Outline of Discussion•The impact of co-morbid disease in HFpEF•Pitfalls and pearls in the diagnosis of HFpEF•Mimics?•Outside of the HFpEFdiagnosis•Inside the HFpEFdiagnosis

HFpEFMimics and When to Look for Them:Plenary Session #3: Novel Concepts in the Diagnosis and Treatment of HFpEFHeart Failure Update 2020Lisa M Mielniczuk MD FRCPCProfessor of Medicine, University of Ottawa Heart InstituteVice Chair, Quality and Clinical Care, Department of MedicineDirector, Advanced Heart Failure ProgramDirector, Pulmonary Hypertension Clinic Conflict of Interest Disclosures•Grants/research support: Astra Zeneca, Bayer, Janssen •Consulting fees: Astra Zeneca, Bayer, Janssen, Novartis•Speaker fees: Astra Zeneca, Bayer, Janssen, Novartis Outline of Discussion•The impact of co-morbid disease in HFpEF•Pitfalls and pearls in the diagnosis of HFpEF•Mimics?•Outside of the HFpEFdiagnosis•Inside the HFpEFdiagnosis The Challenge of HFpEF Zakeriet al; Heart 2018; 104:377-384DunleyS. Nat Rev Cardiol2017; 591 The Co-morbid Collection in HFpEFHTN Diabetes Obesity Chronic Kidney diseaseAtrial Fibrillation Coronary disease sleep apnea with a reduction in all-cause mortality (HR 0.70, 95% CI 0.51–0.96) and a lower rate of cardiovascular-related hospitalizations (RR 0.68, 95% CI 0.56–0.81) compared with placebo167. This finding clearly establishes tran - sthyretin cardiac amyloidosis as a separate disorder that is distinct from HFpEF (TABLE/uni00A02), an important distinction because 5–13% of patients originally con - sidered to have typical HFpEF had evidence of cardiac amyloidosis when evaluated with nuclear scintigraphy or at post-mortem examination 168,169. Now that a specific treatment is available, the approach to separate patients with cardiac amyloidosis from those with HFpEF is well supported. Through more rigorous characterization of specific HFpEF phenotypes, and together with clinical trials testing therapeutic approaches targeted to the specific pathophysiology identified, we will hopefully be able to define other groups of patients who should also be separated from typical HFpEF , recapitulat - ing the successes that have been observed for cardiac amyloidosis167. HFpEFa b Comorbidities Cardiac and pulmonary vascular function Haemodynamics Extra-cardiac structure and function Biomarkers Hypertension Obesity Coronary microvascular and macrovascular disease Diabetes mellitus and metabolic syndrome RV dysfunction Pulmonary vascular dysfunction .8CPF.#F[UHWPEVKQPCPFQTCVTKCNȮDTKNNCVKQP LV dysfunction only /uni2191 RVFP and LVFP at rest /uni2191 LVFP at rest with pulmonary hypertension /uni2193 Pulmonary vasodilatation with exercise /uni2191 LVFP with exercise only 6KUUWGȮDTQUKU Sarcopenia and mitochondrial dysfunction Endothelial and coronary microvascular dysfunction /uni2191#TVGTKCNUVKȭPGUU Fibrotic markers Cardiac injury markers 2TQKPȯCOOCVQT[OCTMGTU Normal natriuretic peptide levels Increasing disease severity and risk of adverse outcomes Fig. 3 | Phenotyping in patients with HFpEF . a | Most clinical trials published to date have broadly enrolled all patients with heart failure with preserved ejection fraction (HFpEF), without regard to specific phenotypes, and have generated largely neutral results. b | Classifying patients with HFpEF into subgroups of pathophysiologically homogeneous phenotypes might allow for more precise and targeted therapies. Several strategies have been proposed to classify patients with different characteristics, including the presence of comorbid conditions, cardiac functional status, invasive haemodynamics data, presence of extra-cardiac abnormalities and plasma biomarker levels. The size of each bar is intended to roughly approximate the relative prevalence of each phenotype in the broad population of ‘garden variety’ HFpEF . Disease severity and risk of adverse outcomes increase on moving from left to right. As illustrated, each of these domains overlaps with one another, both within a specific grouping scheme and between different potential phenotyping schemes. LA , left atrial; LV , left ventricular; LVFP , left ventricular filling pressure; RV , right ventricular; RVFP , right ventricular filling pressure. www.nature.com/nrcardio REVIEWS Borlaug; Nat Rev CardiolMarch 2020 Relationship of Comorbid Burden to Outcome in Heart Failure ErgatoudesC; Clin Res in Cardiol2019:108:1025-1033 Interplay Between Comorbid Disease and Underlying Molecular Mechanisms in HFpEFShah et al Research Priorities for HFpEF STATE OF THE ART March 24, 2020 Circulation. 2020;141:1001–1026. DOI: 10.1161/CIRCULATIONAHA.119.0418861006 have diverse physiological actions, mediated by binding to NP receptor A, thereby increasing cGMP/PKG signal - ing.41,42 The NP receptor C (NPRC) functions to clear the NPs from circulation through receptor-mediated inter - nalization. 43 The ability of the NPs to elicit a biological response depends on the relative ratio of the functional receptor NP receptor A to the clearance receptor NPRC. For any given amount of volume overload and congestion, NPs are lower in HFpEF compared with HFrEF because of lower diastolic wall stress in HFpEF compared with HFrEF. Although LV diastolic pressures can be equally high in HFpEF and HFrEF, concentric LV remodeling in HFpEF (compared with eccentric re - modeling in HFrEF) translates to lower wall stress and thus a reduced stimulus for BNP secretion from the A B D E G F C Figure 1. Proposed molecular mechanisms underlying heart failure with preserved ejection fraction (HFpEF). A, Comorbidities are common in HFpEF and are thought to lead to systemic inflammation, which results in microvascular inflammation, widespread endothelial dysfunction (in multiple organs), and coronary microvascular dysfunction, leading to abnormal systolic and diastolic cardiac mechanics and poor cardiac reserve. Sys - temic inflammation also leads to the activation of monocytes and macrophages, which release profibrotic cytokines, including IL-10 and transforming growth factor- β, thereby promoting interstitial organ fibrosis, which in the heart increases passive myocardial stiffness. B, Several factors promote a relative natriuretic peptide (NP) deficiency state in HFpEF, including obesity, sedentary lifestyle, African ancestry, insulin resistance, increased androgenicity in women, genetic variation in the NPPA and NPPB genes, and a lower amount of wall stress for the severity of heart failure (compared with heart failure with reduced ejection fraction). C, NPs are active in adipose tissue, where the relative ratio of the NP receptor A (NPRA) to NP receptor C (RC) are important in dictating whether beneficial NP effects are possible. With increased NPRA, there is increased cGMP and protein kinase G (PKG) production, leading to lipolysis and the brown-fat thermogenic program. With increased NPRC, these beneficial effects are minimized because there is increased NP breakdown. D, Mechanical and metabolic stressors on the cardiomyocyte lead