Epidemiology of Pulmonary Hypertension in Left Heart Disease

    Epidemiology of Pulmonary Hypertension in Left Heart Disease Ashrith Guha, Javier Amione-Guerra, Myung H. Park PII: DOI: Reference:

S0033-0620(16)30053-6 doi: 10.1016/j.pcad.2016.07.001 YPCAD 739

To appear in:

Progress in Cardiovascular Diseases

Received date: Accepted date:

4 July 2016 4 July 2016

Please cite this article as: Guha Ashrith, Amione-Guerra Javier, Park Myung H., Epidemiology of Pulmonary Hypertension in Left Heart Disease, Progress in Cardiovascular Diseases (2016), doi: 10.1016/j.pcad.2016.07.001

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ACCEPTED MANUSCRIPT Epidemiology of Pulmonary Hypertension in Left Heart Disease

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Authors: Ashrith Guha MD MBBS MPH1, Javier Amione-Guerra MD2, Myung H Park MD2

Myung H Park MD FACC

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Address for correspondence:

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Affiliations: 1Houston Methodist DeBakey Heart and Vascular Center and Weil Cornell Medical College; 2Houston Methodist DeBakey Heart and Vascular Center

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Methodist DeBakey Heart and Vascular Center Houston Methodist Hospital

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6550 Fannin Street Houston, TX 77030

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713-441-1100

[email protected]

Conflict of interest: None Financial disclosures: None

Key Words: Pulmonary Hypertension, Heart Failure, Valvular Heart Disease, Epidemiology

ACCEPTED MANUSCRIPT Abstract Pulmonary hypertension (PH) in the setting of left side heart disease is associated with

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adverse outcomes. The exact prevalence of PH in the different pathologies that affect

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the left ventricle, however, is difficult to access with the current literature. The lack of a standard definition of PH in older studies, the different modalities to assess pulmonary

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artery pressures and the varying disease severity, all account for the great variability in

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the reported prevalence of PH. PH can accompany heart failure (HF) with reduced (HFrEF) or preserved [1] ejection fraction (HFpEF) as well as mitral and aortic valve

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disease; in any of these instances it is important to recognize whether the elevation of pulmonary pressures is driven by elevated left ventricular pressures only (isolated post-

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capillary PH) or if there is an accompanying remodeling component in the pulmonary

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arterioles (combined post-capillary and pre-capillary PH). The objective of this review is to describe the definitions, prevalence and the risk factors associated with the

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development of PH in the setting of HFrEF, HFpEF and valvular heart disease.

ACCEPTED MANUSCRIPT List of Abbreviations AR: Aortic Regurgitation AS: Aortic Stenosis

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AVR: Aortic Valve Repair COPD: Chronic Obstructive Pulmonary Disease

Cpc-PH: Combined Pre and Post Capillary Pulmonary Hypertension

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DPG: Diastolic Pressure Gradient

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EF: Ejection Fraction HF: Heart Failure

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HFpEF: Heart Failure with Preserved Ejection Fraction HFrEF: Heart Failure with Reduced Ejection Fraction Ipc-PH: Isolated Post Capillary Pulmonary Hypertension

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LA: Left Atrium LHD: Left Heart Disease

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LV: Left Ventricle

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LVEDP: Left Ventricular End-Diastolic Pressure mPAP: Mean Pulmonary Artery Pressure

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MR: Mitral Regurgitation MS: Mitral Stenosis

MVR: Mitral Valve Repair NYHA: New York Heart Association Functional Classification PA: Pulmonary Artery PAH: Pulmonary Arterial Hypertension PAWP: Pulmonary Artery Wedge Pressure PH: Pulmonary Hypertension PMV: Percutaneous Mitral Valvuloplasty PVR: Pulmonary Vascular Resistance RHC: Right Heart Catheterization

ACCEPTED MANUSCRIPT RVSP: Right Ventricular Systolic Pressure RVTG: Right Ventricular Tricuspid Gradient sPAP/PASP: Systolic Pulmonary Artery Pressure

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TPG: Transpulmonary Gradient

ACCEPTED MANUSCRIPT Introduction

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Pulmonary hypertension (PH) associated with left heart disease (LHD) has been

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recognized since the 1800s, predominantly in relation to mitral stenosis. PH has been increasingly associated with heart failure due to reduced ejection fraction (HFrEF), heart

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failure due to preserved ejection fraction and other left sided valvular diseases such as

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aortic stenosis and mitral regurgitation. Recent studies have shown that PH in patients with LHD often marks a phenotype of disease progression and increased morbidity [2].

