Native T1, extracellular volume fraction (ECV), and late gadolinium enhancement (LGE) characterize myocardial tissue and relate to patient prognosis in a variety of diseases, including pulmonary hypertension. The purpose of this study was to evaluate if left ventricle (LV) fibrosis measurements have prognostic value for cardiac outcomes in pulmonary hypertension subgroups. 54 patients with suspected pulmonary hypertension underwent right-heart catheterization and were classified into pulmonary hypertension subgroups: pre-capillary component (PreCompPH) and isolated post-capillary (IpcPH). Cardiac magnetic resonance imaging (MRI) scans were performed with the acquisition of balanced cine steady-state free precession, native T1, and LGE pulse sequences to measure cardiac volumes and myocardial fibrosis. Associations between cardiac events and cardiac MRI measurements were analyzed within PreCompPH and IpcPH patients. IpcPH: LV native T1 was higher in patients who experienced a cardiac event within two years vs. those who did not. In patients with LV native T1 > 1050 ms, the rate of cardiac events was higher. ECV and quantitative LGE did not differ between groups. PreCompPH: native T1, ECV, and quantitative/qualitative LGE did not differ between patients who experienced a cardiac event within two years vs. those who did not. LV native T1 may have potential value for forecasting cardiac events in IpcPH, but not in PreCompPH, patients. Pulmonary hypertension (PH) is a progressive, life-threatening, and multifactorial disease process that is characterized by an elevated resting mean pulmonary arterial pressure (mPAP) ,2. PH isRight heart catheterization (RHC) has been the gold-standard diagnostic and prognostic tool for PH. However, because of its invasive nature, there is increasing exploration of alternative prognostic markers in PH patients. In PH patients, cardiopulmonary exercise testing  and cardVentricular fibrosis measurements have been shown to provide more sensitive prognoses in patients with LV diastolic dysfunction  and systGiven the disparate pathophysiologic processes leading to an elevated pulmonary artery pressure, we hypothesized that LV fibrosis measurements would have prognostic significance in IpcPH, and not in PreCompPH.2; acute kidney injury; kidney or liver transplant within 8 weeks; any contraindication to MRI ; pregnant or breastfeeding women; adults unable to provide consent; children; prisoners.Approval from the Institutional Review Board (IRB) was obtained, and all subjects provided written informed consent. The initial cohort was identical to that used in a previous study investigating 4D flow-derived velocities in PH patients . PatientP). PVR (in Wood Units (WU)) was calculated using the formula: PVRRHC = ΔP/QP, where ΔP is the trans-pulmonary pressure gradient (ΔP = mPAP − PCWP) and QP is the flow in the pulmonary artery measured by the Fick principle using the pulmonary artery oxygen saturation.Standard-of-care RHC was performed with a 7–9 French sheath via the internal jugular or femoral veins. A Swan-Ganz catheter, connected to an analog pressure recorder, was used to obtain mPAP, systolic PAP, diastolic PAP, pulmonary capillary wedge pressure (PCWP) and right ventricular cardiac output (QPH patients were classified (MV: a cardiologist with 5 years of experience in cardiac imaging) based on a review of their clinical courses, therapeutic histories, and hemodynamic measurements. Patients’ clinical courses and therapeutic histories were considered in addition to hemodynamic measurements, during classification, because invasive parameters are known to vary with a patient’s fluid and metabolic status, and it has been suggested that hemodynamics should be interpreted in the context of the clinical picture . PatientThe electronic medical record (EMR) was reviewed to determine if a cardiac event occurred after patients’ cardiac MRI scans. Cardiac events were defined as any of the following: heart failure requiring intravenous diuretics; palpitations prompting inpatient observation; or coronary revascularization. If any of these events occurred, the elapsed time between the MRI scan and the event was recorded. Comorbidities  and functional status within 4 months of MRI (New York Heart Association (NYHA) functional class, six-minute walk distance, brain natriuretic peptide (BNP), supplemental oxygen use, ascites, peripheral edema) were also retrieved from the EMR .The Cardiac MRI scans were performed by certified technicians using a 1.5 T MRI system . A three-plane fast localization sequence was used to determine anatomic orientations for subsequent sequences, and four-chamber, two-chamber, and short-axis localizer views were obtained. The pre-contrast portion of the protocol consisted of multiplanar segmented balanced cine steady-state free precession (bSSFP) and native T1 mapping (Modified Look-Locker inversion recovery (MOLLI) technique). After contrast administration , LGE and MOLLI T1 mapping sequences were performed . The combined duration of the MRI sequences was 30 min.The bSSFP cine acquisition was performed in the two-, three-, four-chamber, and short-axis orientations. Data were acquired during breath holds at end-expiration using retrospective electrocardiogram (ECG) gating. Cine sequence MRI parameters were as follows: field of view (FOV) read = 340 mm × 340 mm, spatial resolution = 1.8 mm × 1.8 mm × 6.0 mm, temporal resolution = 35.49 ms, flip angle = 80°, echo time/repetition time (TE/TR) = 1.16/35.49 ms.2, Generalized Auto-calibrating Partial Parallel Acquisition (GRAPPA) with an acceleration factor, R = 2. Imaging reconstruction included the