to T-tubule dis - ruption and abnormal calcium handling within the cardiomyocyte, which leads to intracellular calcium overload and inefficient myocardial contraction and relaxation. E, NPs act through a receptor guanylate cyclase (rGC) pathway that results in the creation of cGMP and stimulation of PKG, which has a variety of beneficial effects in the heart and multiple other organs. There is also an intracellular, soluble guanylate cyclase that is stimulated by nitric oxide (NO), which also leads to increased cGMP and activation of PKG. Phosphodiesterase (PDE) 5 results in the breakdown of the NO-based cGMP pool, whereas PDE9 results in the breakdown of the NP-based cGMP pool. F, Multiple mechanisms present in HFpEF can result in stiffening of titin, the major molecular spring within the cardiomyocyte, thereby lead - ing to increased cardiomyocyte (and subsequently cardiac chamber) passive stiffness. Because of insufficient NPs and NO, PKG is reduced in HFpEF , which leads to hypophosphorylation of key sites within titin and increases its stiffness. Extracellular signal–regulated kinase 2 (ERK-2; stimulated by increased cardiomyocyte stretch), protein kinase A (PKA; stimulated by sympathetic stimulation), calmodulin-dependent protein kinase II (CaMKII; stimulated by reactive oxygen species [ROS]), and protein kinase C α (PKCα; stimulated by endothelin-1 [ET-1] and angiotensin-II) all can have deleterious prostiffening effects on titin. G, Although endothelium-de - rived NO is reduced in HFpEF , inducible NO synthase (iNOS), which is activated by systemic inflammation, is upregulated and could be a pathogenic factor leading to HFpEF. In a recent study that used a novel 2-hit mouse model of HFpEF ( Nω -nitro-L-arginine methyl ester, which induces hypertension (HTN)]+high-fat diet [obesity]), iNOS was upregulated, which resulted in S-nitrosylation (nitrosative stress) of the endonuclease inositol-requiring protein 1 α (IRE1α), leading to defective splicing of an unfolded protein response effector (the spliced form of X-box-binding protein 1 [XBP1s]). XBP1s, in turn, was reduced in both the rodent HFpEF model and in myocardial samples from patients with HFpEF , leading to increased levels of unfolded proteins within the cardiomyocytes, which are thought to interfere in normal cardiomyocyte function. ANP indicates atrial NP; BNP , brain NP; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; eNOS, endothelial NO synthase; IL- interleukin; MAPK, mitogen-activated protein kinase; SNO, S-nitrosylation; and SNP , single nucleotide polymorphism. Downloaded from http://ahajournals.org by on April 7, 2020 Shah et al. Circ 2020; 141:1001-1026 Beyond Diastolic Dysfunction: HFpEFis a Systemic Disease HFpEFDiagnosis: Not for the Faint of Heart…. •Lack of a single objective marker to define the syndrome•High frequency of comorbidities that can mimic or accompany the HF syndrome•Natriuretic peptide levels often below typical clinical thresholds•Notion that diastolic function required to diagnose HFpEF•Underuse of provocative testing to elicit functional abnormalities associated with greater v entricular stiffening (67) , altered substrate utilization decreasing myocardial ef/uniFB01ciency (95) ,a b n o r m a lv e n t r i c u l a rf u n c t i o n (84,96) , and greater burden of pulmonary vascular disease (97) .T h ep a t h o p h y s i o l o g i ce v i d e n c eo fc o m b i n e d , biventricular systolic and diastolic reserve impair- ment in HFpEF described above (6,17,24) suggests that a fundamental disorder in cardiac energy meta- bolism could play a role. Although mitochondrial function has not yet been assessed in human cardiomyocytes in HFpEF, there is evidence for impaired mitochondrial function in skeletal muscle (79) .S a r c o p e n i ac a nl e a dt od e c r e a s e d muscle strength, reduced exercise capacity, and worse quality of life in HFpEF patients (98,99) .S a r - copenia may also coexist with obesity ( “sarcopenic obesity ”), which is characterized by excess fat mass and decreased muscle mass, and it is known to be more related to cardiometabolic and functional abnormalities (99,100) . NEXT STEPS FOR PHENOTYPING. Numerous candi- dates for subphenotyping exist, based upon patho- physiology or comorbidities ( Central Illustration ), but none will gain traction unless there is an effective treatment speci /uniFB01ct ot h a tp h e n o t y p e .F u r t h e rs t u d y is required to better standardize HFpEF phenotyp- ing, including optimal discrimination between overlapping phenotypes, and determination of the best means to separate phenotypes. This may be based upon clinical presentation, characteristic changes in cardiac structure and function, hemody- namic signatures, mechanisms exercise intolerance (cardiac vs. peripheral), the presence of comorbid- ities, or some combination of each of these metrics (Table 2 ). DIAGNOSIS OF HFpEF The diagnosis of HFpEF is obvious in the patient with overt congestion, but evaluation of the euvolemic TABLE 2 Key Questions and Gaps in Evidence With Regard to the Understanding of HFpEF Key Questions Gaps in Evidence Future Studies Needed Phenotyping and pathophysiology Phenotyping HFpEF is promising to better individualize therapy but how HFpEF phenotypes should be de /uniFB01ned remains unclear. There can be several approaches to classifying HFpEF, including pathophysiological, clinical presentation, comorbidities, cardiac structure, and machine learning. What are the roles of noninvasive imaging, biomarkers, or other approaches? Further study is required to standardize HFpEF phenotyping, to identify discrete phenotypes that behave similarly, and to respond to treatment similarly and identify the optimal roles of noninvasive imaging and biomarkers to categorize them. Diagnosis Currently, echocardiography plays a central role for the diagnosis of HFpEF. What are the roles of different modalities in the evaluation for HFpEF? Other imaging modalities such as CMR, cardiac CT, and PET may be promising, but the data to support their usefulness require further investigation. Future studies are needed to investigate the roles for difference modalities in the evaluation for HFpEF. What are the expected roles of novel imaging techniques for HFpEF? Recent studies have reported the possibility of machine learning-based echocardiography analysis for diagnosis and phenotyping in HFpEF. Future studies are needed to establish the roles of machine learning-based imaging in HFpEF, with appropriate standards against which the machine-learning approaches can be compared. Because hemodynamic levels are often normal at rest in HFpEF, diastolic stress echocardiography may be useful to enhance diagnosis, but is this method ready for standard practice? Evidence to support utility of diastolic stress echocardiography across multiple studies in HFpEF is not suf /uniFB01cient. E/e 0 ratio may not change with changes in /uniFB01lling pressure during exercise. How