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Aging population and successful advances in valvular surgery, coronary revascularization and medical therapy of ischemic heart disease have resulted in a

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growing epidemic of PH with LHD. True prevalence of this entity has been difficult to

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ascertain due to varying definitions and differing diagnostic modalities in epidemiological studies. In this review we discuss the definition of PH due to LHD with a focus on the

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prevalence of PH in different phenotypes of LHD, impact of testing conditions on the

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reported prevalence and clinical characteristics associated with PH in LHD.

Definition of PH in LHD PH is defined as mean PA pressure (mPAP) ≥ 25 mm Hg. PH in LHD is differentiated from pulmonary arterial hypertension (PAH) by the presence of pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) of > 15 mm Hg as measured by right (and left) heart catheterization. Since the main differentiating factor here is the PAWP>15 mm Hg which is suggestive of elevated left atrial pressure as the predominant driving force, the term post capillary PH is often used for PH due to LHD.

ACCEPTED MANUSCRIPT Pathophysiologically, this is associated with progressive pulmonary venous remodeling leading to pulmonary vascular structural changes in the advanced stages.

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Epidemiologically the group was further divided into those with isolated post capillary

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PH (Cpc-PH) also known as “out of proportion PH”.

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PH (Ipc-PH) or PH with passive congestion, and those with both pre and post capillary

Patients with Ipc-PH have passive congestion and are characterized by their mean PA

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pressure being responsive to decreasing PAWP with afterload reduction with

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medications such as nitroprusside or to preload reduction with diuresis. Patients with Cpc-PH develop progressive elevation of mPAP that is higher than what would be

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expected from PAWP elevation alone.

Traditionally Ipc-PH (also called as passive PH) was defined based on a

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transpulmonary gradient (TPG: defined as mPAP-PAWP) ≤12 mm Hg and pulmonary

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vascular resistance (PVR) ≤ 3 Wood units and Cpc-PH was defined based on elevated

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TPG (>12 mm Hg) and PVR (>3 WU), also referred to as mixed, disproportionate, or out of proportion PH[3, 4] While these parameters have been used to risk stratify survival in HFrEF patients undergoing heart transplantation and HFpEF populations, both parameters (TPG and PVR) are less than ideal due to their interdependence on cardiac output and PAWP. During the 5th World Symposium on PH, diastolic pressure gradient (DPG) was revived as a marker of Cpc-PH, since it was independent of cardiac output and was not influenced by PAWP[5]. The utility of DPG was seen in a single center study of 3107 patients who underwent RHC. Of these patients1094 (79%) patients had post-capillary

ACCEPTED MANUSCRIPT PH, of which 490 (49%) had TPG > 12. In a ROC analysis DPG had the best predictive value in differentiating patients with marked pre-capillary remodeling, whose poor

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survival rate was comparable to patients with PAH. The cut-off obtained through AUC

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analysis was 7 mm Hg. In addition lung biopsy analysis among 43 patients revealed that TPG and DPG combined correlated with the progressive changes in the pulmonary

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vasculature (medial hypertrophy, fibrosis). Hence a new classification was proposed for

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PH-LHD, namely isolated post-capillary PH (Ipc-PH) identified by DPG < 7 mm Hg and

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combined post-capillary and pre-capillary PH (Cpc-PH) identified by DPG ≥ 7 mm Hg[6]. Two large analysis, including one from UNOS database, evaluating the utility of DPG as

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a marker of pulmonary vascular disease in LHD demonstrated that DPG has no predictive value [7]. One of the major problems with utilizing DPG seems to be the

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reliability of its measurement. DPG is a small number (normal value of 1-3 mm Hg),