auto-calculation of parametric LV T1 maps.The gradient recalled echo (GRE) bSSFP MOLLI acquisitions were collected pre- and post-contrast (delay = 10 min) with sequence parameters as follows: TE 1.33 ms, flip angle 35°, slice thickness 8.00 mm, pixel size = 1.0 × 1.0 mm2, GRAPPA with an acceleration factor, R = 2) a segmented 2D IR gradient recalled echo (turboFLASH) pulse sequence .The LGE pulse sequences were performed with either of two Phase-sensitive Inversion–Recovery (PSIR) pulse sequences: (1) a 2D inversion–recovery (IR) balanced steady-state free precession (bSSFP) pulse sequence  . Each patient’s body surface area (BSA) was calculated using the Mosteller equation, and volumes were divided by BSA to get end-systolic and end-diastolic volume indices .The RV and LV endocardial borders were manually contoured on short-axis bSSFP cine images at the peak end-diastolic and end-systolic time frames using CVI Canada) . CVI42 g42 ) (1)GlobaQualitative: A radiologist (KS: 2 years of experience in cardiothoracic imaging) performed a qualitative analysis of LGE presence. Patients were determined to have: no LGE; or LGE at one insertional point; or LGE at both insertional points. To evaluate interobserver reliability, a second radiologist (BDA: 4 years of experience in cardiothoracic imaging) assessed the presence and location of LGE in a randomly selected subset of 10 subjects.42  on CVI42 . The LV 42 . The basPixel-wise values were converted by the software into average values, on a segment-by-segment basis, for each of the American Heart Association (AHA)-defined myocardial segments. Segmental values were averaged to obtain global ECV and native T1 values for each scan .Descriptive statistics were recorded based on the nature of the compared variables: mean ± standard deviation ; median (interquartile range) ; frequency (percentage) . Shapiro–Wilk test was used to assess continuous variables for normality.U test . Chi-square statistics with Yates correction or Fisher’s exact test were used to compare categorical data, depending on the size of the groups being compared . Kaplan–Meier curve analysis and log-rank test were used to assess cumulative cardiac events.Continuous variables were compared between two groups with independent samples Student’s t-test preceded by Levene’s test  or Mann–Whitney p < 0.05 considered statistically significant.Statistical analyses were performed with SPSS . All tests were two-tailed with Fifty-four patients were involved in the assessment (35 PreCompPH and 19 IpcPH patients). Patients’ clinical information is depicted in p = 0.529), LVESV , LVEDVI , LVESVI , RVEDV , RVESV , or RVESVI  for the occurrence of a cardiac event within 2 years of the cardiac MRI scan. The AUC of LVEF approached significance , and the AUC of RVEF was statistically significant   .p = 0.424), LVESV , LVEDVI , LVESVI , LVEF , RVEDV , RVESV , RVEDVI , RVESVI , or RVEF   .p = 0.920). Similarly, within IpcPH patients, there was no statistically significant difference between the patients who experienced a cardiac event within 2 years (1.6 ± 0.6%) and those who did not %) %) and those who did not %) %) .p = 0.645); 86% vs. 61% (p = 0.380); and 0% vs. 7% (p = 1.000), respectively. Within IpcPH patients, the distributions of the numbers of patients with no LGE at IPs, LGE at one IP, and LGE at both IPs between patients who experienced a cardiac event within two years vs. those who did not were: 63% vs. 64% (p = 1.000); 13% vs. 36% (p = 0.338); 25% vs. 0% (p = 0.164) , LGE at one IP, and LGE at both IPs between patients who experienced a cardiac event within two years vs. those who did not were: 14% vs. 32% (= 0.164) .p = 0.553). ROC analysis showed an AUC of 0.587 for the association between LV native T1 and the occurrence of a cardiac event within two years of cardiac MRI (p = 0.558) (p = 0.835) , though without statistical significance (= 0.558) . Kaplan–= 0.835) .p = 0.041) (p = 0.075) (p = 0.023)  (= 0.041) . ROC ana= 0.075) . Kaplan–= 0.023) .p = 0.224) (p = 0.273).Within PreCompPH patients, there was no statistically significant difference in global LV ECV percent between the patients who experienced a cardiac event within two years of cardiac MRI (33.4 ± 4.4%) and those who did not %) (= 0.224) . ROC anap = 0.093). ROC analysis showed an AUC of 0.314 for the association between LV ECV and the occurrence of a cardiac event within two years of cardiac MRI (p = 0.168).Within IpcPH patients, there was no statistically significant difference in global LV ECV percent between the patients who experienced a cardiac event within two years of cardiac MRI (28.9 ± 3.5%) and those who did not (32.0 ± 5.1%) . Volumetric and hemodynamic measurements appear less promising.p < 0.05) [The results of this study show that LV native T1 measurements may be able to forecast cardiac events in IpcPH patients, but not in PreCompPH patients. No association was found between LGE or ECV and the occurrence of a cardiac event in either subset of PH patients. Though several fibrosis quantification techniques have been simultaneously studied for their potential to prognosticate muscular dystrophy patients , amyloid < 0.05) . The res < 0.05) ,27, pati < 0.05) , and non < 0.05) . We beliOur results showing a lack of statistically significant associations between LGE, ECV, and cardiac outcomes are consistent with the previous literature. In a study using native T1, ECV, and LGE measurement techniques in the non-infarcted myocardium of patients with coronary heart disease, native T1 and ECV were independent predictors of outcome . Both tiIt has also become appreciated that RV functional measures assessed by