The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and observational cohort studies.
This study ...aimed to investigate the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in patients with obstructive HCM.
This double-blind, placebo-controlled, randomized crossover trial enrolled 29 patients with obstructive HCM and New York Heart Association (NYHA) functional class II or higher symptoms from May 2018 to September 2020. Patients received metoprolol or placebo for 2 consecutive 2-week periods in random order. The effect parameters were LVOT gradients, NYHA functional class, Canadian Cardiovascular Society (CCS) angina class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and cardiopulmonary exercise testing.
Compared with placebo, the LVOT gradient during metoprolol was lower at rest (25 mm Hg interquartile range (IQR): 15-58 mm Hg vs 72 mm Hg IQR: 28-87 mm Hg; P = 0.007), at peak exercise (28 mm Hg IQR: 18-40 mm Hg vs 62 mm Hg IQR: 31-113 mm Hg; P < 0.001), and postexercise (45 mm Hg IQR: 24-100 mm Hg vs 115 mm Hg IQR: 55-171 mm Hg; P < 0.0001). During metoprolol treatment, 14% of patients were in NYHA functional class III or higher compared with 38% of patients receiving placebo (P < 0.01). Similarly, no patients were in CCS class III or higher during metoprolol treatment compared with 10% during placebo treatment (P < 0.01). These findings were confirmed by higher KCCQ-OSS during metoprolol treatment (76.2 ± 16.2 vs 73.8 ± 19.5; P = 0.039). Measures of exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide did not differ between the study arms.
Compared with placebo, metoprolol reduced LVOT obstruction at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. (The Effect of Metoprolol in Patients with Hypertrophic Obstructive Cardiomyopathy TEMPO; NCT03532802).
The relationship between exercise hemodynamics, loading conditions, and medical treatment in patients with obstructive hypertrophic cardiomyopathy (HCM) is incompletely understood.
This study aimed ...to investigate the effect of metoprolol on invasive hemodynamic parameters at rest and during exercise in patients with obstructive HCM.
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.
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).
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)
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Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac ...output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.
Patients with obstructive hypertrophic cardiomyopathy (HCM) often experience symptoms of heart failure upon exertion despite having normal left ventricular (LV) ejection fractions. Longitudinal ...strain (LS) may be a more sensitive marker of systolic dysfunction in patients with LV hypertrophy. The aims of this study were to characterize LV segmental LS and global LS (GLS) at rest and during exercise and to assess if first-line treatment with β-blockers improves LV systolic performance.
Twenty-nine patients with obstructive HCM and New York Heart Association functional class ≥ II symptoms were enrolled in a double-blind, placebo-controlled, randomized crossover trial. Patients received metoprolol 150 mg or placebo for two consecutive 2-week periods in random order. Echocardiographic assessment with speckle-tracking-derived LS was performed at rest and during peak exercise at the end of each treatment period.
During placebo treatment, resting values of segmental LS showed an apical-basal difference of -10.3% (95% CI, -12.7% to -7.8%; P < .0001), with a severely abnormal value of the basal segment of -9.3 ± 4.2%. Treatment with metoprolol was associated with more negative LS values of the apical segment (-2.8%; 95% CI, -4.2% to -1.3%; P < .001) and the mid segment (-1.1%; 95% CI, -2.0% to -0.3%; P = .007). During peak exercise there was a deterioration in LV GLS, but treatment with metoprolol was associated with more negative peak exercise LV GLS (-1.3 %; 95% CI, -2.6% to -0.1%; P = .03).
Systolic performance assessed by LV GLS showed impaired values at rest and during exercise, with severely depressed values of the basal and mid segments. Treatment with metoprolol improved LV GLS upon exercise, indicating a beneficial effect of β-blocker treatment on LV systolic function.
Aims
In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short‐term treatment with the ketone body 3‐hydroxy butyrate (3‐OHB) ...has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3‐OHB predicted all‐cause mortality and sought to identify correlations between patient characteristics and circulating 3‐OHB levels.
