Familial occurrences of cardiac wild-type transthyretin amyloidosis: a case series.

Background: Cardiomyopathy caused by aggregation and deposition of transthyretin amyloid fibrils in the heart (ATTR-CM) is divided into a hereditary (ATTRv) and a wild-type (ATTRwt) forms. While ATTR-CM has been considered a rare disease, recent studies suggest that it is severely underdiagnosed and an important cause of heart failure in elderly patients. Familial occurrence is implicit in ATTRv, but it is not expected in ATTRwt. Case summary: We report a case series of two unrelated families each with two brothers diagnosed with ATTRwt. Genetic testing did not reveal mutations in the transthyretin gene. Family screening with electrocardiogram, echocardiography, and genetic testing did not raise any suspicion of ATTR in first-line family members. Discussion: Familial occurrence of a rare, non-hereditary disease is statistically unlikely. Two siblings in two different families diagnosed with ATTRwt highlight that the aetiology of ATTRwt is poorly understood, and that genetic factors distinct from mutations in the transthyretin gene, as well as environmental factors, might contribute to the pathogenesis. Identifying such factors might reveal new therapeutic targets. To investigate this further, clinicians need to be aware of the possibility of familial occurrence of ATTRwt.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Wild-type transthyretin amyloid cardiomyopathy: expect the unexpected-a case report.

Background: General interest and incidence are increasing in wild-type transthyretin amyloidosis (ATTRwt) in recent time. As patient population increases, further knowledge of the management of the frequently encountered interacting cardiac comorbidities is requested to improve treatment of ATTRwt patients. Case summary: A 73-year-old male ATTRwt patient presented to the outpatient clinic (Day 0) with dyspnoea, leg swelling, and palpitations. At diagnosis, 3 years prior to presentation, he exhibited only minor signs of ATTRwt. At Day 0, clinical examination revealed atrial fibrillation and mild peripheral oedema. Anticoagulant and symptomatic treatment with beta-blocker and diuretics was initiated, and the patient was planned for sub-acute direct cardioversion, and the patient was discharged with a Holter monitor to outpatient care. At Day 7, analysis of the monitoring demonstrated spontaneous conversion to sinus rhythm and, unexpectedly, episodes of high-rate self-remittent sustained monomorphic ventricular tachycardia (VT) and frequent ventricular ectopic beats. At Day 8, a sub-acute coronary angiography was performed which revealed a significant proximal left anterior descending artery stenosis which was treated with percutaneous coronary intervention (PCI) and subsequently an internal defibrillator was implanted. Following visits at 1- and 3-month post-PCI at the outpatient clinic revealed no VT and suppression of ventricular ectopic beats. Discussion: The case illustrates some of the frequently encountered cardiac comorbidities (e.g. atrial fibrillation, ventricular arrhythmia, and ischaemic heart disease) associated with ATTRwt. A high level of suspicion is warranted to identify treatable cardiac conditions [atrial fibrillation, atrioventricular (AV) block, and ischaemic heart disease] and to uncover potentially fatal cardiac conditions in patients with ATTRwt.

Strain-derived myocardial work in wild-type transthyretin cardiac amyloidosis with aortic stenosis-diagnosis and prognosis.