should we deal with E-A fusion during exercise? What is the optimal cutoff of E/e0 during exercise? Further research is needed to validate the utility of exercise stress echocardiography, ideally in multicenter studies using simultaneous assessment using echocardiography and invasive hemodynamics, with blinded interpretation from disinterested observers. PET ¼ positron emission tomography; other abbreviations as in Table 1 . TABLE 3 Recent Studies Providing Sensitivity and Speci /uniFB01city of the Current Guidelines for the Di agnosis of HFpEF Among Patients With Unexplained Dyspnea First Author (Ref. #) Year n Guideline (Ref. #) Sensitivity (%) Speci /uniFB01city (%) AUC Indeterminant (%) Reddy et al. (101) 2018 414 (HFpEF 267) ESC (105) 57 78 0.67 0 Obokata et al. (102) 2017 74 (HFpEF 50) ASE/EACVI (5) 34 83 0.65 24 Obokata et al. (102) 2017 74 (HFpEF 50) ESC (105) 60 75 0.68 0 ASE/EACVI ¼recommendations for the evaluation of left ventricular diastolic function by echocardiography from the American Society of Echocardiography and t he European Association of Cardiovascular Imaging; AUC ¼area under the curve; ESC ¼European Society of Cardiology; other abbreviations as in Table 1 . Obokata et al . JACC: CARDIOVASCULAR IMAGING, VOL. 13, NO. 1, 2020 Imaging and Pathophysiology in HFpEF JANUARY 2020:245 –57 252 Real World Diagnostics of HF Patients and7.6% were included based on other ICD- 10 codes (cardiomyopathy: I 42.0,I42.6,I42.8, and I 42.9; hypertension-induced heart disease: I11.0,I13.0, and I13.2). In the primary cohort,49.8%(n=10 389) of patients had an EF measurement available from the electronic medical re- cords (EMRs). Of these, EF was reduced in 39% (EF≤40%, n=4042) and preserved EF in 61% of patients (EF>40%, n=6347)(Figure1). To further de/uniFB01ne these as HFpEF pa- tients in this study, NT-proBNP concentration >125ng/L was required. This excluded an additional 28% of the pa- tients, leading to a/uniFB01nal HFpEF cohort of4590patients (Figure 1). Patients who could be de/uniFB01ned as HFrEF or HFpEF patients according to the above-mentioned criteria formed the pri- mary cohort of this study. Within the patients with HFpEF/HFrEF,72% had echocardiography marked by proce- dure coding, and for the rest, EF value was found as unstructured data. The frequency of marked echocardiogra- phy procedure codes increased in the primary cohort from 64% in year2005to>83% in2017. The primary cohort was further characterized by assessing NT-proBNP concentrations. As described previously in the lit- erature,1,13we also found that the median NT-proBNP was higher in the HFrEF vs. HFpEF patients { 4580[inter-quartile range (IQR): 2065–9765] vs. 2900[2065–9765] ng/L, P<0.001,Table1}. In95.6% of HFpEF and97.9% of HFrEF patients, NT-proBNP was >300ng/L. The distribution of NT-proBNP values is presented inFigure2. HFpEF was more frequent in women (HFpEF vs. HFrEF:52% vs.37%,P<0.001), and HFpEF patients were on average 4years older at diagnosis than HFrEF patients ( Table1). Within the HFpEF group, those with mildly reduced EF ( 41– 50%,n=1468) displayed more similarities to HFrEF, than Figure1Study cohort formation. Patients in the primary cohort had one of the inclusion International Classi /uniFB01cation of Diseases, Tenth Revision (ICD- 10) codes as any diagnosis (*I42.0,I42.6,I42.8,I42.9,I11.0,I13.0,I13.2, and I50), left ventricular ejection fraction (EF)≤40% or EF>40% and elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) (>125ng/L) at index. Heart failure with preserved EF (HFpEF) patients were further strati/uniFB01ed into EF41–50% or>50%. Patients lacking the above-mentioned ICD-10codes but presenting elevated NT-proBNP (>125ng/L) were included to the sec- ondary cohort. Real-world clinical diagnostics of HFrEF and HFpEF 3 ESC Heart Failure(2020) DOI:10.1002/ehf2.12665 50% of Patients with an ICD code of HF had EF data available50% of Patients with an ICD code of HF and no EF measurement also had no NTproBNPassessment Huuskoet al. ESC HF Feb 2020 Use of Echocardiography After a HF Diagnosis in the Champlain LHIN 58,5%56,3%58,9%54,8% 53,2% 61,9%60,1%64,3%62,3% 65,0%0,0%10,0%20,0%30,0%40,0%50,0%60,0%70,0% Central OttawaEasternChamplainEastern OttawaWesternChamplainWestern Ottawa ECHO within a Year of Diagnosis FemaleMale •Data obtained from ambulatory care setting 2009-2013•In all sub regions, ~1/3 of those with HF had an echo within 6 month of prior diagnosis. This number doubled when looking at ECHO within a year of the diagnosis. •Women were less likely than men to have an Echo within one-year of diagnosis than men. 31.4% 32.2% 33.9% 30.6% 34.4% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% Central Ottawa Eastern Champlain Eastern OttawaWestern Champlain Western Ottawa ECHO within 6-month of prior Dx Mielniczuk, Sun unpublished Specialty Based Variability in the Diagnosis of HFpEF Treatment of HFpEF The survey illustrated that noncardiologists were signi /uniFB01cantly less likely than cardiolo- gists to prescribe aldosterone antagonists to manage HFpEF ( Table 4). Rates of prescribing angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, b-blockers, and exercise programs for HFpEF manage- ment were similar between these 2 groups (Table 4). Prognosis and Referrals of HFpEF Compared With HFrEF The survey demonstrated that signi /uniFB01cantly more noncardiologists discussed prognosis or goals of care with patients with HFrEF than with patients with HFpEF ( Table 5 ). Cardiologists were more likely than noncardi- ologists to discuss prognosis and goals of care with patients in both groups ( Table 6 ). In addition, noncardiologists were signi /uniFB01cantly more likely to refer patients with HFrEF to a cardiologist compared with patients with HFpEF ( Table 5 ). The most commonly reported indications for referring patients with HFpEF to a cardiologist were pulmonary hypertension, right heart dysfunction, or recurrent hospitalizations; referrals for diag- nostic evaluation were less common. DISCUSSION This assessment of diagnostic and treatment strategies for HFpEF among noncardiolo- gists and cardiologists revealed 2 key /uniFB01nd- ings. First, despite caring for HFpEF routinely, noncardiologists have limited knowledge about the diagnostic criteria for HFpEF, partly due to a lack of awareness of existing guidelines for HFpEF. Second, treatment patterns differed signi /uniFB01cantly be- tween noncardiologists and cardiologists. Given the rising prevalence of HFpEF in the United States, these /uniFB01ndings have impor- tant implications on caring for a vulnerable population with a complex condition. The results of this survey indicate that diastolic dysfunction and natriuretic pep- tide levels are often interpreted incorrectly TABLE 3. Physicians Who Reported That Certain TTE Findings Individually Would Cause Them to Consider a Diagnosis of HFpEF in the Absence of Other TTE Abnormalities a TTE/uniFB01nding Noncardiologists n (%) Cardiologists n (%) Pvalue Question No. b LV diastolic dysfunction 161 (89.9%) 26 (81.3%) .15 29 Left atrial enlargement 71 (39.7%) 26 (81.3%) <.001 29 LV hypertrophy 94 (52.5%) 19 (59.4%) .47 29 Elevated RVSP 75 (41.9%) 20 (62.5%) .03 29 RV enlargement 47 (26.3) 16 (50.0%) .007 29 LV dilation 44 (24.6%) 8 (25.0%) .96 29 a HFpEF ¼heart failure with preserved ejection fraction; LV ¼left ventricular; RV ¼right ventricular; RVSP ¼right ventricular systolic pressure; TTE ¼transthoracic echocardiography. b Corresponding question number in the Supplemental Appendix . TABLE 4. Physicians Who Reported Prescribing Certain Treatments to at Least Half of Their Patients With HFpEF Speci /uniFB01cally for the Treatment of Heart Failure a Treatment Noncardiologists n (%) Cardiologists n (%) Pvalue Question No. b ACE inhibitor/ARB 92 (57.1%) 13 (41.9%) .12 31 b-Blocker 90 (55.9%) 17 (54.8%) .91 30 Aldosterone antagonist 52 (32.3%) 20 (64.5%) .001 32 Exercise program 71 (44.4%) 13 (41.9%) .80 33 a ACE¼angiotensin-converting enzyme; ARB ¼angiotensin receptor blocker; HFpEF ¼heart failure with preserved ejection fraction. b Corresponding question number in the Supplemental Appendix . MAYO CLINIC PROCEEDINGS 672 Mayo Clin Proc. n April 2020;95(4):669-675 n https://doi.org/10.1016/j.mayocp.2019.09.026 www.mayoclinicproceedings.org RESULTS Demographic Characteristics The survey was distributed to 1010 physi- cians, with 211 completing a signi /uniFB01cant portion of the survey (response rate, 20.9%). Survey respondent characteristics are shown in Table 1. Among respondents, 179 were noncardiologists and 32 were car- diologists. More than 90% (n ¼195) of both groups reported caring for patients with HFpEF routinely. Most cardiologists re- ported practicing more in outpatient set- tings, and most noncardiologists reported practicing more in inpatient settings. Diagnosis of HFpEF The survey revealed that a signi /uniFB01cantly lower percentage of noncardiologists (27.4%, n ¼49) were familiar with diagnostic guidelines for HFpEF ( Table 2 ). Although noncardiologists and cardiologists similarly reported considering an HFpEF diagnosis if diastolic dysfunction or left ventricular hypertrophy was present on TTE, noncardiologists were less likely to consider HFpEF based on TTE /uniFB01ndings of left atrial enlargement, right ventricular enlargement, or elevated right ventricular systolic pressure (Table 3). Importantly, a much higher pro- portion of noncardiologists reported excluding a diagnosis of HFpEF in the absence of diastolic dysfunction on echocar- diography ( Table 2). Noncardiologists were more likely to exclude a diagnosis of HFpEF based on a low BNP level, although the dif- ference was not statistically signi /uniFB01cant (Table 2 ). The BNP cutoff values below which physicians considered a diagnosis of HFpEF highly unlikely varied from 50 to 300 pg/mL (to convert to ng/L, multiply by 1) among noncardiologists compared with 50 to 100 pg/mL among cardiologists; 100 pg/mL was the most commonly used threshold by both groups ( Supplemental Appendix, question 25). Last, noncardiolo- gists were more likely to give a diagnosis of HFpEF to any patient with diastolic dysfunc- tion on echocardiography, regardless of other criteria ( Table 2). TABLE 1. Background Characteristics of the 211 Physicians Who Participated in the Survey Characteristic Noncardiologists (Total n¼179), n (%) Cardiologists (Total n¼32), n (%) Family medicine 22 (12.3%) 0 Internal medicine 133 (74.3%) 0 Medicine and pediatrics 15 (8.4%) 0 Geriatrics 9 (5.0%) 0 Resident 92 (51.4%) 0 Fellow 5 (2.8%) 12 (37.5%) Spend/C2150% of clinical time on inpatient service 114 (63.7%) 12 (37.5%) TABLE 2. Physicians Who Reported Awareness of HFpEF Diagnostic Guidelines and Use of Left Ventricular Diastolic Dysfunction and BNP to Rule In or Rule Out a Diagnosis of HFpEF a Diagnostic consideration Noncardiologists n (%) Cardiologists n (%) Pvalue Question No.b Aware of ESC or ACC/AHA diagnostic guidelines 49 (27.4%) 20 (62.5%) <.001 23 Exclude HFpEF diagnosis if DD not present on TTE 66 (38.4%) 2 (6.5%) .001 27 Diagnose HFpEF in all patients with DD present on TTE 58 (33.9%) 1 (3.2%) .001 28 Use low BNP level to exclude a diagnosis of HFpEF 58 (33.3%) 8 (25.8%) .41 24 a ACC¼American College of Cardiology; AHA ¼American Heart Association; BNP ¼B-type natriuretic peptide; DD ¼diastolic dysfunction; ESC ¼European Society of Cardiology; HFpEF ¼heart failure with preserved ejection fraction; TTE ¼transthoracic echocardiography. b Corresponding question number in the Supplemental Appendix . VARIABILITY IN DIAGNOSING AND MANAGING HFPEF Mayo Clin Proc. nApril 2020;95(4):669-675 n https://doi.org/10.1016/j.mayocp.2019.09.026 www.mayoclinicproceedings.org 671 Saxon et al; Mayo Clin Proc 2020; 95(4)669 HFpEFDiagnosis: Not for the Faint of Heart…. increased E/e’ and PASPLAE, decreased e’, reduced global longitudinal strainEcho Orthopnea, PND: highly specificDyspnea, fatigue: more sensitiveObesity: OR 3.46AF: OR 12.35Clinical History and Physical Exam Lower wall stress due to small cavity size and thicker wallsEffect of obesityNatriuretic peptides Invasive/noninvasivePWP>15 at rest and >25 during exerciseReduced cardiac output reserve Exercise testingIntegrated Diagnostic Approach H2FPEF Score: A validated Diagnostic Algorithm for HFpEF Probability of HFpEF:Score 0-1: LowScore 2-5: IntermediateScore 6-9 High Reddy et al. Circ 2018; 138:861-870 HFA-PEEF Algorithm: Consensus Recommendation from HFA and ESCHow to diagnose heart failure with preserved ejection 393 Figure 1 HFA–PEFF diagnostic algorithm. Overview of the diagnostic heart failure with preserved ejection fraction (HFpEF) steps 1–4 (P–F). CT , computed tomography; PET , positron emission tomography. preserved L VEF , patients with HFpEF have impaired L V long-axis systolic function, which can be measured using mitral annular systolic excursion or systolic velocities or L V global longitudinal strain (GLS). 19 As well as global diastolic dysfunction, they have long-axis diastolic dysfunction which can be measured from the velocity of long-axis lengthening of the LV in early diastole (from mitral annular velocity, e/uni2032.var ). These were not considered in the previous HFA recommendations. 4 Am e a n E/e/uni2032.var index /uni226515 at rest has good diagnostic value for identifying a high mean pulmonary capillary wedge pressure (mPCWP), supporting the likelihood of HFpEF , 20,2 1 but an E/e/uni2032.var ratio within the intermediate range (9– 14) is less sensitive. 22 The E/e/uni2032.var ratio has limitations that are relevant in routine clinical practice 23–29 and its use as a single diagnostic index above all other non-invasive measures of /f_illing pressures (such as retrograde pulmonary venous /f_low) cannot be recommended. In consequence, HFpEF cannot be diagnosed from a single echocardiographic measure, and inclusion of recently validated functional and structural parameters into a diagnostic score may better de /f_ine this heterogeneous disorder . Usefulness of natriuretic peptides In general, NP levels are higher in patients presenting with acute shortness of breath for cardiac reason or in acute HF , than in patients who have chronic HF . 