cardiac MRI are associated with a functional state, exercise capacity, and survival in patients with PAH (a subset of PreCompPH) ,32,33,34Interestingly, invasive measurements were not prognostic in IpcPH or PreCompPH patients. Elevated pulmonary artery pressures have previously been shown to be associated with outcomes in patients with left heart disease and PH . PVR meaThere are several limitations to our study. First, the small sample size of the present cohort, combined with a low death rate (6 out of 54 patients) during the follow-up period, precluded the use of regression and survival analyses in our study. Larger studies are needed to allow for robust statistical testing of our preliminary findings. Second, up to 28 days elapsed between cardiac MRI and RHC. Disease progression or remission may have occurred during this time. For this reason, patients were classified by a cardiology fellow with experience following PH patients. RHC values, volumetric measurements, and clinical factors were all considered during the classification process. Spruijt et al.  similarlThis preliminary proof-of-concept study demonstrates that native T1 measurements of the LV may be able to forecast the occurrence of cardiac events in IpcPH patients, and that this ability does not persist in PreCompPH patients. RVEF does not appear to hold prognostic value in IpcPH patients but may be prognostic in PreCompPH patients.


Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging.We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement.P=0.004), greater incidence of tricuspid stenosis  and tricuspid regurgitation  than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI . AApoAIV-CA most commonly presented with heart failure , and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA . All AApoAIV-CA patients had classical CA features on echocardiography/cardiac magnetic resonance, including an apical-sparing strain pattern, which was less common in AApoAI-CA , whereas cardiac uptake on bone scintigraphy was less common in AApoAIV-CA than AApoAI-CA  . Patients with AApoAI and AApoAIV had a good prognosis , and a lower risk of mortality than matched patients with AL-amyloidosis .Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure  or dysphonia . The Arg173Pro variant universally caused cardiac and laryngeal involvement . AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis. Apo AI amyloidosis and Apo AIV amyloidosis are rare, but increasingly recognized causes of cardiac amyloidosis (CA). Apo AI CA is associated with a strong family history of amyloidosis, multisystemic disease, laryngeal involvement presenting with dysphonia, and right-sided cardiac disease on cardiac imaging. Apo AIV CA commonly presents with heart failure symptoms, and always displays characteristic features of CA on both echocardiography and cardiac magnetic resonance imaging, hence mimicking more common forms of CA. Appreciation of the unique characteristic features of Apo AI amyloidosis but also the capability of Apo AIV amyloidosis to mimic common forms of CA is urgently needed in clinical practice to reduce the risk of misdiagnosis.1 Cardiac amyloidosis (CA) occurs when the deposition of amyloid fibrils causes distortion of the myocardial contractile elements. It is characterized by biventricular wall thickening and stiffening of the myocardium, which ultimately leads to progressive heart failure. Although amyloidosis is a multisystem disease, cardiac involvement remains the leading cause of mortality.3Systemic amyloidosis describes a heterogeneous group of diseases characterized by deposition of misfolded protein fibrils within extracellular space, leading to organ dysfunction.5 Less common, although increasingly recognized causes include Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV).7 The treatment is very different in different types of CA ranging from chemotherapy in systemic AL-amyloidosis to transthyretin stabilizers8 and gene silencers in ATTR.9 It is, therefore, crucial to raise awareness of rare forms of CA, which include AApoAI and AApoAIV, to avoid misdiagnosis and subsequent inappropriate treatment.The vast majority of CA cases are represented by misfolded immunoglobulin light-chain (immunoglobulin light-chain amyloidosis [AL]) and transthyretin (transthyretin amyloidosis [ATTR]) proteins.10 In contrast, the misfolding that occurs secondary to pathogenic mutations in the ApoAI-gene promotes deposition in various organs throughout the body, resulting in disruption of organ structure and function, and development of a systemic disease process known as AApoAI.11ApoAI is a physiological plasma protein of 28 kDa synthesized by the liver and small intestine. It is the major protein component of high-density lipoprotein particles in the plasma and is involved in cholesterol transport. Wild-type ApoAI-amyloid has been identified in atherosclerotic plaques and is thought to form secondary to the atherosclerotic inflammatory process. Wild-type ApoAI-amyloid fibrils remain localized within the atherosclerotic plaque and are not associated with systemic disease.12 Although the more common forms of CA (AL and ATTR) have been well characterized, data on the cardiac phenotype of patients with AApoAI and AApoAIV is sparse, with the majority of available literature being case reports and small case series.7ApoAIV is a 46 kDa protein synthesized predominantly in the small intestine and plays a role in the absorption, transportation, and metabolism of lipids, but unlike AApoAI, the disease is not hereditary and mechanisms that promote the development of AApoAIV remain obscure.The aim of this study was to define