would suggest that her pulmonary hypertension is likely related to “reactive” pulmonary hypertension and/or congestive pulmonary vasculopathy as addressed below. However, she was treated with bosentan on the basis of her worsening pulmonary hypertension. In the absence of significant mitral regurgitation, the presence of a large V wave indicates poor atrial compliance, and as outlined below, reduction in atrial compliance may be an important mediator of secondary pulmonary hypertension in mitral stenosis or in patients with heart failure regardless of ejection fraction. Indeed, large atrial V waves in the absence of mitral regurgitation can occur in patients with several types of cardiac disease.89 This case also underscores the potential for development of worsening pulmonary edema after the initiation of pulmonary vasodilators. This may be related to the preferential vasodilatory effect on the pulmonary vasculature with increased blood flow to a noncompliant left ventricle as has been described with inhaled nitric oxide.10–13 Alternatively, this may be related to volume retention associated with endothelin receptor antagonism.14CASE 2: A 72-year-old man with a history of long-standing hypertension, atrial fibrillation, diabetes mellitus, and previous aortic valve replacement for aortic stenosis and mitral valve repair for mitral regurgitation presents with progressive dyspnea. Echocardiography demonstrated a normal ejection fraction, a normally functioning aortic prosthesis, diastolic dysfunction, and biatrial enlargement. There was no mitral stenosis and only mild mitral regurgitation. The right ventricular systolic pressure was estimated at 51 mmHg. A right and left heart catheterization using a transseptal approach was performed and revealed systemic arterial hypertension with a central aortic pressure of 170/63 mmHg. Contrast ventriculography revealed only mild mitral regurgitation despite the systemic hypertension. Transseptal left atrial and left ventricular pressures revealed the absence of any significant transmitral gradient. Left atrial pressure tracings demonstrated a large V wave of over 50 mmHg with a mean left atrial pressure of 28 mmHg (Figure 2). The pulmonary arterial systolic pressure was 48 mmHg. Nitroglycerin administration reduced the systemic pressure to 121/51 mmHg and the V wave in the left atrium fell to 22 mmHg with a mean left atrial pressure of 15 mmHg.The hemodynamic profile of this patient is one of diastolic heart failure related to hypertensive heart disease with moderate secondary pulmonary hypertension that was largely due to the passive effects of pulmonary venous hypertension and still reversible with normalization of the PCWP. Again, the presence of large atrial V waves suggests decreased atrial compliance.CASE 3: An otherwise healthy 30-year-old woman presents with a 12-month history of progressive dyspnea, fatigue, and peripheral edema. Physical examination revealed a markedly elevated jugular venous pressure, loud S2P, parasternal lift, and peripheral edema. Echocardiography showed normal left ventricular size and function, systolic flattening of the interventricular septum (D-shaped left ventricle), severe right ventricular and right atrial enlargement, a small pericardial effusion (Figure 3), mild tricuspid regurgitation, and severe pulmonary hypertension. The estimated right ventricular systolic pressure calculated from the tricuspid regurgitant velocity was 97 mmHg (107% of systemic systolic blood pressure). Left ventricular diastolic assessment with transmitral inflow pulsed-wave Doppler revealed a reduced early-to-late (E/A) filling velocity ratio and a prolonged deceleration time (Figure 4A), reduced pulmonary venous diastolic flow velocity (Figure 4B), and reduced tissue Doppler early diastolic septal annulus velocity (Figure 4C), all suggesting the presence of impaired left ventricular relaxation (grade I diastolic dysfunction). Right heart catheterization confirmed severe pulmonary hypertension and elevated right ventricular diastolic and right atrial pressures in the presence of a normal PCWP.Although this patient has diastolic dysfunction (impaired relaxation) related to her chronic right ventricular pressure overload, it is not the type of diastolic dysfunction that will be associated with increased filling pressures, at least at rest (see discussion of echo assessment of diastolic function and Figure 5 below). No formal assessment of left ventricular compliance was performed. However, even if reduced compliance was present, it was not associated with elevated filling pressures in this case. However, her transtricuspid inflow pattern showed a high E/A ratio and a short deceleration time (Figure 4D) and her hepatic vein Doppler flow pattern showed reduced systolic forward flow and increased atrial reversal velocities (Figure 4E); all suggestive of severe right ventricular diastolic dysfunction with reduced right ventricular compliance (grade III-IV diastolic dysfunction). This is consistent with the elevated right atrial pressure demonstrated at her catheterization.The echocardiogram from this patient illustrates the effect of severe right ventricular pressure overload on right and left ventricular diastolic function. There is evidence of impaired relaxation but no Doppler evidence of decreased left ventricular compliance or elevated filling pressures. This is the type of diastolic dysfunction most frequently observed in patients with IPAH. The concept of ventricular interdependence and its effect on left ventricular diastolic function is discussed in detail below.Epidemiologic studies have established that 50% of patients with a clinical diagnosis of heart failure have preserved ejection fraction and this entity has been referred to as diastolic heart failure.12 Patients with diastolic heart failure are generally elderly but a significant subset are somewhat younger. Although there is a