BACKGROUND: Several echocardiographic parameters have been suggested to differentiate wild-type transthyretin cardiac amyloidosis (ATTRwt) from other causes of hypertrophy. These studies have all been performed in small samples of mixed cardiac amyloidosis. The purpose of this study was to investigate the role of echocardiographic parameters in patients with ATTRwt and aortic stenosis (AS) versus patients with AS. The secondary aim was to investigate the role of myocardial work in the prognosis of patients with ATTRwt. METHODS: The sensitivity and specificity of the relative apical sparing ratio (RAS), the apical-to-basal ratio (AB), the ejection-fraction-to-global-longitudinal-strain ratio (EF/GLS), and the global myocardial work index (GWI) were calculated using receiver-operated characteristics curves and area under the curve (AUC) in patients with ATTRwt and AS (n = 50) versus patients with AS (n = 354). Multivariable regression was used to assess the prognostic value of GWI in patients with ATTRwt (n = 212). RESULTS: When used to identify AS from ATTRwt + AS, GWI had a sensitivity of 80% and specificity of 70%. The AUC of GWI was larger than that of AB (p = .01) and EF/GLS (p > .01) but not RAS (p = .15). In patients with ATTRwt multivariable regression found age predicted mortality with an estimate of HR = 1.086 (CI: 1.034-1.141) while GWI predicted survival with an estimate of HR = .837 (CI: .733-.956) per 100 mmHg*% increase. CONCLUSION: GWI was demonstrated to be a viable classifier in ATTRwt and AS versus AS. GWI was demonstrated to independently predict survival in patients with ATTRwt. Further studies examining the role of myocardial work in ATTRwt are warranted.

Clinical characteristics and prognostic implications of orthopedic ligament disorders in patients with wild-type transthyretin amyloidosis cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloidosis (ATTRwt) is associated with multiple ligament disorders (LD) such as carpal tunnel syndrome (CTS), lumbar spinal stenosis (LSS), and spontaneous tendon rupture (STR). No studies have investigated the prevalence of these LD in the same cohort of ATTRwt patients. Furthermore, the clinical characteristics and prognostic implications of such disorders have not been studied. METHODS: From 2017 to 2022, 206 consecutive patients with ATTRwt were diagnosed and followed prospectively to the time of death or the censoring date of September 1st, 2022. Patients with and without LD were compared, and the presence of LD was used along with the baseline clinical, biochemical, and echocardiographic characteristics to predict hospitalization with worsening heart failure and death. RESULTS: CTS surgery was performed in 34 % of the patients, 8 % were treated for LSS, and 10 % had experienced an STR. The median follow-up time was 706 days (312-1067). Hospitalization with worsening heart failure occurred more frequently in patients with LD compared to patients without LD (p = 0.035). Presence of LD or surgery for CTS were found to be independent predictors of worsening heart failure with a hazard ratio of 2.0 (p = 0.01). The mortality was comparable between patients with and without LD (p = 0.10). CONCLUSION: Orthopedic disorders are prevalent in ATTRwt cardiomyopathy, and presence of LD was an independent predictor of hospitalization with worsening heart failure.

Association of Right Ventricular Myocardial Blood Flow With Pulmonary Pressures and Outcome in Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is a restrictive and infiltrative cardiomyopathy, characterized by increased biventricular filling pressures and low output. Symptoms are predominantly of right heart origin. The role of right ventricular (RV) myocardial blood flow (MBF) in CA has not been studied. OBJECTIVES: This study aimed to first associate RV MBF measured by using positron emission tomography (PET) with reference standards of RV pressures and then to explore its prognostic value in CA. METHODS: Cardiac PET was performed at rest in 52 patients with CA and 9 healthy control subjects. MBF was quantified from the right and left ventricles by using 11C-acetate, 15O-water, or both (n = 25). RV pressure was measured invasively or by echocardiography. Associations between biventricular MBF toward symptoms, RV function, and outcome (death or acute heart failure) were studied in patients with CA. RESULTS: MBF of the right ventricle (MBFRV) and the ratio of MBFRV and MBF of the left ventricle (MBFRV/LV) for the 2 tracers were significantly correlated (r > 0.92). MBFRV was directly correlated with RV systolic pressures with both tracers (P ≤ 0.005). MBFLV was inversely correlated with wall thickness (P < 0.0001). MBFRV/LV was significantly associated with N-terminal pro-B-type natriuretic peptide levels, NYHA functional class, RV pressures, and RV systolic function (all; P < 0.001). Twenty-six cardiac events (25 deaths) occurred during follow-up (median 44 months). MBFRV/LV higher than 56% was associated with a diagnosis of pulmonary hypertension (AUC: 0.96 [95% CI: 0.91-1.00]; P < 0.0001); and predicted outcome with HR: 9.0 (95% CI: 4.2-14.5), P < 0.0001). CONCLUSIONS: Measurements of MBFRV using PET are feasible, as confirmed with 2 different tracers. Imbalance between RV and LV myocardial perfusion is associated with increased RV load and adverse events in cardiac amyloidosis.