30,3 1 Of note, our recommenda- tions target stable symptomatic HFpEF , and NP levels can be normal in these patients even with invasively con /f_irmed HFpEF . In consequence, normal NP levels do not exclude HFpEF , espe- cially in the presence of obesity. 32,33 Interpretation depends also on whether the patient is in sinus rhythm (SR) or has AF , which itself is associated with increased NP levels even in the absence of HF . 34,35 Besides obesity, sex, age, and renal function affect NP levels, 36,37 but using strati /f_ied cut-points only marginally improves diagnostic accuracy (net reclassi /f_ication index 3%), 38 at the expense of less everyday utility. The variability of repeated measurements in indi- vidual patients is up to 100%, so a rise or fall of /uni2264100% may not necessarily indicate recovery or progression of disease. 39,40 ........................................................... ..................................................... Diagnostic algorithms for heart failure with preserved ejection fraction The concept of a diagnostic algorithm that incorporates imaging and biomarkers (NPs) was recommended by the HFA in 2007, 4 and adapted by others. 41 It allowed parallel diagnostic pathways starting from haemodynamic measurements, echocardiography, or NPs, 4 that could yield different results for the same patients. In addition, the proportion of non-classi /f_iable patients was substantial. Thus, our revised algorithm (see below) proposes a novel stepwise diagnostic approach that has only one entry point, and all patients will be classi /f_iable. De/f_ining aetiology and pathophysiology Heart failure with preserved ejection fraction typically evolves from a combination of risk factors and comorbidities, including advanced age, female sex, obesity, systemic arterial hypertension, diabetes mellitus, renal dysfunction, anaemia, iron de /f_iciency, sleep disorders, and chronic obstructive pulmonary disease. 1,2, 11,42–44 Heart failure with preserved ejection fraction ‘masqueraders’ such as heart valve disease, arrhythmias, and pericardial constriction need to be excluded. Similarly, a patient with a normal L VEF and HF-like symptoms caused by signi /f_icant coronary artery disease (CAD) is also not considered to have HFpEF . Similar to current practice for heart failure with reduced ejec- tion fraction (HFrEF), we recommend applying the descriptive term HFpEF for both the classical form with typical risk factors and comorbidities, and for rarer cases with a speci /f_ica e t i o l o g y , provided that the key diagnostic criteria are met. Speci /f_ica e t i - ologies that may be treatable include inherited or acquired in /f_il- trative, restrictive, in /f_lammatory, or genetic cardiomyopathies 45–48 (Ta b l e 2 ). They should always be considered once a diagnosis of HFpEF has been made ( Ta b l e 2 ; online supplementary Appendix S 1). It has been suggested that patients with HFrEF share a common mechanism that responds to common treatment (inhibition of the ©2 0 2 0E u r o p e a nS o c i e t yo fC a r d i o l o g y HFpEF and 147 control patients with non-cardiac causes of dyspnoea)11. All patients underwent definitive assess - ment of case or control status by the gold standard of invasive haemodynamic exercise testing. The discrimi - natory capacity of different clinical findings from med - ical history, laboratory testing, electrocardiography and imaging were evaluated to determine diagnostic utility (TABLE/uni00A03). The authors then derived a weighted, com - posite score based on six variables (termed the H 2FPEF score), ranging from 0 to 9, incorporating the strong - est independent parameters that discriminated cases from controls and using the variables that remained independent predictors of HFpEF in a multivariable logistic model (FIG./uni00A01). Some variables, such as left atrial volume, showed good discriminatory capacity in a uni - variate analysis (TABLE/uni00A03) but did not remain significant in the multivariable model 11. Plasma natriuretic pep - tide levels were not independently predictive of HFpEF in this analysis and were therefore not included in the final score11. In the derivation cohort, the H 2FPEF score displayed robust discrimination of cases from controls, with an area under the curve of 0.841 ( P < 0.0001)11. This discriminatory capacity was confirmed in a separate validation cohort of 100 patients (61 with HFpEF and 39 controls), in which the H 2FPEF score showed an area under the curve of 0.886 ( P < 0.0001)11. The num- ber of points in the score provides an estimate of the probability that HFpEF is the cause of dyspnoea (FIG./uni00A01). A model incorporating the same values as continuous variables was found to have even better discriminatory capacity11,72. This method enables a Bayesian approach to HFpEF diagnosis, whereby patients with a low or high likelihood of disease are diagnosed, and the more costly and more definitive test (that is, invasive exercise test - ing) is reserved for patients with an intermediate pre-test probability of disease. Importantly, the H 2FPEF score can be calculated using simple clinical characteristics and echocardiographic data that are universally available in clinical practice 11,72. Since the original publication of the H 2FPEF score by Reddy et/uni00A0al.11, the generalizability and prognostic value of the score have been demonstrated in two independ - ent ancillary analyses 73,74. A further study has evaluated a series of patients who were thought to have HFpEF on the basis of physician opinion together with patients deemed to be at risk of HFpEF but assumed not to have the syndrome 75. The overall discriminatory capacity of H2FPEF score HFA-PEFF score Clinical variable Score label Characteristics Points Domains Major criteria (2 points) Minor criteria (1 point) HeavyH2 BMI >30 kg/m2 2 Functional r Septal e/uni2032 <7 cm/s r Lateral e/uni2032 <10 cm/s r Average E/e /uni2032TCVKQű r Velocity of the tricuspid regurgitation >2.8 m/s (pulmonary artery systolic RTGUUWTG  mmHg) r Average E/e /uni2032 ratio 9–14 r Global longitudinal strain <16% Morphological r LAVI >34 ml/m2 r .8/+ű g/m2 (m/w) and relative wall thickness >0.42 r LAVI 29–34 ml/m2 r .8/+  g/m2 (m/w) r Relative wall thickness >0.42 r .GȎXGPVTKEWNCTYCNNVJKEMPGUUűOO Biomarker (sinus rhythm) r NT-proBNP >220 pg/ml r BNP >80 pg/ml r06RTQ$02s pg/ml r $02s pg/ml Biomarker CVTKCNȮDTKNNCVKQP r NT-proBNP >660 pg/ml r BNP >240 pg/ml r06RTQ$02s pg/ml r $02s pg/ml Hypertension űCPVKJ[RGTVGPUKXG medications 1 Atrial ȮDTKNNCVKQP F Persistent or paroxysmal 3 Pulmonary hypertension P Pulmonary artery systolic pressure  mmHg (measured on Doppler echocardiography) 1 Old ageE Age >60 years 1 Filling