predominance among women, the syndrome also frequently affects men. More recently, the term “heart failure with normal ejection fraction” has been suggested because of concerns that diastolic dysfunction may not be present in all patients.1516Risk factors for diastolic heart failure beyond advanced age and female sex include hypertension, coronary artery disease, and risk factors for coronary artery disease, including diabetes.1 Although classically described in patients with left ventricular hypertrophy, echocardiographic evidence of left ventricular hypertrophy is not uniformly present. Indeed, fewer than 50% of patients have left ventricular hypertrophy in several series of patients with diastolic heart failure.1718Although the diagnosis of diastolic heart failure is predicated on the presence of clinical heart failure, a normal ejection fraction, and the absence of significant left-sided valve disease, the proper methods to confirm the presence of diastolic dysfunction remain controversial. To characterize left ventricular diastolic function, invasive assessment of the two primary components of diastolic function, left ventricular relaxation and compliance, is needed.The degree of impairment in left ventricular relaxation can be quantified by calculating the time constant of isovolumic relaxation (tau) from a high fidelity left ventricular pressure tracing. Impairment in relaxation likely contributes to symptoms of dyspnea with exercise where brisk relaxation is needed to enhance early diastolic filling without increased left atrial pressures. Patients with significantly impaired relaxation are dependent on left ventricular filling during atrial contraction (atrial kick) to maintain filling without increased atrial pressure and thus are prone to develop acute diastolic heart failure associated with the onset of atrial fibrillation. As the speed and extent of left ventricular relaxation are very dependent on after-load, relaxation may become severely impaired with hypertensive episodes19 and contribute to elevation in mean left atrial pressures, as is likely the case in patients with a normal ejection fraction (hypertensive pulmonary edema).20Assessment of alterations in left ventricular compliance depends on demonstration of an upward and leftward shift of the end diastolic pressure volume relationship (LV-EDPVR) such that the left atrial pressure required to fill the left ventricle to a normal volume is markedly elevated. Marked reduction in left ventricular compliance is clearly present in patients with rare diseases such as infiltrative cardiomyopathy due to amyloidosis, in those with primary restrictive cardiomyopathies, and in some patients with hypertrophic cardiomyopathy. In these patients, blood pressure is low, left ventricular volumes are normal to reduced, and left atrial pressures are chronically elevated. Attempts to lower atrial pressures with diuretic therapy often result in hypotension as left ventricular filling is dependent on markedly elevated filling pressures. Whether the more typical patients with diastolic heart failure (who are often hypertensive) have reduced left ventricular compliance remains somewhat controversial.21 Demonstration of reduced compliance mandates the need for the instantaneous assessment of left ventricular pressure and volume over a range of pressures and volumes produced by increasing or decreasing preload. Highly accurate instantaneous assessment of left ventricular volume and pressure is very difficult to obtain. In of the is the only of such some studies have echocardiography and left ventricular pressure even once with the the the of the which is it difficult to a that the and of the and advanced are Doppler echocardiography can be very in information diastolic function and filling pressures. Doppler (Figure consistent with impaired relaxation with normal filling pressure (grade I diastolic impaired relaxation with moderate elevation of filling pressures (grade diastolic impaired relaxation with severe elevation of filling pressures that can be with (grade diastolic or impaired relaxation with severe elevation of filling pressures that can not be with (grade diastolic have been described and invasive assessment of left ventricular relaxation and filling these Doppler with the severity of diastolic dysfunction several and among these is that the elevation of filling pressures by these is by a reduction of left ventricular of this is the that this has been to with worsening suggesting that the elevated filling pressures in the Doppler are the result of progressive ventricular and diastolic dysfunction than volume overload. this may not be the case in diastolic assessment is somewhat difficult to and is by atrial fibrillation, and atrial systolic dysfunction. Left atrial may also be a of chronic atrial pressure overload and the Doppler no other assessment of diastolic function frequently performed in clinical Doppler of the tricuspid inflow and hepatic vein inflow can be performed to right ventricular diastolic function, as in the in diastolic function studies have diastolic function in patients with diastolic heart assessment of impaired ventricular relaxation and reduced ventricular compliance has been demonstrated in a of patients with heart failure and normal ejection small but invasive not a significant in relaxation or compliance as to elderly hypertensive patients without heart failure despite the presence of elevated left ventricular diastolic pressures in heart failure However, in these patients blood pressure and left ventricular diastolic pressure increased in with impairment in relaxation with In such patients, arterial which hypertension and diastolic dysfunction, may be an important to diastolic heart failure even if diastolic function is not markedly that not characterize diastolic function but Doppler assessment of left ventricular filling pressures and echocardiography to volume