Health-related quality of life among transthyretin amyloid cardiomyopathy patients.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR CM) is a progressive and severe heart disease with physical and psychological implications. The Nordic PROACT study was conducted to investigate the health-related quality of life (HRQoL) in ATTR CM patients. METHODS AND RESULTS: The Nordic PROACT study was a cross-sectional non-interventional study conducted in 12 cardiology hospital clinics across Norway, Sweden, Finland and Denmark. Men and women aged ≥18 years diagnosed with symptomatic ATTR CM were included. The investigator provided information on medical history, biomarkers, current treatment, co-morbidities and disease severity according to the New York Heart Association (NYHA) class and the National Amyloidosis Centre (NAC) staging. Patients completed the HRQoL questionnaires in the form of the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D-5L index with Visual Analog Scale (VAS), and the Major Depression Inventory (MDI). A total of 169 patients (mean ± SD age 77.7 ± 6.2 years) were included. Ninety-two per cent were men. Seventy-six per cent had wildtype ATTR CM (ATTRwt CM) and 15% had a hereditary form of ATTR CM (ATTRv CM) while 9% were genetically unclassified. Most patients were in NYHA class II (54%) and NAC stage 1 (53%). Participation in randomized clinical trials (RCT) was noted in 58% of the patients. The 169 ATTR CM patients had a mean ± SD KCCQ score of 64.3 ± 23.1 for total symptom score, 64.8 ± 20.9 for overall summary score (OSS) and 65.1 ± 21.5 for clinical summary score. The EQ-5D-5L total utility score was 0.8 ± 0.2 and the EQ-5D-5L VAS score was 62.9 ± 20.6. The vast majority (89%) did not report any signs of depression. Patients with ATTRv CM had a higher KCCQ OSS as compared with ATTRwt CM, while EQ-5D-5L utility score, EQ-5D-5L VAS and MDI were similar. Non-RCT participants had a poorer HRQoL as compared with RCT participants as reflected in lower KCCQ OSS and EQ-5D-5L VAS scores and a higher MDI score. Patients with higher NYHA classes and NAC disease stages had a poorer HRQoL as demonstrated by lower KCCQ and EQ-5D-5L scores and higher MDI scores. Correlation between KCCQ, EQ-5D-5L and MDI and the covariate NYHA class remained significant (P < 0.05) after adjusting for multiple testing. CONCLUSIONS: KCCQ scores were lower than previously reported for patients with other heart diseases of non-ATTR CM origin. The HRQoL measures correlated well to NYHA class and NAC disease stage. The prevalence of depression appeared to be low.

Identification of wild-type transthyretin cardiac amyloidosis in patients with carpal tunnel syndrome surgery (CACTuS).

AIMS: Wild-type transthyretin cardiac amyloidosis (ATTRwt) is an infiltrative cardiomyopathy with a poor prognosis. The condition is associated with carpal tunnel syndrome (CTS), which often precedes the ATTRwt diagnosis by several years. The aim of the study was (i) to screen patients with a recent history of CTS for ATTRwt using red flags, (ii) to determine whether patients with screened ATTRwt had less advanced disease compared with patients with clinical ATTRwt, and (iii) to assess the sensitivity and specificity of known red flags in ATTRwt. METHODS AND RESULTS: Patients aged ≥60 years at the time of CTS surgery were invited for screening. Red flags were defined as elevated biomarker levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) or cardiac troponin, an electrocardiogram pattern associated with ATTRwt, left ventricular hypertrophy (LVH), and impaired longitudinal strain with apical sparring. All patients with a red flag were referred for a diagnostic scintigraphy. Patients with ATTRwt diagnosed by screening were compared with patients with clinical ATTRwt (n = 51) matched by age, gender, and CTS surgery. Among the 120 enrolled subjects (mean age 74.5 years, 90% male), the suspicion of ATTR was raised in 67 (55.8%), and 10 (8.3%) were diagnosed with ATTRwt. Patients identified with ATTRwt were predominantly asymptomatic and had mildly elevated NT-proBNP, mildly increased LVH, preserved left ventricular ejection fraction, and systolic longitudinal function, which differed significantly from clinical ATTRwt controls (P < 0.001). CONCLUSIONS: The study found an ATTRwt prevalence of 8.3% in a population of age and gender-selected patients with a recent history of CTS. The identified patients with ATTRwt had less structural and functional cardiac involvement than clinical ATTRwt controls.