Methods and results
We conducted a cohort study in 218 patients with HFrEF. Plasma 3‐OHB levels were measured using high‐performance liquid chromatography tandem mass spectrometry. Data on all‐cause mortality were obtained by reviewing the patients' medical records, which are linked to the national ‘Central Person Registry’ that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow‐up time was 7.3 (interquartile range 6.3–8.4) years. We observed large variations in 3‐OHB levels between patients (median 59 μM, range: 14–694 μM). Patients with 3‐OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio HR: 2.1 95% confidence interval (CI): 1.3–3.5, P = 0.003}. In a multivariate analysis, 3‐OHB predicted mortality independently of known chronic heart failure risk factors HR: 1.004 (95% CI: 1.001–1.007), P = 0.02 and with a similar statistical strength as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) HR: 1.0005 (95% CI: 1.000–1.001), P = 0.02. For every 100 μmol increase in plasma 3‐OHB, the hazard of death increased by 49%. The following factors significantly predicted 3‐OHB levels in the univariate analysis: free fatty acids (FFAs) β: 238 (95% CI: 185–292), P < 0.0001, age β: 2.43 (95% CI: 1.14–3.72), P < 0.0001, plasma insulin {β: −0.28 95% CI: −0.54–(−0.02), P = 0.036}, body mass index {β: −3.15 95% CI: −5.26–(−0.05), P = 0.046}, diabetes β: 44.49 (95% CI: 14.84–74.14), P = 0.003, glycosylated haemoglobin β: 1.92 (95% CI: 0.24–3.59), P = 0.025, New York Heart Association class β: 26.86 (95% CI: 5.99–47.72), P = 0.012, and NT‐proBNP β: 0.03 (95% CI: 0.01–0.04), P = 0.001. In a multivariate analysis, only FFAs predicted 3‐OHB levels β: 216 (95% CI: 165–268), P > 0.001.
Conclusions
In patients with HFrEF, circulating 3‐OHB was a strong predictor of all‐cause mortality independently of NT‐proBNP. Circulating FFAs were the best predictor of 3‐OHB levels.
Focused cardiac ultrasound can potentially identify reversible causes of cardiac arrest during advanced life support (ALS), but data on the timing of image acquisition are lacking. This study aimed ...to compare the quality of images obtained during rhythm analysis, bag-mask ventilations, and chest compressions.
Adult patients in cardiac arrest were prospectively included during 23 months at a Danish community hospital. Physicians who had completed basic ultrasound training performed subcostal focused cardiac ultrasound during rhythm analysis, bag-mask ventilations, and chest compressions. Image quality was categorised as either useful for interpretation or not. Two echocardiography experts rated images useful for interpretation if all the following characteristics could be determined: 1) right ventricle larger than left ventricle, 2) pericardial fluid, and 3) collapsing ventricles.
Images were obtained from 60 of 114 patients undergoing ALS. A higher proportion of the images obtained during rhythm analysis and bag-mask ventilations were useful for interpretation when compared with chest compressions (rhythm analysis vs chest compressions: OR 2.2 (95%CI 1.3–3.8), P = 0.005; bag mask ventilations vs chest compressions: OR 2.0 (95%CI 1.1–3.7), P = 0.03). There was no difference between images obtained during rhythm analysis and bag-mask ventilations (OR 1.1 (95%CI 0.6–2.0), P = 0.74).
The quality of focused cardiac ultrasound images obtained during rhythm analysis and bag-mask ventilations was superior to that of images obtained during chest compressions. There was no difference in the quality of images obtained during rhythm analysis and bag-mask ventilations. Bag-mask ventilations may constitute an overlooked opportunity for image acquisition during ALS.