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hence vulnerable to errors in measurement. Secondly, DPG appears to have a ‘U shaped’ relationship in risk assessment with low DPG also predicting poor outcome. It

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also increases with increasing heart rate which can be a common confounder in patients with decompensated heart failure[5]. Hence the updated ESC/ERS guideline incorporates both PVR and DPG by defining Ipc-PH as DPG<7 and/or PVR≤3 WU and Cpc-PH as DPG≥7 and/or PVR>3 WU [8]. Impact of Diagnostic Testing Modalities and study population on prevalence of PH in LHD Prevalence of PH in all forms of LHD are impacted by diagnostic modality used to diagnose PH and the population studied. Although diagnosis and classification into

ACCEPTED MANUSCRIPT subtypes of PH due to LHD is based on RHC, most epidemiological studies predate the classification schema and have used echocardiography as a primary diagnostic tool for

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especially when delineating risk factors associated with PH.

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PH. This leads to misclassification bias and often contributes to conflicting information

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It is becoming more evident through epidemiological studies that one of the primary drivers of PH in LHD is worsening diastolic function and restrictive physiology.

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Restrictive filling pattern progresses as the severity of HF advances and hence

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prevalence of PH in LHD likely increases as the underlying disease progresses in severity [2]. However this is accompanied by an increase in mortality with worsening

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LHD which leads to survivor risk bias in prevalence studies depending on the stage of the disease when the population is sampled.

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In addition invasive diagnostic tests such as right heart catheterizations may not be

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performed in certain centers till late in the advanced stage of LHD (ACC/AHA stage C-

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D) which limits data in the early stages of disease.

A. Echocardiography as a diagnostic modality in epidemiological assessment Utilizing echocardiographic derived systolic PA pressure rather than invasively measured mPAP as guidelines recommend is very common in epidemiological studies. Though the invasive definition uses mean PA pressure ≥ 25 mm Hg, the echocardiographic definitions of PH often use calculated systolic PA pressure cut offs ranging from 40 to 60 mm Hg. This can often reflect a mean PA pressure of 25 mm Hg or greater based on either of Chemla (mPAP = 0.61×sPAP +2 mmHg)[9] or Syyed

ACCEPTED MANUSCRIPT (mPAP = 0.65×sPAP +0.55 mmHg)[10] formula to derive mPAP. However the limits of agreement of echo based measurements to catheter based mPAP measurements are

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wide ranging from -12 mm Hg to +12 mm Hg[11]. Hence echo can often misclassify

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patients and it has been noted that echo can underestimate pulmonary artery pressure in up to 80% of patients and overestimate pulmonary pressures in 38% with an

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accuracy of only 48%[12].

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Recently there have been 2 different scores using echo parameters such as e/e’, LA

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dimensions, RV eccentricity index and IVC dimension to detect PH in LHD and differentiate Ipc-PH and Cpc-PH with reasonable accuracy [13, 14]. However there are

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no independent prospective epidemiological studies which have validated these in other centers [15].

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Prevalence of PH in HFrEF,HFpEF and valvular diseases based on echocardiography

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is summarized in tables 1,2 and 3. In summary the prevalence appears to be upward of

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50% when a sPAP cut off of 35 mm Hg is chosen while with a higher cut off such as 50 mm Hg the prevalence drops down to 40-50% in all the subgroups[16-21].

B. Impact of RHC performance variables on classification of PH due to LHD Since the diagnosis is made primarily based on right heart catheterization, performance technique heavily impacts classification of patients. It is common practice for pulmonary artery wedge pressure measurement to be made during the end expiratory phase. While this minimized misclassification of patients with PH due to LHD as PAH, a recent study showed that it may classify up to 29% of patients with PAH as PH due to LHD[15].

ACCEPTED MANUSCRIPT The study included patients with lung disease, increased body mass index and COPD who exhibited marked respiratory variation. In these patients the end expiratory mean

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may not be the best measure of true left ventricular end diastolic pressure and the

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computer generated mean may be the closest measure to the true left sided filling

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pressure.