the clinical phenotype in patients with AApoAI and AApoAIV-CA using extensive characterization comprising biomarkers and multimodality cardiac imaging.The data that support the findings of this study are available from the corresponding author upon reasonable request.We performed a retrospective search of the National Amyloidosis Center database, to identify all patients with a confirmed diagnosis of AL, ATTR, AApoAI, and AApoAIV amyloidosis who underwent a cardiac assessment, between 2000 and 2021. This study included 66 patients with AL, 66 patients with ATTR, 45 patients with AApoAI, and 21 patients with AApoAIV amyloidosis.TTR-gene variant or the presence of heart failure symptoms, characteristic cardiac imaging, and either biopsy proof of ATTR-amyloid, or grade 2 to 3 uptake on bone scintigraphy in the absence of biochemical evidence of a plasma cell dyscrasia. AApoAI was confirmed by identification of a pathogenic ApoAI-gene variant with either histological proof of AApoAI-amyloid organ deposition or imaging evidence of organ deposition. AApoAIV was confirmed by histological and proteomic proof of AApoAIV tissue infiltration.13 Of note, data from 36 patients had been included within a prior article from our center, but the current study includes updated analysis.14 Patients were managed in accordance with the Declaration of Helsinki and provided written informed consent for analysis and publication of their data.Diagnoses were confirmed based on validated diagnostic criteria. All biopsies were stained with Congo red dye and viewed under crossed polarized light. The definitive amyloid fibril type was established by immunohistochemical staining of amyloid deposits using monospecific antibodies or by microdissection of amyloid deposits and proteomic analysis. The diagnosis of AL-amyloidosis was confirmed by central review of histology. The diagnosis of ATTR-amyloidosis was based on either the presence of polyneuropathy, biopsy proof of ATTR-amyloid, and 15 and right ventricular (RV) involvement was defined as RV uptake on single-photon emission computed tomography. Echocardiograms were described as suggestive of CA or characteristic of CA if the maximal wall thickness was >12 mm and a total score of 2 to 7 points or ≥8 points respectively using the following scoring system: relative wall thickness >0.6=3 points, E/e′ >11=1 point, tricuspid annular plane systolic excursion <19 mm=2 points, longitudinal strain >−13%=1 point, systolic apex-to-base ratio >2.9=3 points.16 RV involvement was defined as an RV free wall thickness >5 mm, and valvular regurgitation deemed significant if at least moderate or severe. CMR images were characterized using the following grading system: no features of CA , early cardiac amyloid infiltration , and characteristic of CA . RV involvement was defined as subendocardial or transmural RV LGE.Cardiac amyloid infiltration was ascertained using a combination of bone scintigraphy, echocardiography, and cardiac magnetic resonance (CMR) imaging, and in some cases corroborated with direct endomyocardial biopsy proof of cardiac infiltration. Intensity of cardiac uptake on the planar bone scintigraphy was categorized as 0–3 according to the grading system described by Perugini et al,Supplemental Material.Technical aspects related to the acquisition of bone scintigraphy, serum amyloid P component scintigraphy, echocardiographic, and CMR images are described in the 2 test or Fisher exact test as appropriate. Case-control matching was used to match patients diagnosed with AApoAI and AApoAIV for age, sex, and presence or absence of cardiac involvement, to corresponding patients with AL- and ATTR-amyloidosis in a 1:1 ratio.Statistical analysis was performed using Stata . All continuous variables were tested for normal distribution (Shapiro-Wilk test) and presented as mean±SD or median (interquartile range), other than NT-proBNP  which was natural log-transformed for parametric testing. One-way ANOVA if the data were normally distributed in each group was used to compare means, or its nonparametric equivalent  was used to compare the distribution of multiple groups. A significant result was followed by a post hoc Bonferroni corrected pairwise comparison to establish where differences lay. Categorical data are presented as absolute numbers (n) and frequencies (%) and compared using the χP<0.05.All mortality data were obtained via the UK Office of National Statistics. The mortality end point was defined as time to death from baseline for all deceased patients and time to censor date  from baseline among the remainder. Survival was evaluated using Cox proportional hazards regression analysis, providing estimated hazard ratios (HRs) with 95% CIs. The proportional hazards assumption was checked and confirmed. Kaplan-Meier curves were constructed, with statistical significance being assessed with a log-rank test. Statistical significance was defined as We identified 4364 patients with AL-amyloidosis, of which 2730 (62.6%) had cardiac involvement, 2057 patients with ATTR-amyloidosis, of which 1984 (96.5%) had cardiac involvement, 45 patients with AApoAI, of which 13 (28.9%) had cardiac involvement and 21 patients with AApoAIV, of which 15 (71.4%) had cardiac involvement. The patients with AApoAI and AApoAIV made up 1.0% of cases assessed at the National Amyloidosis Center during the study period.ApoAI-gene variants: Gly26Arg=22, Arg173Pro=7, Leu60Arg=3, Phe71Tyr=3, His155Met=2, Leu90Pro=2, Trp50Arg=2, E70_W72=1, Gln172Pro=1, Glu34Lys=1, IL60Arg=1. Biopsy and ethnicity data are presented in the Supplemental Material.We identified 45 patients with AApoAI  who had the