Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Post-Bariatric Hypoglycemia: an Impaired Metabolic Response to a Meal.

AIMS/HYPOTHESIS: Post-bariatric hypoglycemia (PBH) is caused by postprandial hyperinsulinemia, due to anatomical alterations and changes in post-prandial metabolism after bariatric surgery. The mechanisms underlying the failing regulatory and compensatory systems are unclear. In this study, we investigated the differences in post-prandial hormones and metabolic profiles between patients with and without PBH. METHODS: We performed a mixed meal test (MMT) in 63 subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery. Blood was withdrawn at 0, 10, 20, 30, 60, and 120 min after ingestion of a standardized meal. Glucose, insulin, GLP-1, FGF-19, and FGF-21 were measured and untargeted metabolomics analysis was performed on blood plasma to analyze which hormonal and metabolic systems were altered between patients with and without PBH. RESULTS: Out of 63, a total of 21 subjects (33%) subjects developed PBH (glucose < 3.1 mmol/L) after surgery. Decreased glucose and increased insulin excursions during MMT were seen in PBH (p < 0.05). GLP-1, FGF-19, and FGF-21 were elevated after surgery (p < 0.001), but did not differ between PBH and non-PBH groups. We identified 20 metabolites possibly involved in carbohydrate metabolism which differed between the two groups, including increased carnitine and acylcholines in PBH. CONCLUSION: Overall, 33% of the subjects developed PBH 1 year after RYGB surgery. While GLP-1, FGF-19, and FGF-21 were similar in PBH and non-PBH patients, metabolomics analysis revealed changes in carnitine and acyclcholines that are possibly involved in energy metabolism, which may play a role in the occurrence of PBH.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. RESULTS: A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. CONCLUSIONS: Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

Changes and Prognostic Implications of Myocardial Work in Aortic Stenosis Subtypes Undergoing Transcatheter Valve Implantation.

Background: Evaluation of left ventricle (LV) systolic function in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) is challenging, as LV ejection fraction (LVEF) and global longitudinal strain are afterload dependent. LV global work indices (GWIs) estimate the afterload corrected systolic function. Objectives: The purpose of this study was to evaluate changes in and prognostic implications of GWIs in subtypes of AS patients before and 1 month after TAVI. Methods: We included 473 patients undergoing TAVI. GWI was estimated using strain imaging and by adding the aortic valve mean gradient to the systolic blood pressure. The primary endpoint was all-cause mortality, evaluated by Cox proportional hazards and Kaplan-Meier curves. Results: High gradient, low flow/low gradient, and normal flow/low gradient AS was found in 48%, 27%, and 25%. In patients with LVEF ≥50% delta GWI decreased from preoperative assessment to 1-month follow-up across all subtypes; high gradient (-353 ± 589 mm Hg%, P < 0.01), low flow/low gradient (-151 ± 652 mm Hg%, P = 0.13), and normal flow/low gradient (-348 ± 606 mm Hg%, P < 0.01). For patients with LVEF <50% delta GWI increased; high gradient 127 ± 491 mm Hg%, P = 0.05; low flow/low gradient 106 ± 510 mm Hg%, P = 0.06; normal flow/low gradient 107 ± 550 mm Hg%, P < 0.27. The median follow-up time was 60 months (IQR: 45-69 months). Each step of 100 mm Hg% higher GWI at pre-TAVI assessment was associated with a reduction in all-cause mortality in multivariable analysis (HR: 0.96 [95% CI: 0.92-1.00], P = 0.033). Conclusions: GWI increases in patients with reduced LVEF after TAVI across AS subtypes whereas GWI decreases in patients with preserved LVEF. Assessment of GWI offers additional prognostic implications beyond LVEF and global longitudinal strain.

Lymphatic morphology and function in chronic right heart failure due to secondary tricuspid valve regurgitation.

BACKGROUND: In heart failure, the capacity of the lymphatic system dictates symptoms of circulatory congestion. This study aimed at describing structural and functional changes of the lymphatic system in patients with chronic right-sided heart failure. METHODS: Individuals with long-standing severe tricuspid valve regurgitation and symptoms of heart failure were compared with age- gender- and weight-matched controls. Lymphatic structure and function were examined using non-contrast MR lymphangiography and near-infrared fluorescence imaging. Microvascular fluid dynamics and distribution were evaluated using strain gauge plethysmography and bio-impedance. RESULTS: In total nine patients and nine controls were included. Lymphatic morphology was unchanged in cases compared to controls with similar thoracic duct diameters 3.1(2.1-3.5) mm vs. 2.0(1.8-2.4) mm (p-value = 0.11), similar lymphatic classifications (p-value 0.34), and an identical number of lymphatic vessels in the legs 6 ± 1 vs. 6 ± 3 vessels/field (p-value = 0.72). Lymphatic function was comparable with contraction frequencies of 0.5 ± 0.2 and 0.5 ± 0.3 /min (p-value = 0.52) and a maximal lymphatic pumping pressure of 60 ± 13 and 57 ± 12 mmHg (p-value = 0.59) for cases and controls respectively. Finally, microvascular capillary filtration, isovolumetric threshold, and fluid distribution were similar between groups (p-value≥0.16 for all comparisons). CONCLUSION: In this small exploratory study, individuals with severe secondary tricuspid valve regurgitation and right-sided heart failure displayed a largely similar lymphatic anatomy and function. Thoracic duct diameter displayed a trend towards increased size in the patient group. We speculate that cases were indeed stable and optimally treated at the time of examination, and with a lymphatic system largely unaffected by any of the current or prior hemodynamic changes.

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.

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.

