Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Optimization of pharmacotherapies for ambulatory patients with heart failure and reduced ejection fraction is associated with improved outcomes.

BACKGROUND: In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.4%); 2) in-titration (29.0%); 3) undertreated (32.7%); and 4) intolerant/contraindicated (12.9%). Risk of mortality or HF events (hospitalization, emergency visit or ambulatory administration of intravenous diuretics) within one year was assessed using Cox regression models and Kaplan-Meier curves. RESULTS: Compared to optimized patients, those intolerant (HR: 4.60 [95%CI: 2.23-9.48]; p < 0.0001) had the highest risk of outcomes, followed by those undertreated (3.45 [1.78-6.67]; p = 0.0002) and in-titration (1.99 [0.97-4.06]; p = 0.0588). Overall predictors of outcomes included loop diuretics' use (4.54 [2.39-8.60]), undertreatment (2.38 [1.22-4.67]), intolerance/ contraindication to triple therapy (3.08 [1.47-6.42]), peripheral vascular disease (2.13 [1.29-3.50]) and NYHA class III-IV (1.89 [1.25-2.85]); all p < 0.05. CONCLUSION: Level of adherence to guidelines is associated with outcomes, with intolerant/contraindicated patients having the worst prognosis and those undertreated and in-titration at intermediate risk compared to those optimized. Up-titration of therapy should be attempted whenever possible, considering patients' limitations, to potentially improve outcomes.

Learning Curve in Left Ventricular Assist Device Implantation: Low Volumes Do Not Equate Bad Outcomes.

INTRODUCTION: Most implantations of left ventricular assist devices (LVAD) are performed in low-volume centers. This study aimed to evaluate the procedural learning curve of HeartMate II (HM2) implantations by comparing outcomes between two time periods in a low-volume center. METHODS: All 51 consecutive patients undergoing HM2 implantation between January 2009 and December 2017 were reviewed and allocated into 2 groups: early-era group (from 2009 to 2014; n=25) and late-era group (from 2015 to 2017; n=26). The primary outcome was the 90-day mortality rate, and the secondary outcome was a composite of mortality, neurological event, reoperation for bleeding, need for temporary right ventricular assist device, and pump thrombosis at 90 days. Median follow-up time was 51 months (0-136). A cumulative sum (CUSUM) control analysis was used to establish a threshold of implantations that optimizes outcomes. RESULTS: Patients in the early era had a higher rate of diabetes, previous stroke, and inotrope support before HM2 implantation. The 90-day mortality rate was not significantly higher in the early era (24% vs. 15%, P=0.43), but the composite endpoint was significantly higher (76% vs. 42%, P=0.01). The CUSUM analysis found a threshold of 23 operations after which the composite endpoint was optimized. CONCLUSION: Patients undergoing HM2 implantation in a low-volume center have improving outcomes with number of cases and optimized results after a threshold of 23 cases. Significant changes in patient selection, surgical techniques, and patient management might lead to improved outcomes after LVAD implantation.

Learning Curve in Left Ventricular Assist Device Implantation: Low Volumes Do Not Equate Bad Outcomes

ABSTRACT Introduction: Most implantations of left ventricular assist devices (LVAD) are performed in low-volume centers. This study aimed to evaluate the procedural learning curve of HeartMate II (HM2) implantations by comparing outcomes between two time periods in a low-volume center. Methods: All 51 consecutive patients undergoing HM2 implantation between January 2009 and December 2017 were reviewed and allocated into 2 groups: early-era group (from 2009 to 2014; n=25) and late-era group (from 2015 to 2017; n=26). The primary outcome was the 90-day mortality rate, and the secondary outcome was a composite of mortality, neurological event, reoperation for bleeding, need for temporary right ventricular assist device, and pump thrombosis at 90 days. Median follow-up time was 51 months (0-136). A cumulative sum (CUSUM) control analysis was used to establish a threshold of implantations that optimizes outcomes. Results: Patients in the early era had a higher rate of diabetes, previous stroke, and inotrope support before HM2 implantation. The 90-day mortality rate was not significantly higher in the early era (24% vs. 15%, P=0.43), but the composite endpoint was significantly higher (76% vs. 42%, P=0.01). The CUSUM analysis found a threshold of 23 operations after which the composite endpoint was optimized. Conclusion: Patients undergoing HM2 implantation in a low-volume center have improving outcomes with number of cases and optimized results after a threshold of 23 cases. Significant changes in patient selection, surgical techniques, and patient management might lead to improved outcomes after LVAD implantation.