Incidence and predictors of worsening heart failure in patients with wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Prognostic markers of survival have been identified in wild-type transthyretin amyloidosis (ATTRwt), but limited data exist with respect to hospitalizations with worsening heart failure (WHF). Predictive markers of WHF have yet to be identified. METHODS: From April 2017 to February 2021, 104 patients with ATTRwt were diagnosed and prospectively followed from the time of diagnosis to the time of death or the censoring date of 1 February 2021. Baseline patient characteristics, biomarkers, and advanced echocardiography were used to predict hospitalization with WHF. RESULTS: During the median follow-up period of 23 months, 51% of patients were hospitalized due to WHF. Seventy-three per cent of patients with WHF were admitted at least twice. Patients with WHF during the first year had significantly poorer survival (P < 0.001). Independent predictors of WHF during follow-up were pacemaker implantation prior to diagnosis (PMI, P = 0.037) and right atrial volume index (RAVi, P = 0.008). Patients with PMI had a higher left ventricular mass index and poorer left ventricular and right ventricular systolic function indicating a more advanced stage of amyloid disease. CONCLUSIONS: A high incidence and recurrence of hospital admissions with WHF were demonstrated in contemporary patients with ATTRwt, which was associated with reduced survival. Patients with pacemaker devices prior to ATTRwt diagnosis experienced more frequent hospitalizations with WHF. PMI and right atrial enlargement were identified as independent predictors of WHF during follow-up.

Assessment of Acute Rejection by Global Longitudinal Strain and Cardiac Biomarkers in Heart-Transplanted Patients.

Aims: The aim of this study was to evaluate left ventricular global longitudinal strain (LVGLS), N-terminal pro brain natriuretic peptide (Nt-ProBNP), and Troponin T as non-invasive markers for acute cellular rejection (ACR) diagnosis and severity assessment after heart transplantation (HTx). Methods: We retrospectively included all HTx patients transplanted from 2013 to 2019. At each visit, the patients were subjected to endomyocardial biopsy (EMB), measurement of Nt-ProBNP and Troponin T, and protocoled echocardiography with assessment of LVGLS. Sudden drop in graft function (SDGF) was defined as a drop in LVGLS ≥-2% in combination with either an increase in Troponin T ≥20% or Nt-ProBNP ≥30% compared with levels at the latest visit. Results: We included 1,436 EMBs from 83 HTx patients. The biopsies were grouped as 0R (n = 857), 1R (n = 538), and ≥2R (n = 41). LVGLS was lower and Troponin T and Nt-ProBNP higher in the 2R group than in the 0R and 1R groups (LVGLS: -12.9 ± 3.8% versus -16.9 ± 3.1% and -16.1 ± 3.3%; Troponin T: 79 [33;230] ng/l versus 27 [13;77] ng/l and 27 [14;68] ng/l; Nt-ProBNP: 4,174 [1,095;9,510] ng/l versus 734 [309;2,210] ng/l and 725 [305;2,082], all p < 0.01). A SDGF was seen at 45 visits of which 19 had ≥2R ACR. EMBs showed ACR in 20 cases without SDGF. Finally, neither was SDGF seen nor did the EMB show rejection in 1,136 cases. Thus, the sensitivity of SDGF for ≥2R ACR detection was 49% (32-65) and specificity 98% (97-99). The positive predictive value (PPV) was 42% (31-55) and the negative predictive value (NPV) 98% (98-99). The diagnostic value improved in a sub-analysis excluding EMBs within 3 months after HTx, clinically interpreted false positive ≥2R ACR cases, and cases with ≥2R ACR who recently (<2 weeks) were treated with intravenous methylprednisolone due to ≥2R ACR (sensitivity 75% (48-93), specificity 97% (96-98), NPV 99% (99-100), and PPV 39% (27-52). Conclusions: Patients with ≥2R ACR have lower LVGLS and higher Troponin T and Nt-ProBNP than patients without 2R rejection. A non-invasive model combining changes in LVGLS and Troponin T or Nt-ProBNP showed excellent negative predictive value and moderate sensitivity and may be used as a gatekeeper to invasive biopsies after HTx.