pressure F E/e/uni2032 ratio >9 (measured on Doppler echocardiography) 1 Low probability, unlikely HFpEF (H2FPEF score of 0–1, HFA-PEFF score of 0–1) Intermediate probability (H2(2'(UEQTGQHs*(#2'((UEQTGQHs Haemodynamic exercise test High probability, likely HFpEF (H2(2'(UEQTGQHs*(#2'((UEQTGQHs Assessment of pre-test probability: clinical evaluation plus echocardiography Patient with unexplained dyspnoea Fig. 1 | Diagnostic approach for HFpEF . In the patient with unexplained dyspnoea, assessment of the pre-test probability that heart failure with preserved ejection fraction (HFpEF) is present is first performed via clinical, echocardiographic and laboratory testing. Two scoring systems have been developed for this purpose: the H 2FPEF score11 (left) and the HFA–PEFF score12 (right). With either system, patients deemed at high and low probability are generally diagnosed as having or not having HFpEF , respectively , without further testing. In patients with intermediate probability of HFpEF , haemodynamic exercise testing is needed, which can be performed using cardiac catheterization or stress echocardiography. BNP , B-type natriuretic peptide; LAVI, left atrial volume index; LVMI, left ventricular mass index; m/w , men/women; NT -proBNP , N-terminal pro-B-type natriuretic peptide. www.nature.com/nrcardio REVIEWS Probability of HFpEF:Score 0-1: LowScore 2-4: IntermediateScore 5-6:High Pieskeet al; Eur J HF 2020; 22:391-212 HFA-PEEF Algorithm: Consensus Recommendation from HFA and ESC394 B. Pieske et al . renin–angiotensin system) 3 but there are other treatments for subsets of patients with HFrEF that are speci /f_ic( s u c ha st r e a t i n g ischaemia when there is hibernating myocardium, using targeted antiviral therapy or immune modulation in in /f_lammatory HFrEF , and corticosteroid therapy in sarcoidosis-related HFrEF); in that respect, our proposed use of the generic term HFpEF is similar and should include speci /f_icm y o c a r d i a la e t i o l o g i e s . Basic mechanisms affecting the myocardium in HFpEF include myocyte hypertrophy, systolic and diastolic dysfunction, ener- getic abnormalities, interstitial /f_ibrosis, in /f_lammation, increased oxidative stress, endothelial dysfunction, and impaired density and autoregulation of the microcirculation. 9,10,12,45–48, 154, 155 Cardio- vascular pathophysiological processes include increased systemic vascular resistance, increased conduit arterial stiffness, abnormal ventricular-arterial coupling, reduced LV long-axis systolic func- tion, slowed early diastolic relaxation, reduced L V compliance with increased end-diastolic stiffness, reduced LA reservoir and contractile function, impaired right ventricular (RV) function, and chronotropic incompetence. 52, 156– 164 Patients often have reduced reserve of stroke volume, heart rate, and cardiac output (CO), and the increase in CO relative to oxygen consumption is blunted. 165 Heart failure with preserved ejection fraction patients typically have high L V /f_illing pressures, whether at rest and/or on exercise, and they may develop /f_luid retention and an expanded plasma volume. 28, 159, 164, 166, 167 All these mechanisms might be targets for treatment. In a meta-analysis, exercise capacity in HFpEF was related to chronotropic incompetence, high mPCWP , blunted augmentation of arteriovenous oxygen-content difference (implying inadequate perfusion of exercising skeletal muscles), reduced stroke volume reserve, and pulmonary hypertension. 168 Changes in pulmonary artery pressure (PAP) on exercise are determined by the interplay between CO, pulmonary artery compliance, pulmonary vascular resistance, and mPCWP . The increase in PAP is /f_low-dependent so it is best reported in relation to the increase in CO; the upper limit of normal is +3m m H g / L / m i n . 169 There are haemodynamic differ- ences between patients with pre- and post-capillary pulmonary hypertension. 164 We recommend that the pathophysiological phenotype(s) pre- vailing in an individual HFpEF patient are determined, as that may allow the selection of speci /f_ict h e r a p i e s( s e ed i a g n o s t i cS t e p4 below). The new Heart Failure Association diagnostic recommendations The /f_lowchart ( Figure 2 )p r o v i d e sa no v e r v i e wo ft h en e wd i a g n o s - tic algorithm. Step 1(P): Pre-test assessment Step 1(P) should be performed in any patient who presents with symptoms and/or signs compatible with a diagnosis of HF . It ................................................................ ............................................................... ......................................... Figure 2 Flowchart of the HFA–PEFF diagnostic algorithm. Step P is meant to identify patients with the potential diagno- sis of heart failure with preserved ejection fraction (HFpEF), and exclude or identify other speci /f_icc a u s e sf o rt h e i rh e a r t failure-like symptoms. Patients likely to have HFpEF are those with typical demographics (e.g. elderly, female, and comorbidi- ties), a preserved left ventricular ejection fraction on a stan- dard echocardiography, and other easily detectable /f_indings such as elevated natriuretic peptides or atrial /f_ibrillation. Alternative causes such as coronary artery disease, signi /f_icant valvular dis- ease, pulmonary disease, and anaemia should be excluded during this initial workup. If Step P is positive, the second Step E should be done, which includes a comprehensive echocardiography and brain natriuretic peptide/N-terminal natriuretic peptide levels, if not already done on Step P . Step F 1 should be done, if Step E is inconclusive. Depended on clinical facilities and patient con- ditions, an invasive or non-invasive stress test is recommended. However , the invasive stress test has a higher validity and is an option, if the result of the non-invasive stress test is not conclu- sive. The fourth Step, Step F 2 is designed to identify a speci /f_ic aetiology, if appropriate, when HFpEF has been diagnosed. For details of steps 2–4, see Figures 3–5 . requires a detailed clinical and demographic history; an electrocar- diogram (ECG); blood tests; standard echocardiography to exclude other causes such as HFrEF or heart valve disease; and investiga- tions for ischaemia, arrhythmias, anaemia, or pulmonary disease (Figure 2 ). NP levels can be obtained if the assay is available; ele- vated levels suggest heart disease but normal levels do not exclude ©2 0 2 0E u r o p e a nS o c i e t yo fC a r d i o l o g y Pieskeet al; Eur J HF 2020; 22:391-212 Mimics of HFpEFin a patient with Established or High Probability of HFpEF Cardiac ischemia Anemia Chronotropic incompetence Untreated lung diseaseUntreated sleep apnea Obesity deconditioning Pulmonary hypertension Why is my Patient SOB? The Role of Noninvasive Exercise Testing How to diagnose heart failure with preserved ejection 401 A B Figure 4 Step 3(F): Functional tests in cases of diagnostic uncertainty. ( A)I