Comparison of 18F-sodium fluoride positron emission tomography imaging and 99mTc-pyrophosphate in cardiac amyloidosis.

BACKGROUND: Pyrophosphate (PYP) scintigraphy provides high diagnostic accuracy for the detection of transthyretin (ATTR) cardiac amyloidosis (CA). There has recently been emerging interest in using 18F-sodium fluoride (NaF) for this application, yet its sensitivity has never been directly compared to that of PYP, the current molecular gold standard METHODS: Twelve subjects with ATTR-CA and 5 controls referred for PYP-SPECT were prospectively enrolled. 18F-NaF PET/CT scans were performed at 1 and 3 hours. Qualitative and quantitative analyses of the images were performed, and the sensitivity of 18F-NaF PET/CT and PYP-SPECT were compared RESULTS: Visual interpretation of NaF PET/CT yielded a sensitivity of 0.25 (95% CI 0.089 to 0.53) for the detection of ATTR-CA, which is significantly inferior to that of PYP-SPECT/CT (100%, P = .016). Visual interpretation at 3 hours yielded a similar sensitivity of 0.30 (95% CI 0.11 to 0.60, P = 1.00). There were no false-positive NaF PET studies. Mean target-to-background ratio (TBRmean) at 1h did not differ significantly (P = .21) in ATTR-CA subjects (0.83 ± 0.15) compared to controls (0.72 ± 0.15). Receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.69 ± 0.16 (95% CI 0.37 to 1.00, P = .23). CONCLUSION: With qualitative and quantitative analyses, sensitivity of NaF PET/CT is significantly inferior to that of PYP-SPECT for the diagnosis of ATTR-CA.

Early and Long-Term Outcomes after Direct Bridge-to-Transplantation with Extracorporeal Membrane Oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as direct bridge-to-transplantation (dBTT) remains controversial. We compared the short- and long-term outcomes of adult patients undergoing urgent heart transplantation (HT) with (dBTT) and without (non-BTT) VA-ECMO support at the time of HT. METHODS: Adults who underwent urgent HT in two institutions were assessed (N = 133; dBTT: N = 34 and non-BTT: N = 99). Patient characteristics, donor characteristics, in-hospital outcomes, and overall survival were compared. Mean follow up was 77±38 months and was 100% complete. Mortality predictors were identified using univariate and multivariate analyses. RESULTS: Before HT, patients with dBTT had higher rates of ischemic cardiomyopathy, acute kidney injury, liver failure, respiratory failure, and longer graft ischemia times. More patients in the dBTT group had complications, such as requiring VA-ECMO postoperatively (dBTT=50% vs. non-BTT=20%, P < 0.01). Hospital deaths (dBTT=23% vs. non-BTT=19%, P = 0.58), one-year (74% vs. 80%) and five-year survival (62% vs. 75%, P = 0.74 for overall survival) were not significantly different. The MELD-XI score and previous cardiac surgery were independent predictors of hospital mortality. CONCLUSION: Direct bridge-to-transplantation in patients on VA-ECMO support was not associated with worse long-term outcomes compared with non-VA-ECMO urgent HT, especially in recipients without any associated organ failure and a low MELD-XI score before HT.

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Examining the sensitivity of 18F-NaF PET for the imaging of cardiac amyloidosis.