Suspicion, screening, and diagnosis of wild-type transthyretin amyloid cardiomyopathy: a systematic literature review.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non-invasive diagnosis by bone scintigraphy, and the development of disease-modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at-risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light-chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at-risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high-quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at-risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment.

Reduction in myocardial function and oxygen consumption after chemoradiotherapy in patients with esophageal cancer.

BACKGROUND: Chemoradiotherapy (CRT) may induce myocardial dysfunction, congestive heart failure, and impaired physical performance in patients with esophageal cancer (EC). We aimed to investigate left ventricular (LV) function at rest and during stress, using echocardiography (echo) and a cardiopulmonary exercise (CPX) test both before and immediately after completing CRT. MATERIAL AND METHODS: Consecutive EC patients referred for curative treatment were enrolled. Patients attended either definitive CRT or neoadjuvant CRT with subsequent surgery. The evaluation included cardiac biomarkers, electrocardiogram, echo, and CPX test. The primary endpoint was changes in left ventricular (LV) global longitudinal strain (GLS) at rest. Secondary endpoints were LV ejection fraction (LVEF), LV diastolic function, LVEF and GLS at peak exercise, and maximal oxygen consumption (VO2max). The trial was registered with ClinicalTrials.gov (NCT03619317). RESULTS: Among 47 patients enrolled (94% male; median age 67 years, range 50-86 years), cardiac examinations were performed a median of three days [Interquartile range (IQR (1-5))] before CRT and one day [IQR (0-6)] after CRT. At rest, GLS and LVEF decreased, 17.6 vs. 16.4% and 56.4 vs. 55.1%, respectively (p = 0.004; p = 0.030). Furthermore, an absolute decrease of at least 5% in LVEF and 2.5% in GLS was noted in 21% of the patients. Signs of LV diastolic dysfunction increased from 13 to 21% (p = ns). VO2max significantly decreased; 21.2 ml/kg/min vs. 18.8 ml/kg/min (p < 0.001). CONCLUSION: LV function and physical performance decreased in EC patients after CRT, and the LV systolic reserve capacity declined. This study highlighted that EC treatment was associated with early cardiac side effects, which may have clinical and prognostic implications.

Impaired left and right systolic ventricular capacity in corrected atrial septal defect patients.