ts h o w st h ed i a s t o l i cs t r e s st e s tw o r k u pw i t he x e r c i s e echocardiography. If key haemodynamic abnormalities are identi /f_ied, a de /f_inite heart failure with preserved ejection fraction (HFpEF) diagnosis can be made. ( B)I ts h o w st h ei n v a s i v eh a e m o d y n a m i cm e a s u r e m e n t sa tr e s t( l e f t )o rd u r i n ge x e r c i s e( r i g h t )t h a tm a yc o m p l e m e n ts t r e s s echocardiography and are recommended in cases with remaining diagnostic uncertainty. L VEDP , left ventricular end-diastolic pressure; PCWP , pulmonary capillary wedge pressure; TR, tricuspid regurgitation. During supine exercise in healthy control subjects, cut-offs for peak PCWP and LVEDP are <20–23 mmHg 258,259 and <25 mmHg, 260,26 1 respectively. Patients with values <25 mmHg during peak exercise are classi /f_ied as having non-cardiac dyspnoea. A steep increase in PCWP during exercise is a typical haemodynamic response in HFpEF , 256,262 indicating that the dyspnoea on exertion is mainly of cardiac origin. Patients with peak exercise PCWP /uni226525 mmHg are classi /f_ied as having HFpEF (online supplementary Appendix S 1). An increase in L V /f_illing pressure during exercise that is not accompanied by increases in end-diastolic volume, indicates limitation to L V /f_illing or the development of pericardial constraint. 256 Ah i g hr e s t i n gm P C W Pa n dap a t h o l o g i c a li n c r e a s ei nm P C W P during exercise predict poor outcomes from HFpEF . 168,249,263 Patients with a normal mPCWP at rest ( <12m m H g ) b u t a s t e e p increase during exercise (to /uni226525 mmHg) have a two-fold increase in mortality. 263 Te n - y e a r m o r t a l i t y w a s 6 . 6 % i f r e s t i n g m P C W P w a s .................................................. /uni226412m m H g a n d p e a k e x e r c i s e m P C W P w a s <25 mmHg; 28.2% in patients with low mPCWP at rest and high exercise mPCWP; and 35.2% in those with high resting mPCWP and high peak exercise mPCWP ( /uni226525 mmHg). 263 Exercise mPCWP reclassi /f_ies patients with a normal resting mPCWP and strati /f_ies risk. If other investigations have been inconclusive, invasive measurement of mPCWP or L VEDP is considered as the clinical reference investigation for diagnosing HFpEF 28 (see online supplementary Appendix S 1about how to per- form an invasive stress test). Other causes such as signi /f_icant CAD, mitral stenosis, or pericardial constriction must be excluded. Step 4(F 2):Final aetiology Most cases of HFpEF are related to common risk factors and comorbidities, but the possibility of a speci /f_ic underlying aeti- ology should always be considered ( Ta b l e 2 , Figure 5 ;o n l i n e ©2 0 2 0E u r o p e a nS o c i e t yo fC a r d i o l o g y Pieskeet al; Eur J HF 2020; 22:391-212 Invasive Exercise Testing in HFpEF How to diagnose heart failure with preserved ejection 401 A B Figure 4 Step 3(F): Functional tests in cases of diagnostic uncertainty. ( A)I ts h o w st h ed i a s t o l i cs t r e s st e s tw o r k u pw i t he x e r c i s e echocardiography. If key haemodynamic abnormalities are identi /f_ied, a de/f_inite heart failure with preserved ejection fraction (HFpEF) diagnosis can be made. ( B)I ts h o w st h ei n v a s i v eh a e m o d y n a m i cm e a s u r e m e n t sa tr e s t( l e f t )o rd u r i n ge x e r c i s e( r i g h t )t h a tm a yc o m p l e m e n ts t r e s s echocardiography and are recommended in cases with remaining diagnostic uncertainty. L VEDP , left ventricular end-diastolic pressure; PCWP , pulmonary capillary wedge pressure; TR, tricuspid regurgitation. During supine exercise in healthy control subjects, cut-offs for peak PCWP and LVEDP are <20–23 mmHg 258,259 and<25 mmHg,260,261respectively. Patients with values <25 mmHg during peak exercise are classi /f_ied as having non-cardiac dyspnoea. A steep increase in PCWP during exercise is a typical haemodynamic response in HFpEF , 256,262 indicating that the dyspnoea on exertion is mainly of cardiac origin. Patients with peak exercise PCWP /uni226525 mmHg are classi /f_ied as having HFpEF (online supplementary Appendix S 1). An increase in L V /f_illing pressure during exercise that is not accompanied by increases in end-diastolic volume, indicates limitation to L V /f_illing or the development of pericardial constraint. 256 Ah i g hr e s t i n gm P C W Pa n dap a t h o l o g i c a li n c r e a s ei nm P C W P during exercise predict poor outcomes from HFpEF . 168,249,263 Patients with a normal mPCWP at rest ( <12m m H g ) b u t a s t e e p increase during exercise (to /uni226525 mmHg) have a two-fold increase in mortality. 263Te n - y e a r m o r t a l i t y w a s 6 . 6 % i f r e s t i n g m P C W P w a s .................................................. /uni226412m m H g a n d p e a k e x e r c i s e m P C W P w a s <25 mmHg; 28.2% in patients with low mPCWP at rest and high exercise mPCWP; and 35.2% in those with high resting mPCWP and high peak exercise mPCWP ( /uni226525 mmHg). 263 Exercise mPCWP reclassi /f_ies patients with a normal resting mPCWP and strati /f_ies risk. If other investigations have been inconclusive, invasive measurement of mPCWP or L VEDP is considered as the clinical reference investigation for diagnosing HFpEF28(see online supplementary Appendix S 1about how to per- form an invasive stress test). Other causes such as signi /f_icant CAD, mitral stenosis, or pericardial constriction must be excluded. Step 4(F 2):Final aetiology Most cases of HFpEF are related to common risk factors and comorbidities, but the possibility of a speci /f_ic underlying aeti- ology should always be considered ( Ta b l e 2,Figure 5;o n l i n e ©2 0 2 0E u r o p e a nS o c i e t yo fC a r d i o l o g y Pieskeet al; Eur J HF 2020; 22:391-212 Maron; Circ 2013: 123 Pulmonary Hypertension in Left Heart Disease 316 www.thelancet.com/respiratory Vol 4 April 2016 Review Limitations of studies of pulmonary hypertension The epidemiology of pulmonary hypertension is much more di/uniFB03 cult to study than the epidemiology of systemic hypertension because a reliable diagnosis requires right heart catheterisation, which is an invasive procedure. Therefore, large-scale population-based studies have to rely on echocardiography because invasive tests for epidemiological studies would be neither ethical nor feasible. The interpretation of these data must take into account that echocardiography is not a reliable method to diagnose pulmonary hypertension. Several catheter-based studies have been done in patients at risk for pulmonary arterial hypertension and in patients with left-sided heart disease and chronic lung disease. The results of these studies have been largely consistent, therefore confi rming each other and also to a large extent, confi rming studies on the basis of echocardiography, Figure /two.OT: Estimated global distribution of the most prevalent forms of (A) pulmonary hypertension and (B) pulmonary arterial hypertension Interpretation should be done with caution as most of the underlying evidence has been derived from populations at risk for pulmonary hypertension and echocardiography data rather than from population-based studies involving right heart catheterisation. Data from the developing world are particularly sparse. Additionally, variations exist within the world regions. In Latin America, for instance, schistosomiasis highly prevalent in Brazil, Venezuela, and the Caribbean, but not in other countries. Schistosomiasis is also prevalent in sub-Saharan Africa and Southeast Asia, but there is almost no data on the association between schistosomiasis and pulmonary arterial hypertension from these areas. HIV is not evenly distributed in Africa and is particularly frequent in some areas of sub-Saharan Africa. 