suggested that volume with normal systolic and diastolic function may the clinical syndrome in some is likely that heart failure with normal ejection fraction is a condition with multiple mechanisms to chronic pulmonary venous left-sided heart failure is the most common cause of pulmonary hypertension has been The passive effect of pulmonary venous hypertension pulmonary artery However, patients also develop “reactive” pulmonary hypertension with in the gradient. This of pulmonary hypertension may be related to factors and dysfunction in chronic heart failure associated with severe systolic dysfunction or mitral chronic pulmonary venous hypertension may to congestive pulmonary vasculopathy characterized by pulmonary with and hypertension related to pulmonary hypertension and/or congestive pulmonary vasculopathy result in pulmonary hypertension beyond that associated with the passive effects of pulmonary venous hypertension and may not be reversible with acute reduction in pulmonary venous pressures or acute pulmonary if have PCWP or if PCWP elevated with or when blood pressure it may be for patients with diastolic heart failure to have elevated pulmonary arterial pressures but a normal PCWP at rest at catheterization and may be needed to the pulmonary venous common in patients with left heart disease, the development of pulmonary hypertension is The factors that to development of significant pulmonary hypertension in the presence of chronic pulmonary venous hypertension are not As the presence of and dysfunction likely a Although early case described severe pulmonary hypertension in patients with diastolic heart failure, the with which patients with diastolic heart failure develop pulmonary hypertension and its severity remain poorly described the presence of pulmonary hypertension in patients with diastolic heart failure in a series of patients with diastolic heart failure and found that the right ventricular systolic pressure in patients with diastolic heart failure was mmHg using Doppler In patients with aortic most of had a normal ejection fraction, the severity of diastolic dysfunction than the severity of aortic stenosis with the severity of pulmonary hypertension and a significant of patients developed severe pulmonary in patients with heart failure and a reduced ejection fraction heart it was the severity of concomitant diastolic dysfunction than ejection fraction or cardiac that with the severity of pulmonary Thus, diastolic dysfunction associated with disease, reduced ejection fraction, or in is the common mediator that in chronic pulmonary venous hypertension and secondary pulmonary hypertension. is not that patients with diastolic heart failure will develop pulmonary to that elderly would be more to the development of pulmonary hypertension as age related systemic vascular has been and pulmonary artery may in arterial are in than in Thus, the elderly patients develop diastolic heart failure may also be more prone to pulmonary hypertension in to chronic pulmonary venous hypertension associated with diastolic heart Alternatively, some patients may have a primary pulmonary of onset and have concomitant diastolic dysfunction related to compliance is a that may contribute to the of diastolic heart failure and to pulmonary hypertension as the of atrial compliance from early hemodynamic studies where large left atrial V waves were described in patients with cardiac diseases in the absence of mitral The large V wave large in left atrial pressure in to the atrial filling that during ventricular mitral and thus reduced atrial Although is on left ventricular diastolic pressures in chronic pulmonary venous hypertension, it is mean left atrial pressure that the degree of pulmonary vascular and high left atrial pressure during ventricular contributes to elevated mean left atrial Indeed, in patients with mitral two studies that in the absence of mitral regurgitation, the presence of reduced atrial compliance as by large atrial V waves was a of the severity of pulmonary hypertension in mitral right ventricular pressure overload can left ventricular diastolic function in several in left ventricular relaxation as as in compliance by the have been ventricular relaxation is the of and the of in and In chronic right ventricular pressure overload, the on the septum is increased and as it the of the septum are The of the septum in and is these factors could contribute to impairment in left ventricular In Doppler echocardiographic studies of impaired relaxation with decreased E/A ratio and increased isovolumic relaxation time and deceleration time have been An pattern (grade I diastolic is associated with normal left ventricular filling pressures and patients with severe IPAH clinical have normal PCWP. Thus, on Doppler echocardiographic the effect of chronic right ventricular pressure overload on relaxation with in left ventricular filling patients have normal PCWP to be with there is evidence that chronic right ventricular pressure overload can cause reduced left ventricular The the include right ventricular pressure and pericardial The effect of right ventricular pressures on the is and is in the presence of an both acute and chronic pulmonary and showed that the was leftward by acute or chronic right ventricular pressure The shift in the with acute right ventricular pressure overload was related to ventricular interdependence with in left ventricular volume related to leftward shift of the septum as right ventricular pressures effects were also in chronic right ventricular pressure overload, but a in compliance by the was also This not in acute right ventricular pressure overload, suggests that chronic right ventricular pressure overload left ventricular Whether this effect is by the or whether the left ventricular also is However, showed that the effect of right ventricular pressures on the was in the presence of chronic right ventricular pressure overload