Resting right ventricular (RV) systolic function has in some studies been shown to be impaired after correction of an atrial septal defect (ASD) whereas impairment of left ventricular (LV) systolic function is uncertain. In the present study we examine the LV and RV systolic response to exercise in patients with a previously corrected ASD in order to investigate the myocardial capacity. Thirty-six adult ASD patients with a corrected isolated secundum ASD and eighteen adult age-matched controls underent a semi-supine exercise stress echocardiographic examination. At rest, LV parameters were comparable between groups, and RV global longitudinal strain (RV-GLS) was lower for the ASD group (-18.5%, 95% CI -20.0--17.0%) compared with controls (-24.5%, 95% CI -27.7--22.4%, p < 0.001). At peak exercise, LV ejection fraction (LVEF) was lower for ASD patients (61%, 95% CI 58-65%) compared with controls (68%, 95% CI 64-73% p = 0.01). Peak LV global longitudinal strain (LV-GLS) was borderline significantly lower (ASD: -18.4%, 95% CI -20.2--16.6%, controls: -21.3%, 95% CI -23.6--19.0%, p = 0.059). Both RVEF (ASD: 64%, 95% CI 60-68%, controls: 73%, 95% CI 65-80%, p = 0.05) and tricuspid annular plane systolic excursion (TAPSE) (ASD: 2.5 cm, 95% CI 2.3-2.7 cm, controls: 3.2 cm, 95% CI 2.9-3.6 cm, p < 0.001) at peak exercise were lower for ASD patients. Exercise assessed peak oxygen uptake was comparable between groups (ASD: 32.8 mL O2/kg/min, 95% CI 30.3-35.5 mL O2/kg/min, controls: 35.2 mL O2/kg/min, 95% CI 31.6-38.8 mL O2/kg/min, p = 0.3). Corrected ASD patients demonstrate a reduced LV and RV systolic exercise response decades after ASD correction whereas resting parameters of LV and RV systolic function were within normal range. The presence of subclinical systolic myocardial dysfunction during exercise might be associated with the long-term morbidities documented in this patient group.

Reverse remodeling of tricuspid valve morphology and function in chronic thromboembolic pulmonary hypertension patients following pulmonary thromboendarterectomy: a cardiac magnetic resonance imaging and invasive hemodynamic study.

BACKGROUND: To investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects. METHODS: 20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after. RESULTS: Right atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/m2, p < 0.005). TA annular area in systole remained unchanged (p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p < 0.005). There was correlation between the changes of right ventricular-pulmonary artery coupling and changes of TV tenting height (r = - 0.54, p = 0.02), TV tenting volume (r = - 0.73, p < 0.001) and TV leaflet area (- 0.57, p = 0.01) from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p < 0.01) reduced from baseline (30 ± 13%) to 12 months after PEA (9 ± 10%). CONCLUSION: In CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling.

Prognostic implications of left ventricular myocardial work indices in cardiac amyloidosis.

AIMS: Left ventricular (LV) myocardial work index (LVMWI) derived from pressure-strain analysis resembles a novel non-invasive method for LV function evaluation. LV global longitudinal strain (LVGLS) has proven beneficial for risk stratification in cardiac amyloidosis (CA) patients. This study aimed to evaluate the potential additive value of LVMWI for outcome prediction in CA patients. METHODS AND RESULTS: We enrolled 100 CA patients in the period 2014-19 from Aarhus University Hospital, Denmark and Uppsala University Hospital, Sweden. All patients underwent comprehensive echocardiographic evaluation and were prospectively followed until censuring date on 31 March 2019 or death. During follow-up, we registered major adverse cardiac events (MACE) comprising heart failure requiring hospitalization and all-cause mortality. The median follow-up was 490 (228-895) days. During follow-up, a total of 42% of patients experienced MACE and 29% died. Patients with LVMWI <1043 mmHg% had higher MACE risk than patients with LVMWI >1043 mmHg% [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2-4.3; P = 0.01]. Furthermore, patients with LVMWI <1039 mmHg% also had higher all-cause mortality risk than patients with LVMWI >1039 mmHg% (HR 2.6, 95% CI 1.2-5.5; P < 0.05). Moreover, the apical-to-basal segmental work ratio was a significant MACE and all-cause mortality predictor. By combining LVMWI and apical-to-basal segmental work ratio, we obtained an independent model for all-cause mortality prediction (high vs. low risk: HR 6.4, 95% CI 2.4-17.1; P < 0.0001). In contrast, LVGLS did not predict all-cause mortality. CONCLUSION: LV myocardial work may be of prognostic value in CA patients by predicting both MACE and all-cause mortality.

The relation of structural valve deterioration to adverse remodelling and outcome in patients with biological heart valve prostheses.