50% 45% 5% South America 50% 45% 5% North America 48% 48% 4% Europe 40%30% 1% 10% 10% Africa 45%40% 5% 6% 4% Asia 50% 45% 5% Australia 50%40% 5% 5% Middle East 9% A 25% 20% 30% South America 55%27% 2% 5% 11% 10% 10% 5% North America 56%20% Europe 30%35% 25% 38% 15% 40% 55%27% 5% 2% Australia 55%15% 27% 3% 5% 2% Middle East B Left-sided heart disease Lung disease Rheumatic heart disease Sickle cell disease HIV Other Idiopathic Connective tissue disease HIV Portal hypertension Congenital heart disease Schistosomiasis 11% 10% 3% 5% 5% Africa 11% Asia PROPOSED NEW DEFINITIONS OF PH IN LEFT HEART DISEASE:•Isolated post capillary PH (IpcPH)•PCWP > 15 mmHg AND mean PAP > 20 mmHg AND PVR ≤ 3 WU•Combined Post and Precapillary PH (CpcPH)•PCWP > 15 mmHg and mean PAP> 20 mmHg AND PVR > 3 WU 6thWorld Symposium on PH (Nice 2018)Hoeper; Lancet RespMed 2016; 4:306 Combined Pre and Post Capillary PH in HFpEF Gerges; Am J Resp CritCare Med; 2015; 192:1234 highly morbid covariates (including body mass index, chronic obstructive pulmonary disease, interstitial lung disease, atrial/uniFB01brillation, and connective tissue disease). These differences in study design and sta- tistical analysis may account for the discrepant all-cause mortality seen in our studies. Of note, we observed increased mortality in patients with PH- LHD with an elevated PVR in one of our sensitivity analyses. PVR is a function of cardiac output, whereas DPG is merely a small difference in pressures. CENTRAL ILLUSTRATIONPatients With Cpc-PH and PAH: Clinical and Genetic Similarities Assad, T.R. et al. J Am Coll Cardiol. 2016;68(23):2525–36. Despite a similar prevalence of systemic, vascular, and cardiac comorbidities, patients with combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH) develop more severe pulmonary vascular disease at a younger age than patients with isolated post-capillary pulmonary hypertension (Ipc-PH). Compared with Ipc-PH patient control subjects, 141 single-nucleotide polymorphisms (SNPs) shared between patients with Cpc-PH and pulmonary arterial hypertension (PAH) were identi/uniFB01ed. These SNPs were associated with genes that are highly expressed in lung tissue and involve gene ontology groups previously implicated in PAH pathophysiology, such as cytoskeletal structure and function. MHC¼major histocompatibility complex; LV¼left ventricular. JACC VOL. 68, NO. 23, 2016 Assadet al. DECEMBER 13, 2016:2525 –36 Combined Post- and Pre-Capillary Pulmonary Hypertension Characteristics 2533 Assad; JACC 2016; 68:2525-36 Pre and post cap PH Isolated post cap PH Right Heart Failure Phenotype in HFpEF Guazzi, CircHF 2014;367-377 Is This “Garden Variety” HFpEFor Something Else?Abnormalities of the MyocardiumIschemic CADToxicSubstance useEtoH, cocaine, steroidsHeavy metalsCopper, iron, lead, colbaltImmune and inflammatoryInfectionHIV, hepatitis, parasitesNon-infectiousLymphocytic myocarditis, CTD, eosinophilic myocarditisInfiltrativeMalignantdirect infiltrationmetastasesNon-malignantAmyloid, sarcoid, hemochromatosis, storage disease, Pompe, Gaucher’sMetabolicHormonalThyroid, parathyroid, Cushing, Addison, Conn’sNutritionalThiamine, selenium, complexGenetic HCMEarly muscular dystrophyEndomyocardialEMF, carcinoid, Pagets, endocardial fibroelastosis Important “Mimics” of HFpEFDifferential DiagnosisClinical CluesEcho CluesConfirmatory /Ancillary TestingHypertrophic CMPresyncope/syncope, arrhythmia, younger age, family historyAsymmetric hypertrophy, ⇈wall thickness, LVOT obstruction, SAMCMRGenetic testingConstrictive pericarditisPrevious surgery, exposure, JVP findingsPericardial thickening, septal bounce, increased respiratory variation in M/T flow, hepatic vein diastolic flow reversal during expiration, absence of IVC collapse CT, CMRRight heart catheterization Valvular heart diseaseMurmurMorphological valve abnormality, DopplerDetailed echo assessment, TEECADRisk factors, ischemic painRegional WMA, thinningPerfusion imagingCoronary angiographyHigh output statesAnemia, sepsis, pregnancy, AV fistula, thyrotoxicosisIncreased Doppler derived CO, increased 4 chamber volumesRight heart catheterization Important “Mimics” of HFpEF: Cardiac Amyloid•5-13% of patients considered to have HFpEFhave CA•ATTRwtCA identified in 32% of PM cases of ”HFpEF” >75 years age•All forms of amyloid can present with typical HF symptoms•Consider:•Decreased exercise tolerance•Low BP•Syncope•Arrhythmia and conduction blocks•Amyloid associated neuropathy (autonomic or sensorimotor)•Diagnostic delay associated with:•Increased cardiac biomarkers•Worsening conduction abnormalities and arrhythmia•Worse prognosis Echo Clues:•Small LV cavity•Increased LV wall thickness•Sparkling myocardium•Apical sparing•Severely reduced tissue doppler•Pericardial effusion•Hepatic vein diastolic flow reversal during inspiration Subsequent Testing:CMRNuclear scintigraphyBiopsy Important “Mimics” of HFpEF: Pulmonary Arterial Hypertension Pulmonary Arterial Hypertension Clinical Cues•Evidence of ”Associated Conditions”•Variable age distributionEcho Clues•No evidence of increased LV filling pressure•Isolated right heart dilatation•PA dilatation•RV outflow tract doppler mid systolic notchSubsequent TestingRight Heart Catheterization Important “Mimics” of HFpEF: Chronic Thromboembolic PH Chronic Thromboembolic Disease Clinical Cues•History of DVT/PE•Hypercoaguablestate Echo Clues•No evidence of increased LV filling pressure•Isolated right heart dilatation•PA dilatation•RV outflow tract doppler mid systolic notchSubsequent TestingVQ scanCT pulmonary angiogramRight heart catheterization Summary •HFpEFis the dominant form of HF worldwide•Continues to present a diagnostic and therapeutic challenge•HFpEFdiagnosis requires an integrated approach•Clinical evaluation•Biomarkers•Echocardiography is essential in assessing pathophysiologic mechanisms and phenotyping•Exercise testing may help to solicit the cause of a patients undiagnosed dyspnea•HFpEFmimics exist inside and outside the diagnosis•Identification and treatment of co-morbidities•Functional testing•High index of suspicion for diagnoses with distinct natural history and management