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C. Effect of continuous hemodynamic monitoring in reclassification of PH Determining pulmonary pressures based on a single measurement in time often only

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provides a snapshot assessment and could lead to under diagnosis. Since the recent approval of the implantable PA pressure monitoring device, data is emerging providing

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more insight into this phenomenon. In a recent study by Raina et al. in a group of both HFrEF (70%) and HFpEF(30%) patients who had symptomatic HF (NYHA class III) with

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one recent heart failure hospitalization, 48% of patients who did not have PH on RHC

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had a mPAP>25 mm Hg on remote PA pressure monitoring (mPAP of 31 mm Hg). Also

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these patients had higher risk of repeat hospitalizations compared to patients who did not have PH on remote monitoring [22]. Pulmonary Hypertension in Patients with Heart Failure with Reduced Ejection Fraction (HFrEF) Prevalence of PH in patients with HFrEF is high around 60-70% irrespective of the diagnostic modality or the corresponding definition (Table 1). However the prevalence and proportion of Cpc-PH patients increase as the disease progresses. In a study 836 patients with an EF <45%(likely more Stage C), the prevalence of PH was 69% (mPAP ≥25 mmHg and PAWP ≥15 mmHg) with most common type of PH being Ipc-PH 58%,

ACCEPTED MANUSCRIPT with Cpc-PH present in 11% of the patients with PH(defined by DPG). In a study of patients with LVEF<35% (likely Stage C and Stage D), 73% had PH with 33% having

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Ipc-PH and 40% having Cpc-PH (using PVR>3 as definition of Cpc-PH). In a population

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corresponding to later disease stages of HFrEF (Stage D patients undergoing transplant evaluation), higher proportion of patients, about 40% had PVR>2.5, and about 19% of

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Prevalence of PH in HFpEF Patients

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patients with PVR>5 WU [23].

There has been growing evidence that PH in the setting of HFpEF (PH-HFpEF) is a

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very prevalent condition that is associated with adverse outcomes [17]. Independent of the methodology for the diagnosis of PH (echocardiography or invasive

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hemodynamics), pulmonary hypertension in HFpEF has been shown to be strongly

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associated to adverse outcomes [24, 25].

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Identical to HFrEF echocardiography defined prevalence of PH appears to be higher when compared to invasive studies. In a community-based study by Lam and colleagues they found that 83% of their HFpEF patients had PH [17] defined as PASP >35 mmHg by Doppler echocardiography and PAWP was estimated using the E/e’ ratio. In two different studies using invasive hemodynamics to diagnose PH (mean PA >25 mmHg and LVEDP >15 mmHg) the prevalence of PH-HFpEF was 52.5% [6, 26]

ACCEPTED MANUSCRIPT PH prevalence in patients with left atrial dysfunction

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Stiff Left Atrial Syndrome

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Left atrial dysfunction is increasingly being recognized as a major contributor to development of PH. As a classic phenotype of left atrial dysfunction, stiff left atrium

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syndrome has been described in patients undergoing mitral valvular surgery and atrial

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fibrillation ablation. After atrial fibrillation ablation it develops in 2% of patients and PH is reported to be present in almost 100% of the patients and is the primary cause of

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dyspnea. Large left atrial size (pre procedure LA size>45 mm), obesity, sleep apnea and increased left atrial scar (>60% of atrium) have been associated with development

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of PH after atrial fibrillation ablation [27].

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PH due to Valvular Disease

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Pulmonary hypertension is an established pathophysiological manifestation of advanced aortic and mitral valve disease. As in HFpEF and HFrEF, true prevalence is unknown due to the use of echocardiography to define PH (table 3). a. Aortic Valvular Disease The presence of PH in patients with aortic stenosis has been reported in the range of 20-40% depending on diagnostic modality and definition used. A recent study of invasive catheterization in patients with severe aortic stenosis found that prevalence of PH was high as 75%. In this study they also used the newer definition with DPG to divide patients into Ipc-PH and Cpc-PH [28]. Patients with Cpc-PH had an immediate

ACCEPTED MANUSCRIPT improvement in systolic pulmonary pressure after aortic valve replacement (57.8 ±14 versus 50.4 ±17 mmHg; p=0.01) while those with Cpc-PH did not (49.0 ±12 versus 51.6

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±14.3 mmHg; p=0.3). While those with Ipc-PH had two fold higher risk of mortality, risk

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increased to three fold in patients with Cpc-PH.