following The most common reason for referral was for investigation of chronic kidney disease , followed by genetic screen for a positive family history , symptoms of heart failure, and local cardiac imaging suggestive of CA , and amyloid infiltration seen on a biopsy . On taking a detailed medical history, 26 (57.8%) patients reported a family history of amyloidosis, and 5 (11.1%) reported symptoms of peripheral neuropathy. Multisystemic disease was common in patients with AApoAI. Renal involvement was most common , followed by splenic involvement , hepatic involvement , cardiac involvement , and laryngeal involvement .A total of 13 (28.9%) patients had cardiac involvement . Patients with cardiac involvement were referred with heart failure symptoms and imaging suggestive of CA  or amyloid infiltration identified on biopsy . The Arg173Pro variant was always associated with CA and also always associated with laryngeal involvement , with all patients reporting dysphonia, 4 of whom had a laryngeal biopsy confirming amyloid infiltration. The Arg173Pro variant was also associated with a petechial rash in some patients . Visceral organ involvement was common in those with cardiac involvement, 6 (46.2%) had renal involvement, 5 (38.5%) had liver involvement, and 4 (30.8%) had spleen involvement.1 to V3 (n=4), followed by right bundle branch block (n=2).The baseline 12-lead ECG demonstrated sinus rhythm (n=9) in the majority of patients , 2 had atrial fibrillation, and 2 had a ventricular paced rhythm. Two patients had QRS complexes that met the low voltage criteria . All the remaining patients had a normal QRS amplitude . The most common QRS pattern was Q waves in leads VP=0.045).At diagnosis, all patients with AApoAI-CA underwent echocardiographic assessment. All patients had prominent RV free wall thickening , but only 5 (38.5%) patients had an echocardiogram characteristic of CA and 8 (61.5%) had an echocardiogram suggestive of CA. When compared with matched patients, those with AApoAI-CA less commonly had an apical sparing strain pattern than AL-CA and ATTR-CA , and resulted in significant tricuspid regurgitation  and the majority had a raised pulmonary artery systolic pressure . Mitral valve leaflet thickening was associated with tethering of the posterior leaflet , but this resulted in moderate regurgitation in only 1 patient.P=0.004), greater incidence of tricuspid stenosis , greater incidence of tricuspid regurgitation , and greater incidence of raised pulmonary artery systolic pressure  than AL-CA and ATTR-CA.When compared with matched patients, those with AApoAI-CA had a thicker RV free wall  scintigraphy, which demonstrated no cardiac uptake in 4 patients and grade 1 myocardial radiotracer uptake in 7 patients. Of the 4 patients who had no cardiac uptake at diagnosis, 2 had repeat 99mTc-DPD scintigraphy at 1 and 7 years that demonstrated grade 1 myocardial radiotracer uptake; whereas 2 patients with grade 1 uptake at diagnosis had repeat scans at 1-year which did not demonstrate any changes. RV or right atrial (RA) uptake was observed in 7 out of 9 (77.8%) patients with cardiac radiotracer uptake . Only 3 matched patients with AL-CA underwent 99mTc-DPD scintigraphy, and therefore, no meaningful comparisons could be made.At diagnosis 11 patients with AApoAI-CA underwent Table S1; Figure At diagnosis 6 patients with AApoAI-CA underwent CMR assessment, all of whom had prominent RA and RV thickening, RV LGE and a raised ECV. Patients with cardiac involvement had either of early features of amyloid infiltration (n=4), with normal LV structure and function, but abnormal tissue characterization; or characteristic features of CA n=2) with increased LV mass, diffuse subendocardial/transmural LGE, and raised ECV . The following P<0.001), spleen involvement  and family history of amyloidosis .The most common reason for referral was for investigation of heart failure symptoms and local cardiac imaging suggestive of CA , followed by investigation of chronic kidney disease  and an incidental finding of amyloidosis on a duodenal biopsy . AApoAIV commonly presented with cardiac involvement  and chronic kidney disease stage 3-5 , of which only 1 patient had nephrotic syndrome. All patients who underwent a renal biopsy had medullary amyloid infiltration with very characteristic morphology. However, due to the absence of proteinuria in the majority of patients, it is unclear whether chronic kidney disease, which was almost universal, was due to renal amyloid infiltration or secondary to heart failure and subsequent renal hypoperfusion. None of the patients in our cohort had liver or spleen involvement, peripheral neuropathy, or a family history of amyloidosis. When compared with AApoAI, patients with AApoAIV had a significantly lower prevalence of liver involvement . The most common reason for referral was for investigation of heart failure symptoms and local cardiac imaging suggestive of CA , and 3 (20.0%) were referred for investigation of chronic kidney disease. Patients with AApoAIV-CA had a significantly lower median estimated glomerular filtration rate than matched patients with AL-CA and ATTR-CA .A total of 15 patients had cardiac involvement, and cardiac involvement was more common than in AApoAI  (one of which had first-degree heart block), 6 had atrial fibrillation, and 1 had a ventricular paced rhythm. Only 1 patient had QRS complexes that met the low voltage criteria. All remaining patients had a normal QRS amplitude , 1 had right bundle branch block, and 1 had left bundle branch block.P=0.003) and an echocardiogram characteristic of CA .At diagnosis, all patients with AApoAIV-CA