BACKGROUND: Conventional nuclear imaging with bone-seeking radiopharmaceuticals has been shown to be a sensitive test for the detection of transthyretin cardiac amyloidosis (ATTR); however, to date, few data exist on the utility of 18F-sodium fluoride (NaF) positron emission tomography (PET) in subjects with cardiac amyloidosis (CA). METHODS: Myocardial perfusion imaging and cardiac 18F-NaF PET/CT of 7 subjects with ATTR, four with light-chain CA (AL), and four controls were retrospectively reviewed. Qualitative interpretation and quantitative analyses with average left ventricular standardized uptake values (SUVmean) and target-to-background ratios (TBRmean) were performed. RESULTS: Average TBRmean was significantly increased in subjects with ATTR (0.98 ± 0.09) compared to AL (0.85 ± 0.08, P = .026) and CTL (0.82 ± 0.07, P = .020), while SUVmean was not (P = .14). Receiver-operator characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.91, with a sensitivity/specificity of 75%/100% for TBRmean using a cutoff value of 0.89 for the diagnosis of ATTR. Qualitative interpretation resulted in a sensitivity/specificity of 57%/100% for ATTR. CONCLUSIONS: While 18F-NaF PET/CT demonstrates good diagnostic accuracy for ATTR, particularly when using quantitative analysis, the low TBRmean values observed in ATTR indicate poor myocardial signal. 18F-NaF PET/CT is not yet ready for clinical use in CA until further comparison studies are performed with 99mTc-DPD/PYP.

Care Gaps in Adherence to Heart Failure Guidelines: Clinical Inertia or Physiological Limitations?

OBJECTIVES: This study evaluated the impact of clinical and physiological factors limiting treatment optimization toward recommended medical therapy in heart failure (HF). BACKGROUND: Although guidelines aim to assist physicians in prescribing evidence-based therapies and to improve outcomes of patients with HF and reduced ejection fraction (HFrEF), gaps in clinical care persist. METHODS: Medical records of all patients with HFrEF followed for at least 6 months at the authors' HF clinic (n = 511) allowed for drug optimization and were reviewed regarding the prescription rates of recommended pharmacological agents and devices (implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy [CRT]). Then, an algorithm integrating clinical (New York Heart Association [NYHA] functional class, heart rate, blood pressure and biologic parameters (creatinine, serum potassium) based on the inclusion/exclusion criteria of landmark trials guiding these recommendations) was applied for each agent and device to identify potential explanations for treatment gaps. RESULTS: Gross prescription rates were high for beta-blockers (98.6%), mineralocorticoid receptor antagonist (MRA) (93.4%), vasodilators (90.3%), ICDs (75.1%), and CRT (82.1%) among those eligible, except for ivabradine (46.3%, n = 41). However, achievement of target physiological doses was lower (beta-blockers, 67.5%; MRA, 58.9%; and vasodilators, 63.4%), and one-fifth of patient dosages were still being up-titrated. Suboptimal doses were associated with older age (odds ratio [OR]: 1.221; p < 0.0001) and history of stroke or transient ischemic attack (TIA) (no vs. yes, OR: 0.264; p = 0.0336). CONCLUSIONS: Gaps in adherence to guidelines exist in specialized HF setting and are mostly explained by limiting physiological factors rather than inertia. Older age and history of stroke/TIA, potential markers of frailty, are associated with suboptimal doses of guideline-directed medical therapy, suggesting that an individualized rather than a "one-size-fits-all" approach may be required.

Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis.

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease.

Association of recreational drug consumption, cardiac toxicity and heart transplantation

Summary: Cardiac toxicity from recreational drug use remains difficult to establish. We report the cases of 3 young patients who were hospitalized for cardiogenic shock. All were bridged to transplantation with implantation of a left ventricular assist device (LVAD). They underwent uneventful heart transplantation. The patients did not have any significant personal or family medical history, but all admitted consuming large quantities of recreational drugs daily. Histological examination of the native heart did not show any inflammation or infiltrative myocardial disease. In this series of young patients presenting in cardiogenic shock with minimal histologic findings on examination of the native hearts, the association between cardiac toxicity and active use of recreational drugs remains a strong possibility. The transplant community should be made aware of this possible association in the current era of legalization and social trivialization of drug consumption.

