Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction. METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents. RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes. CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

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.

Outcome prediction by myocardial external efficiency from 11 C-acetate positron emission tomography in cardiac amyloidosis.

AIMS: This study aimed to study the prognostic value of myocardial oxygen consumption (MVO2 ) and myocardial external efficiency (MEE) from 11 C-acetate positron emission tomography (PET) in cardiac amyloidosis (CA) patients. METHODS AND RESULTS: Forty-eight CA patients, both transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis, and 20 controls were included. All subjects were examined with 11 C-acetate PET and echocardiography. MVO2 , forward stroke volume (FSV), and left ventricular mass (LVM) were derived from 11 C-acetate PET and used to calculate MEE. CA patients were followed for survival and the prognostic impact of clinical, echocardiographic, and 11 C-acetate PET parameters was analysed. MVO2 and MEE were reduced in CA compared with controls, but without significant difference between deceased and surviving CA patients. The ratio of 11 C-acetate PET-derived FSV and LVM was also reduced in CA and significantly lowered in deceased patients compared with survivors. In univariate analysis, New York Heart Association class, N-terminal pro-brain natriuretic peptide, and the 11 C-acetate PET parameters FSV/LVM and MEE were the strongest prognostic factors. Of the 11 C-acetate PET parameters, FSV/LVM was the strongest survival predictor with hazard ratio of 0.56 per 0.1 mL/g (95% confidence interval 0.39-0.81, P = 0.002) and independently prognostic in a multivariate model. MEE significantly separated deceased from surviving CA patients with the cut-off of 15.7% (P = 0.032). Survival was significantly shorter with FSV/LVM below 0.27 mL/g (P < 0.001), also when separating AL- and ATTR-CA. CONCLUSIONS: Reduced MEE was associated with shorter survival in CA patients, but FSV/LVM was the strongest survival predictor and the only independently prognostic 11 C-acetate PET parameter in multivariate analysis.

Exercise Hemodynamics and Mitochondrial Oxidative Capacity in Disease Stages of Wild-Type Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloid (ATTRwt) cardiomyopathy is increasingly recognized in the development of heart failure. The link between cardiac performance, hemodynamics, and mitochondrial function in disease stages of ATTRwt has not previously been studied but may provide new insights into the pathophysiology and clinical performance of the patients. METHODS AND RESULTS: The study investigated 47 patients diagnosed with ATTRwt at Aarhus University Hospital, Denmark. Patients were stratified according to the disease stages of the National Amyloidosis Centre (NAC) as NAC I with low levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (NAC I-L, n=14), NAC I with high levels NT-proBNP (NAC I-H, n=20), and NAC II-III (n=13). Exercise testing with simultaneous right heart catheterization was performed in all patients. Endomyocardial biopsies were collected from the patients and the mitochondrial oxidative phosphorylation capacity was assessed. All NAC disease groups, even in the NAC I-L group, a significant abnormal increase in biventricular filling pressures were noted during exercise while the filling pressures was normal or near normal at rest. The inotropic response to exercise was reduced with diminished increase in cardiac output which was significantly more pronounced in the NAC I-H (Diff. -2.4, 95% CI (-4.2: -0.7), P=0.00) and the NAC II-III group (Diff: -3.1 L/min, 95% CI (-5.2: -1.1), P=0.00) compared with the NAC I-L group. The pulmonary artery wedge pressure to cardiac output ratio at peak exercise was significantly different between NAC I-L and NAC II-III (Diff: 1.6 mm Hg*min/L, 95% CI (0.01:3.3, P=0.04)). Patients with ATTRwt had a reduced oxidative phosphorylation capacity which correlated to left ventricular mass but not to cardiac output capacity. CONCLUSIONS: An abnormal restrictive left ventricle and right ventricle response to exercise was demonstrated, even present in patients with early-stage ATTRwt. In more advanced disease stages a progressive impairment of the pressure-flow relationship was noted. The myocyte energetics is deranged but not associated to the contractile reserve or restrictive filling characteristics in ATTRwt.

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.

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.

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.

Effects of Metoprolol on Exercise Hemodynamics in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: The relationship between exercise hemodynamics, loading conditions, and medical treatment in patients with obstructive hypertrophic cardiomyopathy (HCM) is incompletely understood. OBJECTIVES: This study aimed to investigate the effect of metoprolol on invasive hemodynamic parameters at rest and during exercise in patients with obstructive HCM. METHODS: This randomized, double-blind, placebo-controlled crossover trial enrolled 28 patients with obstructive HCM and New York Heart Association functional class ≥II. Patients were randomized to initiate either metoprolol 150 mg or placebo for 2 consecutive 2-week periods. Right-heart catheterization and echocardiography were performed at rest and during exercise at the end of each treatment period. The primary outcome was the difference in pulmonary capillary wedge pressure (ΔPCWP) between peak exercise and rest. RESULTS: No treatment effect on ΔPCWP was observed between metoprolol and placebo treatment (21 ± 9 mm Hg vs 23 ± 9 mm Hg; P = 0.12). At rest, metoprolol lowered heart rate (P < 0.0001), left ventricular outflow tract (LVOT) gradient (P = 0.01), and increased left ventricular end-diastolic volume (P = 0.02) and stroke volume (SV) (+6.4; 95% CI: 0.02-17.7; P = 0.049). During peak exercise, metoprolol was associated with a lower heart rate (P < 0.0001), a lower LVOT gradient (P = 0.0005), lesser degree of mitral regurgitation (P = 0.004), and increased SV (+9 mL; 95% CI: 2-15 mL; P = 0.008). CONCLUSIONS: In patients with obstructive HCM, exercise was associated with an abnormal rise in PCWP, which was unaffected by metoprolol. However, metoprolol increased SV at rest and peak exercise following changes in end-diastolic volume, LVOT gradient, and degree of mitral regurgitation. (The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).

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.

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.

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.

Diagnostic delay in wild type transthyretin cardiac amyloidosis - A clinical challenge.

AIM: To determine the diagnostic delay in patients with wild-type transthyretin cardiac amyloiodosis (ATTRwt). To determine the clinical and echocardiogtraphic characteristics of patients with an early and a late diagnosis and to study the suspected diagnoses and identification of diagnostic "red flags" before the ATTRwt diagnosis was established. METHODS: In 50 consecutive patients with ATTRwt diagnosed from 2017 to 2019, clinical and echocardiographic patient characteristics were investigated based on electronic patient charts and echocardiographic database review at Aarhus University Hospital, Denmark. RESULTS: The median diagnostic delay was 13 months (2-47 months) and a diagnostic delay above 3 months was associated with more advanced symptoms and left ventricular (LV) diastolic dysfunction at the time of the diagnosis. Thirty patients (60%) were investigated for at least two non-ATTRwt diagnoses during the time period from the first cardiac examination to the time of the confirmed diagnosis. ATTR red flags were significantly less used in patients with the longest diagnostic delay (p < 0.001). Abormal LV global longitudinal strain (LV-GLS < 18%) and apical sparring ratio (APSR ≥ 1.5) were present in 96% and 94% of the ATTRwt patients, respectively. CONCLUSION: The diagnostic delay in ATTRwt was substantial and a prolonged diagnostic delay was associated with more advanced symptoms and LV diastolic dysfunction at the time of the diagnosis. Established ATTR red flags are poorly utilized in the diagnostic process. Echocardiographic analysis of LV-GLS and APSR contributes significantly to the evaluation of LV myocardial performance and helps raise the suspicion of ATTRwt.