High incidence of imperforate vagina in ADGRA3-deficient mice.

BACKGROUND: Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear. RESULTS: In this study, we found Adgra3 to be expressed throughout the murine female urogenital system, with higher expression pre-puberty than after sexual maturation. We generated a global Adgra3-/- mouse line and observed imperforate vagina in 44% of Adgra3-/- females, resulting in distension of the reproductive tract and infertility. Ovarian morphology, plasma estradiol, ovarian Cyp19a1, and vaginal estrogen receptor α (Esr1) expression were unaffected. However, compared to controls, a significantly lower bone mineral density was found in Adgra3-/- mice. Whereas vaginal opening in mice is an estrogen-dependent process, 17ß-estradiol treatment failed to induce vaginal canalization in Adgra3-/- mice. Furthermore, a marked reduction in vaginal and ovarian progesterone receptor expression was observed concomitant with an upregulation of apoptotic regulators Bcl2, Bid, and Bmf in adult Adgra3-/- females with a closed vagina. CONCLUSIONS: Our collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.

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.

Myocardial work across different etiologies of right ventricular dysfunction and healthy controls.

Evaluating right ventricular (RV) function remains a challenge. Recently, novel echocardiographic assessment of RV myocardial work (RVMW) by non-invasive pressure-strain loops was proposed. This enables evaluation of right ventriculoarterial coupling and quantifies RV dyssynchrony and post-systolic shortening. We aimed to assess RVMW in patients with different etiologies of RV dysfunction and healthy controls. We investigated healthy controls (n=17), patients with severe functional tricuspid regurgitation (FTR; n=22), and patients with precapillary pulmonary hypertension (PCPH; n=20). Echocardiography and right heart catheterization were performed to assess 1) RV global constructive work (RVGCW; work needed for systolic myocardial shortening and isovolumic relaxation), 2) RV global wasted work (RVGWW; myocardial shortening following pulmonic valve closure), and 3) RV global work efficiency (RVGWE; describes the relation between RV constructive and wasted work). RVGCW correlated with invasive RV stroke work index (r=0.66, P<0.001) and increased in tandem with higher afterload, i.e., was low in healthy controls (454±73 mmHg%), moderate in patients with FTR (687±203 mmHg%), and highest among patients with PCPH (881±255 mmHg%). RVGWE was lower and RVGWW was higher in patients with FTR (86±8% and 91 mmHg% [53-140]) or PCPH (86±10% and 110 mmHg% [66-159]) as compared with healthy controls (96±3% and 10 mmHg%). RVMW by echocardiography provides a promising index of RV function to discriminate between patients with RV volume or pressure overload. The prognostic value of this measure needs to be settled in future studies.

High Incidence of Cardiovascular Disease in Patients With Oesophageal Cancer-A Registry-Based Cohort Study.

BACKGROUND: The cardiovascular disease (CVD) burden among patients with oesophageal cancer (EC) treated with curative intent is unclear. AIM: To determine CVD incidence and all-cause mortality in patients with EC. METHOD: Danish national health registries were used to identify patients diagnosed with primary EC between 2008 and 2018. Each EC patient was matched with 10 individuals from the general population. The primary endpoint was a CVD hospital contact (CVD-HC), either admission or outpatient contact. Cox proportional hazard regression models were used to compare the risk of incident CVD-HCs between the cohorts. RESULTS: The study included 1,525 patients with EC and 15,250 individuals from the general population. Patients with EC had a post-diagnosis one-year adjusted hazard ratio (HR) of CVD-HC of 6.1 (95% confidence intervals [CIs] 5.6-6.8) compared with the general population. During the next nine years, the risk of CVD-HC was comparable between the two cohorts, with an adjusted HR of 1.0 (95% CI 0.9-1.3). Patients with EC, and particularly those with prevalent CVD, had a high risk of atrial fibrillation, ischaemic heart disease, and venous thromboembolism within the first year after EC diagnosis. Prevalent CVD among patients with EC was not associated with higher mortality. CONCLUSIONS: CVD morbidity was transiently increased in the first year following EC diagnosis compared with the general population. All-cause mortality risks were high but did not appear to be affected by prevalent CVD. The very high risk of CVD in patients with primary EC to be treated with curative intent calls for healthcare initiatives to advance preventive and post-treatment strategies.

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.).

Prolonged Endurance Exercise Increases Macrophage Content and Mitochondrial Respiration in Adipose Tissue in Trained Men.

BACKGROUND: The aim of this study was to investigate the effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in younger and older men. METHODS: "Young" (aged 30 years, n = 7) and "old" (aged 65 years, n = 7) trained men were exposed to an exercise intervention of 15 consecutive days biking 7 to 9 hours/day at 63% and 65% of maximal heart rate (young and old, respectively), going from Copenhagen, Denmark to Palermo, Italy. Adipose tissue was sampled from both the gluteal and abdominal depot before and after the intervention. Mitochondrial respiration was measured by high-resolution respirometry, and adipose inflammation was assessed by immunohistochemical staining of paraffin embedded sections. RESULTS: An increased number of CD163+ macrophages was observed in both the gluteal and abdominal depot (P < .01). In addition, an increased mitochondrial respiration was observed in the abdominal adipose tissue from men in the young group with complex I (CIp) stimulated respiration, complex I + II (CI+IIp) stimulated respiration and the capacity of the electron transport system (ETS) (P < .05), and in the older group an increase in CIp and CI+IIp stimulated respiration (P < .05) was found. CONCLUSION: Overall, we found a positive effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in both young and old trained men, and no sign of attenuated function in adipose tissue with age.

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.

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.

The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.

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.