Abstract Introduction Remote ischaemic conditioning (RIC) protects against ischaemia-reperfusion injury through cellular protective pathways, but may also modulate haemostasis. We aimed to ...investigate the effect of long-term RIC on platelet function and fibrinolysis in patients with chronic ischaemic heart failure (CIHF). Material and methods In a prospective, outcome-assessor blinded, paired study, 16 patients with CIHF and 21 age- and gender-matched controls without ischaemic heart disease (IHD) were treated with RIC once daily for 28 ± 4 days. RIC was performed as four cycles of 5 min upper arm ischaemia and reperfusion. We evaluated collagen and arachidonic acid induced platelet aggregation (Multiplate®Analyzer), platelet turnover (Sysmex® XE-5000), platelet activation (plasma soluble-platelet-selectin) and fibrinolysis (clot lysis time, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1)). We compared blood samples assessed at baseline and following long-term RIC. Results Long-term RIC did not affect platelet aggregation, turnover or activation or PAI-1 in any study groups. Long-term RIC did not affect fibrin clot lysis time in patients with CIHF but reduced fibrin clot lysis time in matched controls without IHD (median: 773 s (interquartile range: 689–936) vs. 658 s (618–823), p = 0.03). t-PA was increased following long-term RIC in CIHF patients (2.5 (1.7–3.4) vs. 2.9 (1.8–4.0), p = 0.03) and in matched controls without IHD (1.5 (1.3–1.9) vs. 1.6 (1.4–2.3), p = 0.03). Conclusions While long-term RIC did not affect collagen or arachidonic acid induced platelet aggregation, platelet turnover or sP-selectin, fibrinolysis was increased although most consistently in matched controls without IHD. This finding suggests that RIC may stimulate fibrinolysis potentially reducing the risk of thrombosis.
Tumor necrosis factor-alpha (TNF-alpha) has widespread metabolic actions. Systemic TNF-alpha administration, however, generates a complex hormonal and metabolic response. Our study was designed to ...test whether regional, placebo-controlled TNF-alpha infusion directly affects insulin resistance and protein breakdown. We studied eight healthy volunteers once with bilateral femoral vein and artery catheters during a 3-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. One artery was perfused with saline and one with TNF-alpha. During the clamp, TNF-alpha perfusion increased glucose arteriovenous differences (0.91 + or - 0.17 vs. 0.74 + or - 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-alpha perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-alpha, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-alpha. TNF-alpha directly increased net muscle protein loss, which may contribute to cachexia and general protein loss during severe illness. The finding of increased insulin sensitivity, which could relate to IL-6, is of major clinical interest and may concurrently act to provide adequate tissue fuel supply and contribute to the occurrence of systemic hypoglycemia. This distinct metabolic feature places TNF-alpha among the rare insulin mimetics of human origin. Diabetes 62:4023-4029, 2013
Tumor necrosis factor-α (TNF-α) has widespread metabolic actions. Systemic TNF-α administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether ...regional, placebo-controlled TNF-α infusion directly affects insulin resistance and protein breakdown. We studied eight healthy volunteers once with bilateral femoral vein and artery catheters during a 3-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. One artery was perfused with saline and one with TNF-α. During the clamp, TNF-α perfusion increased glucose arteriovenous differences (0.91 ± 0.17 vs. 0.74 ± 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-α perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-α, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-α. TNF-α directly increased net muscle protein loss, which may contribute to cachexia and general protein loss during severe illness. The finding of increased insulin sensitivity, which could relate to IL-6, is of major clinical interest and may concurrently act to provide adequate tissue fuel supply and contribute to the occurrence of systemic hypoglycemia. This distinct metabolic feature places TNF-α among the rare insulin mimetics of human origin.
Transfer of full-length genes including regulatory elements has been the preferred gene therapy strategy for clinical applications. However, with significant drawbacks emerging, targeted gene ...alteration (TGA) has recently become a promising alternative to this method. By means of TGA, endogenous DNA repair pathways of the cell are activated leading to specific genetic correction of single-base mutations in the genome. This strategy can be implemented using single-stranded oligodeoxyribonucleotides (ssODNs), small DNA fragments (SDFs), triplex-forming oligonucleotides (TFOs), adeno-associated virus vectors (AAVs) and zinc-finger nucleases (ZFNs). Despite difficulties in the use of TGA, including lack of knowledge on the repair mechanisms stimulated by the individual methods, the field holds great promise for the future. The objective of this review is to summarize and evaluate the different methods that exist within this particular area of human gene therapy research.
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