underwent echocardiographic assessment. All 15 (100.0%) patients had a characteristic echocardiogram, with increased biventricular wall thickness, increased RWT, diastolic dysfunction, impaired longitudinal strain, and a typical apical-sparing strain pattern. There were no significant differences in echocardiographic parameters when compared with matched patients with AL-CA and ATTR-CA. However, when compared with patients with AApoAI-CA, those with AApoAIV-CA more commonly had an apical-sparing strain pattern , whereas patients with AApoAI-CA more commonly demonstrated grade 1 cardiac uptake than patients with AApoAIV-CA .At diagnosis 14 patients with AApoAIV-CA underwent P=0.004; Table S1).At diagnosis, 9 patients with AApoAIV-CA underwent CMR assessment, all of which had a CMR with characteristic findings of CA. All 9 patients had an increased maximal wall thickness, increased LV mass, and abnormal tissue characterization with LV LGE and an increased ECV Table . There wFigure S1A). Univariable Cox regression analysis revealed that NT-proBNP , LV mass , biatrial size , LV ejection fraction , longitudinal strain  and pulmonary artery systolic pressure , were all predictors of mortality. Survival was compared to a cohort of 45 patients with AL-amyloidosis and 45 patients with ATTR-amyloidosis who were matched for age, sex, and presence or absence of cardiac involvement. Patients with AApoAI had a reduced risk of mortality compared with patients with AL-amyloidosis, but there was no significant difference when compared to matched patients with ATTR-amyloidosis . Median survival was >172 months , during which 11 patients died, 5 of whom had evidence of cardiac involvement. However, there was no difference in survival between patients with cardiac involvement and those without cardiac involvement . Univariable Cox regression revealed that NT-proBNP , interventricular septal diameter , LV mass , LV ejection fraction , and longitudinal strain  were all predictors of mortality. Survival was compared with a cohort of 21 patients with AL-amyloidosis and 21 patients with ATTR-amyloidosis who were matched for age, sex, and presence or absence of cardiac involvement. Patients with AApoAIV had a reduced risk of mortality compared with patients with AL-amyloidosis, but there was no significant difference when compared with matched patients with ATTR-amyloidosis . Median survival was >30 months , during which 7 patients had died, all of whom had evidence of cardiac involvement. Patients with cardiac involvement had a statistically significant reduction in survival compared with those without cardiac involvement (log-rank This is the first study to extensively characterize the cardiac phenotype in patients with AApoAI and AApoAIV. Our study has demonstrated that: (1) AApoAI is commonly associated with multisystemic disease, and cardiac involvement presented with heart failure or dysphonia; (2) the Arg173Pro variant was always associated with both cardiac and laryngeal involvement; (3) AApoAI-CA commonly displays right-sided involvement, with RV thickening, tricuspid valve dysfunction, RA and RV radiotracer uptake, and RA and RV LGE; (4) AApoAIV presented with cardiac or renal involvement; (5) AApoAIV-CA commonly presented with heart failure symptoms and always displayed classical features of CA on echocardiography and CMR, hence mimicking more common forms of CA; (6) both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of morality than matched patients with AL-amyloidosis.17 Our data confirm a strong association between the Arg173Pro variant and cardiac involvement and highlight the need to fully assess the degree of cardiac infiltration if the Arg173Pro variant is identified. Furthermore, the presence of dysphonia or a petechial rash in a patient with imaging features of CA should prompt consideration of AApoAI within the differentials.AApoAI is commonly associated with a strong family history of amyloidosis and multisystemic disease resulting in renal, splenic, hepatic, cardiac, laryngeal, nerve, and cutaneous involvement. Therefore, CA in a patient with a family history of amyloidosis or multisystemic involvement, especially when associated with dysphonia, should raise the suspicion of AApoAI. Cardiac involvement appears to be highly dependent on the genetic variant and was most commonly associated with the Arg173Pro variant. This variant was also strongly associated with laryngeal involvement and in some cases associated with a petechial rash.Following extensive characterization with multimodality imaging, we identified distinctive features of right-sided involvement with RA thickening, RV thickening, and tricuspid valve dysfunction seen on echocardiography. The prominent right-sided cardiac disease was evident on bone scintigraphy with RA and RV radiotracer uptake; and CMR which demonstrated prominent RA and RV thickening, alongside marked RA and RV LGE. Patients had significant valvular involvement, with thickening of the tricuspid valve leaflets and subvalvular apparatus, tethering of the septal leaflet leading to significant tricuspid regurgitation or stenosis. The degree of RV thickening and prevalence of tricuspid valve dysfunction was significantly greater than in matched patients with ATTR-CA and AL-CA. AApoAI-CA can produce a spectrum of imaging findings, with some patients having classical imaging features of CA, whereas the majority presented with right-sided cardiac disease. Underappreciation of this rare form of CA among clinicians could result in patients being incorrectly labeled as having one of the more prevalent forms of CA (ATTR or AL). Identification of key aspects