AIMS: Native valve aortic stenosis is associated with adverse remodelling of the left ventricle and remodelling is stopped or even reversed with aortic valve replacement (AVR). However, the degeneration of bioprostheses and development of structural valve deterioration (SVD) may affect this. METHODS AND RESULTS: To assess the association with SVD, remodelling and outcome 451 patients from a single surgical centre who had undergone AVR with a Mitroflow pericardial bioprosthesis were studied. All patients were assessed in 2014 and a subgroup of patients (N = 327) were re-exanimated again after at least 18 months [median time of 27 (interquartile range, IQR 26-33) months] including echocardiography, measurements of N-terminal pro-brain natriuretic peptide, and assessment of functional status. SVD was based on echocardiography. Moderate SVD was present in 63 patients (14%) and severe SVD in 19 (4%), in the subgroup with follow-up echocardiography 48 patients (15%) patients had moderate to severe SVD at first examination. Patients with SVD had significantly greater increase in left ventricular (LV) mass index [21.6 g/m2 (IQR 5.7-48.3 g/m2) vs. 9.1 g/m2 (-8.6 to 27.3 g/m2), P = 0.01]. Further, patients with SVD had lower LV ejection fraction [55% (IQR 51-62%) vs. 60% (IQR 54-63%), P = 0.01] at follow-up. During follow-up, 94 patients (21%) met the composite endpoint of death or reoperation due to SVD and 41 patient readmitted for heart failure. In multivariable Cox regression analysis, severe SVD [hazard ratio (HR) 2.64 (1.37-5.07), P = 0.004] was associated with composite endpoint, and readmission for heart failure [HR 3.82 (1.53-9.51), P = 0.004]. CONCLUSION: SVD in aortic bioprostheses is associated with adverse LV remodelling and adverse outcome.

Prevalence and Prognostic Implications of Increased Apical-to-Basal Strain Ratio in Patients with Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: The aim of this study was to investigate the preoperative prevalence, relation to symptoms, and prognostic implications of elevated left ventricular (LV) apical-to-basal strain ratio (ABr) in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement. METHODS: A total of 499 contemporary consecutive patients with AS treated with transcatheter aortic valve replacement were retrospectively included. Patients were included if they underwent preoperative echocardiography with adequate image quality for assessment of LV global longitudinal strain. Baseline clinical and echocardiographic data were collected and analyzed in ABr subgroups. From two-dimensional echocardiographic apical images, ABr was calculated as mean longitudinal strain of the five LV apical segments divided by the mean of the six basal segments. RESULTS: Median follow-up time was 743 days. Mean age was 79.8 ± 7 years. The prevalence of severely increased ABr ≥4 was 16% (n = 78). Patients with ABr ≥4 had higher preoperative New York Heart Association functional class; 77% of those with ABr ≥4 were in New York Heart Association functional class III or IV compared with 59% of those with ABr of 0 to 1.9 (P < .01). Median preoperative N-terminal pro-brain natriuretic peptide level in patients with ABr ≥4 was 1,781 pmol/L, compared with 876 pmol/L in those with ABr of 0 to 1.9 (P = .003). N-terminal pro-brain natriuretic peptide levels at 3-month follow-up remained considerably elevated in patients with ABr ≥4 (the median in patients with ABr ≥4 was 1,262 pmol/L vs 645 pmol/L in those with ABr of 0 to 1.9, P < .01). AS severity was comparable across ABr subgroup levels. Overall, increased ABr ≥4 was associated with poor survival, as overall 3-year survival was 67% among patients with ABr ≥4 compared with 83% in those with ABr of 2 to 3.9 and 86% in those with ABr of 0 to 1.9 (P = .04). CONCLUSION: Among patients with increased ABr ≥4, pre- and postoperative New York Heart Association functional class, serum N-terminal pro-brain natriuretic peptide level, and mortality were significantly increased, and ABr may thus serve as a new echocardiographic marker of high mortality risk among patients with AS treated with transcatheter aortic valve replacement.