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Data on PH in relation to aortic regurgitation is scant. Prevalence seems to be about 24-28% based on echo estimates of sPAP>40 mm Hg and may impact survival in

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these patients postoperatively[29].

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b. Mitral Valvular Disease

Prevalence of PH in patients with mitral stenosis can be as high as 56%, based on

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invasive hemodynamic study [30]. In patients with primary mitral regurgitation (MR),

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prevalence of PH depends on the severity of mitral regurgitation. It has been reported between 20-30% at rest [31, 32] and as high as 58% during exercise in patients with no

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or mild symptoms [19, 33]. Pulmonary hypertension in patients with functional or

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secondary mitral regurgitation is also a common phenomenon seen in about 50-60% of patients. Presence of PH in mitral valvular disease is associated with poor survival and increased morbidity.

Data for impact of PH on survival after valvular procedure is mixed. In patients with MS, 10-year survival after surgical MVR has been reported between 60-80% with no difference in perioperative death between groups with and without PH [34-36]. Similarly in 926 patients undergoing percutaneous mitral valvuloplasty (PMV), PVR was not a predictor of long term survival [37]. However in patients with mitral regurgitation PH has

ACCEPTED MANUSCRIPT an adverse impact on post procedure survival with lower 10 year survival in patients with PH (85.2 ± 4% vs 89.7±1%) compared to those without PH.

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Epidemiological associations and clinical characteristics associated with PH in LHD

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Identification of risk factors are important, to screen and intervene in patients with PH in LHD. Increasing age appears to be risk factor for PH in LHD [24, 38]. This is likely

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related to age related increase in vascular stiffness and impaired LV relaxation [39]. In a

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recent study by Gerges et al. age less than 77 years appeared to be predictive of CpcPH[6]. Though this points to a U shaped relationship with age, this likely represents

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survivor bias with increased mortality in older patients more severe PH.

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Metabolic syndrome also appears to have an inconsistent relationship with risk of PH. This may be due to the obesity paradox seen in HF where in obesity seems to have a

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protective effect on ventricular function deterioration.

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Some of these associations, especially demographic characteristics have been inconsistent between different studies, likely due to non-standardization of diagnostic modalities and definitions across studies. However elevated end diastolic pressure, severity of diastolic dysfunction and presence of mitral regurgitation have been most consistently associated with PH with LHD. (Table 3) Conclusion PH has been increasingly associated with all forms of LHD and has been associated with poor prognosis. Progress in standardizing definitions has improved our ability to recognize the phenotype. Associated demographic characteristics enable us to identify

ACCEPTED MANUSCRIPT the at risk population though effect of some of the characteristics to actual development

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of disease remains unknown.

ACCEPTED MANUSCRIPT Table 1. Epidemiology of WHO Group II PH in patients with HFrEF Definitions/Selection Overall Criteria Used Prevalence of PH

Phenotype of PH Ipc-PH CpcPH Catheter Based Studies

Impact on Outcomes

Miller et al[21]. (n= 463)

EF: ≤40% mPAP ≥25 mmHg PAWP ≥15 mmHg iPcPH vs cPcPH: PVR ≥3 WU

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77%

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EF: <45% mPAP ≥25 mmHg PAWP ≥15 mmHg iPcPH vs cPcPH: DPG ≥7 mmhg

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43% 57% (TPG: (TPG: 9 17 mmHg) mmHg)

Patients with cPcPH had a 2-fold increase in mortality.

69%

84%

16%

Benza et al[22] (n= 412)

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Gerges et al[6] (n= 836)

62%

mPAP increases of 5mmHg had an adjusted HR of 1.1 for overall survival.