in the clinical presentation such as a family history of amyloidosis, multisystemic disease, dysphonia, or identification of right-sided cardiac disease on cardiac imaging should prompt consideration of AApoAI within the differentials and subsequent genetic screening Table .18 However, we have identified 2 cases of AApoAIV-CA that resulted in grade 1 cardiac uptake on bone scintigraphy. Considering the cardiac phenotype of patients with AApoAIV-CA, there is a considerable overlap with AL-CA, and hereditary ATTR-CA variants, such as Ser77Tyr, Tyr114Cys and Phe64Leu,21 which can all present with heart failure symptoms, classical features of CA on echocardiography/CMR, but a disproportionately low cardiac radiotracer uptake on bone scintigraphy . This is further supported by the similarities seen on echocardiography and CMR between patients with AApoAIV-CA and matched patients with ATTR-CA and AL-CA. The diagnostic pathway for cardiac radiotracer uptake grade 2 to 3 is well established,22 but grade 0 to 1 still present a diagnostic challenge.21 This is further complicated by the knowledge that AApoAIV-CA can mimic the phenotype of more common forms of CA .24In contrast to more prevalent forms of CA, the treatment for AApoAI and AApoAIV is largely supportive, with the mainstay of medical therapy revolving around managing complications of the disease process. There have been reports of organ regression in AApoAI following successful liver transplantation, due to a reduction in hepatic synthesis of the ApoAI-amyloid protein. However, given the significant morbidity and mortality associated with liver transplantation, this treatment option remains reserved for selected cases.2 Our study has demonstrated that in both AApoAI and AApoAIV, increased NT-proBNP, LV mass, biatrial size, and longitudinal strain were all associated with an increased risk of mortality. Despite these observations, both AApoAI and AApoAIV are slowly progressive and carry a good prognosis.Cardiac involvement is regarded as the main driver of mortality in amyloidosis, although to date this has mainly been demonstrated in patients with more common forms of amyloidosis, namely systemic AL-amyloidosis and ATTR.The main limitation of our study is that it is a single-center study with a small sample size, but this reflects the rare nature of these diseases. Acquisition of the RV-focused view required for RV strain measurements was not part of our standard echocardiographic protocol, but considering the right-sided cardiac disease in AApoAI-CA, this could be considered in future studies. CMR imaging was only available in some patients within our cohort who had a clinical indication for a CMR at the time of diagnosis. The small sample size meant that our survival analysis was limited to univariable Cox regression, and underpowered for a multivariable analysis.In summary, AApoAI-CA commonly presents with heart failure symptoms or dysphonia, and right-sided cardiac disease. AApoAIV-CA commonly presents with heart failure symptoms and always displays characteristic features of CA on echocardiography/CMR. Appreciation of not only the unique characteristic features of AApoAI but also the capability of AApoAIV to mimic common forms of CA is urgently needed in clinical practice to reduce the risk of misdiagnosis. Finally, both AApoAI and AApoAIV are slowly progressive and associated with a good prognosis.Dr Fontana is supported by a British Heart Foundation (BHF) Intermediate Clinical Research Fellowship (FS/18/21/33447). Daniel Knight is supported by a BHF Clinical Research Leave Fellowship (FS/CRLF/20/23004).Dr Fontana has consulting income from Intellia, Novo-Nordisk, Pfizer, Eidos, Prothena, Alnylam, Alexion, Janssen, and Ionis. Dr Gillmore has consulting income from Ionis, Alexion, Eidos, Intellia, Alnylam, and Pfizer. A. Wechelakar has consulting income from Alexia, Astra-Zeneca, Janssen, Attralus, and Prothena. Dr Hawkins has consulting income from Alnylam. The other authors report no conflicts.Supplemental MethodsBiopsy DataTable S1Figure S1


P < .001 and P = .017, respectively) were observed in the RVD group (n = 120). In the high SII score group (≥590.4), hospitalization and the need for positive inotrope treatment were significantly higher , and left ventricular ejection fraction (LVEF) was significantly lower (P = .015). In addition, in the high SII score group, right heart catheterization values, including cardiac output and index, were significantly impaired compared with those in the lower SII score group. There was a significant negative correlation between the SII score and the LVEF, cardiac output, and cardiac index in the correlation analyses. A significant relationship was observed between indirect inflammation and RVD in patients with HFrEF. The hemodynamic volume status and functional capacity were impaired in patients with high SII scores. These results indicated that advanced HF with worse outcomes may be related to the inflammatory process.Heart failure (HF) is a clinical syndrome with various etiologies and presentations. The role of the inflammatory pathway in HF prognosis is not fully understood. We investigated the association between the systemic immune-inflammation index (SII) and HF complicated by right ventricular dysfunction (RVD) and whether the SII is related to compromised hemodynamic volume status. A total of 235 patients with HF with reduced ejection fraction (HFrEF) were enrolled and divided into 2 groups according to the presence of RVD. The relationship between the SII score, hemodynamic parameters, and clinical endpoints was evaluated. Higher SII scores and neutrophil counts ( Studies have supported an association between high SII and poor outcomes in cancer, coronary artery disease, and HF.