produced by pulmonary artery in the with concepts by showed that when the of the septum was than the of the left ventricular right ventricular pressures had effect on the Although this was performed in the absence of the showed that the in chronic right ventricular pressure overload and that not right or left ventricular filling pressures or cardiac these studies and studies in the confirm effects of right ventricular pressure overload on left ventricular diastolic function, the clinical of left ventricular diastolic dysfunction associated with chronic right ventricular pressure overload is difficult to In the studies of and with acute and chronic right ventricular pressure overload had left ventricular diastolic pressures that were not from those of Although the compliance of the left ventricle was reduced, it was not reduced to result in elevated left ventricular filling pressures. in with chronic pulmonary hypertension related to disease, of left ventricular diastolic compliance were reduced and after but PCWP was normal both and after Lastly, patients IPAH have severe pulmonary hypertension, often with severe right ventricular and dysfunction and yet have normal PCWP. studies would suggest that left ventricular diastolic function is in it is not to result in elevated PCWP. However, as most studies in IPAH were performed in the of a patients with elevated PCWP are the of left ventricular diastolic dysfunction severe to result in elevated filling pressures in patients with IPAH may be is likely that diastolic heart failure is an cause of pulmonary hypertension and that otherwise unexplained dyspnea and pulmonary hypertension in elderly patients with a normal ejection fraction and normal of diastolic heart failure as as IPAH. diastolic heart failure with secondary pulmonary hypertension and IPAH with secondary diastolic dysfunction can be may be and evidence of left ventricular hypertrophy, left atrial enlargement, and Doppler evidence of advanced diastolic dysfunction may favor the diagnosis of diastolic heart However, not all patients with diastolic heart failure have echocardiographic evidence of left ventricular hypertrophy and not all echocardiographic a diastolic assessment left atrial patients with significant pulmonary hypertension undergo right heart catheterization and if the PCWP is elevated a diagnosis of pulmonary be made even if there is a significant In patients with an elevated one for evidence of systemic hypertension and if present, of a systemic to lower arterial pressures be reduction in PCWP with normalization of blood pressure the diagnosis of diastolic heart with exercise in elderly patients with pulmonary hypertension in diastolic heart failure is may be Marked elevation in PCWP and blood pressure with exercise would the diagnosis of diastolic heart failure that could be causing the symptoms and pulmonary hypertension. Patients with severe IPAH not in PCWP during one for evidence of reduced atrial compliance V waves in the PCWP may also be and if associated with in a diagnosis of diastolic heart failure would be if diastolic heart failure is be with of that are very for the pulmonary vasculature as inhaled nitric as in right heart in the presence of a noncompliant left ventricle may result in in left atrial pressure and pulmonary as outlined patients with pulmonary hypertension and a PCWP of 15 mmHg or have been from pulmonary arterial hypertension remains often patients with pulmonary arterial hypertension and an elevated PCWP are treated with and whether whether patients with diastolic heart failure and pulmonary hypertension would from of the pulmonary hypertension is Although of was associated with increased in patients with systolic heart the for the increased is and the in diastolic heart failure, or with may be and This patient the progressive development of pulmonary hypertension on a of longstanding and diastolic heart would that she has secondary pulmonary hypertension and not IPAH of her pulmonary hypertension may be characterized by some as of to her left heart without of severity of her chronic pulmonary venous hypertension, one can not that is the case. chronic pulmonary venous hypertension related to mitral stenosis diastolic can result in severe pulmonary hypertension that is by increased and that can to to after of mitral for diastolic heart failure is as no therapy has been to in this Thus, of therapy for pulmonary hypertension in such patients is not As the of for IPAH have been to patients with pulmonary hypertension related to tissue disease, to in patients with diastolic heart failure and secondary pulmonary hypertension would be a for However, the potential for worsening pulmonary congestion be as was observed in this This patient a of pulmonary hypertension secondary to diastolic heart In this the pulmonary hypertension is largely related to the passive effect of the pulmonary venous hypertension and is acutely The diagnosis of diastolic heart failure with secondary pulmonary hypertension is to in this This patient has IPAH and has diastolic dysfunction but not have elevated PCWP. The impairment in left ventricular relaxation by the septum and septal causes in the left ventricular diastolic that are generally associated with normal filling pressures at Although in left ventricular compliance related to ventricular interdependence have been described in and could to elevated left ventricular filling pressures, elevated left ventricular filling pressures are not commonly in patients with IPAH. However, as formal assessment of left ventricular compliance with pressure volume over a range of was not performed in this can not the presence of decreased compliance with normal PCWP related to decreased filling as a result of her severe pulmonary hypertension and right ventricular dysfunction. In she has severe right ventricular systolic and diastolic dysfunction with elevated right ventricular diastolic