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EF: <35% mPAP > 20 mmHg iPcPH vs cPcPH: Not Analyzed

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Ghio et al[2]. (n= 379)

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Study (n)*

EF: <40% mPAP > 25 mmHg iPcPH vs cPcPH: Not Analyzed

63%

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cPcPH patients had decreased survival versus iPcPH (median survival 72 mos. vs 110 mos.) Patients with PH had higher HF hospitalization rates vs non PH (0.77/year vs 0.37/year)†

Echocardiography Based Studies Miller et al[40] (n = 1,541) Szwejkowski et al[41] (n = 1612)

EF ≤40% PASP ≥45 mmHg

35%

Qualitative LVSD PH Not defined

RVSP ≥45 mmHg: 48% RVSP >52 mmHg:

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No outcome analysis

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Every 5 mmHg increase in RVSP is associated with a 6%

ACCEPTED MANUSCRIPT

Damy et al[42] (n =270)

EF <45% RVTG >35mmHg

35% PASP >45 mmHg

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Mean EF 23% No predefined criteria for PH

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Shalaby et al[38] (n = 270)

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24%

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29%

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increase in mortality PASP >45 mmHg was associated with a 2.6 fold risk of death or transplant and a 6 fold increase in HFadmissions RVTG >35 mmHg was associated with a 2 fold increase in mortality†.

†This conclusion applies to a mixed population of HFrEF and HFpEF

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*In studies with mixed populations (i.e. HFrEF and HFpEF) the data represents only that pertinent to patients with HFrEF

ACCEPTED MANUSCRIPT Table 2. Epidemiology of WHO Group II PH in patients with HFpEF. Definitions/Selection Criteria Used

Leung et al[26] (n = 455)

EF ≥50% PASP >25 mmHg PAWP: 15 mmHg Cutoff for diastolic dysfunction not specified PASP >25 mmHg PAWP: 15 mmHg

Prevalence

Phenotype of PH Ipc- CpcPH PH Catheter Based Studies

Impact on Outcomes

62%

Benza et al[22] (n= 116)

EF: ≥40% mPAP > 25 mmHg iPcPH vs cPcPH: Not Analyzed

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Gerges et al[6] (n =618)

EF: ≥45% mPAP ≥25 mmHg PAWP ≥15 mmHg iPcPH vs cPcPH: DPG ≥7 mmhg

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52.5%

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Hurdman et al[43] (n =157)

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Study (n)*

77%

23%

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47%

Echocardiography Based Studies EF ≥50% PASP >35 mmHg 83% PAWP: 11.96 + 0.596 * E/e’

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Lam et al[17] (n = 203)

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54%

Shah et al[25] (n= 450)

EF ≥45% TR Velocity: >2.9 m/s

Vanhercke et al[44] (n = 192)

ADHF Age: ≥75 years EF ≥50% PH: TR gradient >30 mmHg

36%

51%

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No outcomes studied No significant difference in outcome between PH-HFpEF vs PHHFrEF cPcPH patients had decreased survival versus iPcPH (median survival 54 mos. Vs 102 mos.) Patients with PH had higher HF hospitalization rates vs non PH (0.77/year vs 0.37/year, p<0.01)† There was a 30% increase in mortality per 10 mmHg of PASP. Higher PAP was predictive of HF admission and cardiovascular death PH was an independent predictor of allcause mortality.

ACCEPTED MANUSCRIPT

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*In studies with mixed populations (i.e. HFrEF and HFpEF) the data represents only that pertinent to patients with HFrEF

ACCEPTED MANUSCRIPT Table 3. Epidemiology of WHO Group II PH in patients with VHD.

Faggiano et al (n =388)[46]

RHC

Kapoor et al (n =626)[47]

ECHO

Zlotnick et al (n =1116)[11]

O’Sullivan et al (n =433)[28]

Naidoo et al (n= 139) [29]

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ECHO

Patients undergoing AVR for AS Doppler PASP >35 mmHg

47%

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RHC

Patients undergoing AVR for AS Mean PA pressure ≥25 mmHg

48%

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RHC

RHC

Impact on Outcomes

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19%

Patients undergoing TAVI Mean PA pressure ≥25 mmHg 62% 82% LVEDP >15 mmHg iPcPH vs cPcPH: DPG ≥7 mmHg Aortic Valvular Disease: Aortic Regurgitation Patients with isolated, severe AR 24% PASP >60 mmHg

PH patients had a higher incidence of HF, lower EF and CI.