–11Currently, several risk-scoring methods have been developed for HF using comorbidities, risk factors, and hematological markers. to the best of our knowledge, no study has investigated any possible association between the SII and RVD in patients with HFrEF. We aimed to evaluate the association of SII in predicting RVD in patients with HFrEF and whether this association is associated with HF biomarkers, hemodynamic catheterization data, and New York Heart Association (NYHA) class.Although previous evidence has shown that the SII could provide an improved prediction of poor outcomes in patients with HFrEF,In the current retrospective observational study, a database of the medical records of 291 consecutive patients in both genders aged between 18 and 80 years with left ventricular ejection fraction (LVEF) < 40 who were admitted to our center between 2010 and 2019 was retrospectively reviewed. Patients with chronic stable HF (no recent diuretic dose increment and/or positive inotrope administration within the last month) and symptoms with a functional NYHA class of I and IV were included in the study . Patients with LVEF ≥ 40, recent myocardial infarction or coronary artery bypass graft surgery (≤6 months), decompensated HF, malignancies, chronic inflammatory disease, or hematological disorders were excluded (n = 56) . The SII was calculated as the total peripheral platelet count (P) × N/L (SII = P × N/L ratio). Clinical endpoints were defined as hospitalizations for worsening HF or cardiac death during the follow-up period.P < .05.Statistical analyses were performed using SPSS software . Normal distribution was assessed using the Kolmogorov–Smirnov test. Categorical variables are presented as frequencies (n) and percentages (%), and normally distributed variables are presented as mean ± SD. Spearman correlation analysis was also performed. The Kruskal–Wallis test was used for comparisons between more than 2 independent groups. The optimal cutoff points of the SII score to determine RVD were estimated using receiver operating characteristic curve analysis to calculate the area under the curve. Kaplan–Meier survival estimates were calculated. Statistical significance was set at P < .001), and the SII score and neutrophil count were higher . The need for loop diuretics was significantly higher in group 2 (P < .001). Furthermore, the ejection fraction was significantly lower and the left atrial diameter was significantly higher in group 2 (P < .001). In addition, deterioration in functional class was more prominent in group 2 .This study included 235 patients with HF, with a median age of 52 years, of whom 36 15.3%) were women. The median follow-up time was 14 (12–25) months. The baseline characteristics of the study population are presented in Table 5.3% wereP < .001). The SII score was significantly negatively correlated with LVEF, RV fractional area change, tricuspid annular plane systolic excursion, cardiac output, and cardiac index . When clinical endpoints and LVEF were evaluated for a high SII score (≥590.4), hospitalization rates at the 1-year follow-up and the need for positive inotropes at hospitalization were significantly higher, and LVEF was significantly lower in the high SII score group  (Table P = .032). However, the Kaplan–Meier survival analysis showed that death during follow-up did not change according to a high SII score (P = .052) , can effectively reflect the balance between the host immune and inflammatory status. Wojciechowska et al showed a relationship between inflammation and systemic and pulmonary hemodynamic parameters; serum activities of superoxide dismutase isoenzymes were significantly correlated with pulmonary capillary wedge pressure, mean pulmonary artery pressure, and LVEF. Similarly, we showed that the SII score is associated with both LVEF and invasively derived hemodynamic parameters. This indicates that indirect inflammation parameters not only show advanced disease, but are also informative regarding hemodynamic volume status.In patients with HF, the hemodynamic volume status is modifiable with medications, and a deteriorated volume status is related to pulmonary and systemic congestion, which results in worse functional capacity. There is a relationship between systemic inflammation and RV failure.The current study has some limitations. This was a single-center, retrospective study with a small sample size. Inherent to the retrospective design, the patients were not randomized regarding their demographic properties. Additionally, further inflammation markers, including mean platelet volume possibly related to HF progression, were not evaluated, and follow-up time was relatively short.In patients with HFrEF, a higher SII score was associated with lower LVEF, RVD, and hemodynamically confirmed advanced disease. Among patients with a higher SII score, the incidence of hospitalization and need for positive inotrope support during decompensation were higher. In addition, a higher SII score was associated with deterioration in hemodynamic volume status and functional capacity. These findings may indicate neurohumoral activation of the subject and a stress response to HF owing to the inflammatory process.The data of the patients enrolled in the present study were also included in the Master thesis of Doctor İlke Erbay.Data curation: İlke Erbay, Mustafa Balci.Investigation: Kevser Balci, İlke Erbay, Burcu Demirkan.Methodology: Kevser Balci, Mustafa Balci.Supervision: Burcu Demirkan, Ahmet Temizhan.Writing – review & editing: Kevser Balci.