Should the septum be included in the assessment of right ventricular longitudinal strain? An ultrasound two-dimensional speckle-tracking stress study.

Right ventricular longitudinal strain (RVLS) by 2D speckle-tracking echocardiography (2D-STE) is a useful parameter for assessing systolic function. However, the exact method to perform it is not well defined as some authors evaluate only free wall (FW) segments while others include all six RV segments. To compare the assessment of RVLS at rest and during exercise by these two approaches. Echocardiography was performed on 80 healthy subjects at rest and during exercise. The analysis consisted of standard and 2D-STE assessment of RV global and segmental strain tracing only RVFW and also tracing all six RV segments. At rest, RVLS could be assessed in 78 (feasibility 97.5%) subjects by both methods. However, during exercise, RVLS by RVFW method was feasible in 67 (83.8%) as compared to 74 (92.5%) by RV6S approach. Both at rest and during exercise, RVLS values by the two methods showed excellent correlation (r = > 0.90). However, RVLS values assessed by RV6S were lower (absolute values) than those by RVFW approach (RV6S vs. RVFW; rest: - 27.0 ± 3.9 vs. - 9.5 ± 3.9, p < 0.001 and exercise: - 30.7 ± 5.2 vs. - 33.3 ± 5.1, p < 0.001). Furthermore, basal strain was higher and apical strain lower (absolute values) by RV6S approach. At rest, reproducibility for RVLS was excellent and similar for the two methods. However, during exercise, reproducibility for RVFW method was poorer, especially at the apex. The two currently described methods for RVLS assessment by 2D-STE demonstrated excellent agreement. However, the RV6S approach seemed to be more feasible and reproducible, particularly during exercise. Moreover, global and segmental strain values are different with both methods and should not be interchanged.

Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited.

BACKGROUND: There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size. METHODS: During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls. RESULTS: The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61). CONCLUSION: Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

Molecular Imaging of Cardiac Amyloidosis.

PURPOSE OF REVIEW: The aim of this review is to give an update on the molecular imaging tools currently available as well as to discuss the potential roles and limitations of molecular imaging in cardiac amyloidosis. RECENT FINDINGS: Molecular imaging plays a central role in the evaluation of patients with suspected cardiac amyloidosis. It can be used to diagnose and distinguish between the different types of cardiac amyloidosis. The diagnostic properties of bone scintigraphy are such that it allows reliable diagnosis of transthyretin cardiac amyloidosis without the need of endomyocardial biopsy in a significant proportion of patients. Furthermore, molecular tracers assessing amyloid plaque burden and sympathetic innervation may be useful for the non-invasive evaluation diagnosis and risk stratification of patients with suspected cardiac amyloidosis. Cardiac amyloidosis is an under-recognized cause of left ventricular hypertrophy and heart failure in the elderly. The role of molecular imaging in cardiac amyloidosis is expected to grow considering the arrival of new therapies and molecular imaging probes.

Aortic regurgitation in patients with a left ventricular assist device: A contemporary review.

Aortic regurgitation (AR) developing while using a continuous-flow left ventricular assist device (CF-LVAD) affects 25% to 30% of patients within the first year of implantation and is increasingly being recognized as a cause of recurrence of symptomatic heart failure (HF). The underlying mechanisms are likely multifactorial, including changes in the leaflets of the aortic valve (AV), altered root biomechanics, and excessive left ventricular (LV) unloading, together promoting cusp remodeling and commissural fusion. Known risk factors for the development of AR while under support include advanced age, lower body surface area, systemic hypertension, large aortic root diameter, permanently closed AV, and duration of support. Further, variants in the anastomotic angle between the outflow graft and the ascending aorta have recently been recognized to induce structural changes in the aortic wall, contributing to the development and progression of AV disease. Nevertheless, it remains controversial as to whether AR on LVAD has an independent impact on prognosis, and no clear recommendation exists regarding its optimal diagnosis criteria and treatment. Herein we briefly review the literature and focus on the latest results regarding development of AR in patients supported with CF-LVADs. We also provide a structured echocardiographic approach for an accurate assessment of AV dysfunction in this challenging situation.

Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy.

Aims: Risk stratification in heart failure (HF) relies on several established clinical risk scores, however, myocardial deformation, right heart metrics, and exercise performance have not usually been considered. This study sought to assess the incremental value of advanced echocardiographic and cardiopulmonary exercise testing (CPX) parameters to validated risk scores in HF. Methods and results: The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) and Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI) scores were applied to 208 ambulatory patients with dilated cardiomyopathy (DCM) who completed echocardiography in conjunction with CPX as part of the Stanford Exercise Testing registry. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation, and hospitalization for acute HF. Mean age, left ventricular ejection fraction (LVEF), and left ventricular global longitudinal strain (LVGLS) were 47 ± 13 years, 33 ± 13%, and -10.6 ± 4.4%, respectively, while right ventricular free-wall longitudinal strain was -18.8 ± 5.5%. Partial correlation mapping identified strong correlations between LVEF, LVGLS, and LV systolic strain rate, with a moderate correlation between these metrics and peak VO2. Over a median follow up of 5.3 years, the composite end point occurred in 60 patients. Cox proportional hazards identified MAGGIC score [hazard ratio (HR) (2.04 [1.39-3.01], P < 0.01], peak VO2 HR (0.52 [0.28-0.97], P = 0.04), and right atrial volume indexed (RAVI) HR (1.31 [1.07-1.61], P < 0.01) as independent correlates of outcome. RAVI remained an independent correlate when combined with the MECKI score (2.21 [1.59-3.07]), P < 0.01, RAVI, 1.33 [1.06-1.67], P = 0.01). Conclusion: Our study demonstrates that RAVI is complementary to well-validated HF risk scores and highlights the importance of exercise performance in DCM.

Changes in Outcomes of Cardiac Allograft Vasculopathy Over 30 Years Following Heart Transplantation.

OBJECTIVES: This study investigated temporal changes in the demographics and the prognosis of cardiac allograft vasculopathy (CAV) over 30 years following heart transplantation (HTx). BACKGROUND: Effects of the changing HTx demographics on CAV outcomes, based on International Society for Heart and Lung Transplantation (ISHLT) classification of CAV, have been incompletely investigated. METHODS: Patients who underwent HTx at the Montreal Heart Institute were classified according to the severity of CAV (CAV 0 is no presence of CAV; CAV 1 is mild, CAV 2 to 3 is moderate to severe) and era of HTx (early: 1983 to 1998; recent: 1999 to 2011). We compared the risk of progression, survival, and independent predictors of outcomes among the groups. RESULTS: A total of 298 patients were followed for 11.6 ± 6.6 years. Patients who received transplants in the early era exhibited a higher risk for progression from CAV 1 to a higher grade (adjusted odds ratio: 8.0; 95% confidence interval [CI]: 1.01 to 62.6). The presence of CAV was associated with a significantly increased risk for all-cause mortality in the early era (hazard ratio [HR]: 1.6; 95% CI: 1.1 to 2.5) but not in the recent era (HR: 1.1; 95% CI: 0.2 to 4.9). Regardless of the era, CAV classes 2 to 3 and CAV 1 were associated with a significantly increased risk for all-cause mortality compared to CAV 0 (HR: 6.5; 95% CI: 2.7 to 15.7; and HR: 1.750; 95% CI: 1.001 to 3.046, respectively). CONCLUSIONS: The progression and prognosis of CAV have improved over 30 years. The ISHLT CAV classification accurately and independently predicts long-term outcome following HTx.