Not an outcomes study

Patients

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Severe AS Doppler PASP ≥60 mmHg

Pre-op PH increased postop mortality (9% vs 5%) as well as LOS (8 vs 7 days) Association with PH and 5-year survival, adjusted HR: 2.4 for severe PH

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Melby et al (n =1080)[20]

Phenotype of PH Ipc-PH CpcPH Aortic Valvular Disease: Aortic Stenosis Severe AS PASP >50 mmHg 29% 62% 38% iPcPH vs cPcPH: TPG ≥10 mmHg Mean TPG in Symptomatic AS Mild-Mod: 8.8 Mild-Moderate PH: PASP Mild-Mod: mmHg 31 – 50 mmHg 50% Mean TPG in Severe PH: PASP >50 Severe: 15% Severe: 15 mmHg mmHg

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RHC

Prevalence

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Silver et al (n= 45)[45]

Definitions/Selection Criteria Used

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Study (n)*

Diagn ostic Modal ity

18%

Cpc-PH was a strong predictor of 1yr mortality (Adjusted HR: 3.28)

Elevated PASP did not influence early outcome after AVR.

ACCEPTED MANUSCRIPT

Patients with Severe AR PASP ≥60 mmHg

16%

-

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MBV was safe and effective in treating patients with MS and PH

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ECHO

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Khandhar et al (n =506)[16]

Patients with PH and AVR had better survival than those with PH and no repair (90% vs 58% 1yr survival)

Mitral Valvular Disease: Mitral Stenosis

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RHC

Patients undergoing MBV PASP ≥50 mmHg

38%

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Fawzy et al (n= 559)[48]

Mitral Valvular Disease: Mitral Regurgitation Patients with pre-op PH had Patients with organic MR decreased long ECHO 32% PASP ≥50 mmHg term survival (58% vs 86% 8yr survival) Asymptomatic patients Exercise PH was with degenerative MR Resting PH: associated with Magne et Resting PH: PASP >50 12% reduced al ECHO mmHg Exercise PH: symptom free (n= 89)[19] Exercise PH: PASP >60 51% survival (20% vs mmHg 60%) SPAP was a Ghoreishi 53% predictor of ECHO Patients undergoing MV et al SPAP ≥60 operative and/or surgery for MR (n = mmHg in mortality (OR: RHC PH: PASP ≥40 mmHg 873)[49] 17% 1.02) and late death (HR: 1.01) RHC: Right Heart Catheterization. AS: Aortic Stenosis. AVR: Aortic Valve Replacement. LOS: Length of Stay. TAVI: Transcatheter Aortic Valve Implantation. MBV: Mitral Balloon Valvotomy *Unpublished Data

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Le Tourneau et al (n = 256)[18]

ACCEPTED MANUSCRIPT Table 4. Risk Factors for Developing WHO Group II PH by Disease Condition. HFrEF

HFpEF

Female[40, 50]

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Metabolic Syndrome[26, 51]

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Lung Disease[6, 26]

COPD associated with higher risk of CpcPH (OR: 3.57)

Atrial Arrhythmia[26, 38]

Patients with PH had more often a diagnosis of Atrial Arrhythmias (49% vs 34% in no PH)

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COPD associated with higher risk of PH (OR: 2.36)

Atrial Arrhythmias associated with higher risk of PH (OR: 3.0)

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≥Moderate MR was more often present in patients with PH (58%)

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Diastolic Dysfunction[26, 38, 40]

BMI ≥40 kg/m2 associated with increased risk of PH (OR: 3.37)

In patients ≥75 years and HF the prevalence of PH increased with increasing severity of MR: Mild (65%), Moderate (67%), Severe (85%)

Increased LA size, E/e’ ratio ≥15 or DT ≤150 ms associated with higher risk of PH (OR ~3.5)

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Mitral Regurgitation[38, 40, 44]

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Patients with PH were older than those without PH

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Age[6, 24, 26, 38]

Older patients had a higher risk of developing PH (OR: 2.84) Younger patients had a higher risk of developing cPcPH (OR: 0.96) Patients with PH were more often female (82%)

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Risk Factor

LVEDP ≥25 mmHg associated with higher risk of developing PH (OR: 4.3)

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