Altered intramuscular network of lipid droplets and mitochondria in type 2 diabetes.

Excessive storage of lipid droplets (LDs) in skeletal muscles is a hallmark of type 2 diabetes. However, LD morphology displays a high degree of subcellular heterogeneity and varies between single muscle fibers, which impedes the current understanding of lipid-induced insulin resistance. Using quantitative transmission electron microscopy (TEM), we conducted a comprehensive single-fiber morphological analysis to investigate the intramuscular network of LDs and mitochondria, and the effects of 8 wk of high-intensity interval training (HIIT) targeting major muscle groups, in patients with type 2 diabetes and nondiabetic obese and lean controls. We found that excessive storage of intramuscular lipids in patients with type 2 diabetes was exclusively explained by extremely large LDs situated in distinct muscle fibers with a location-specific deficiency in subsarcolemmal mitochondria. After HIIT, this intramuscular deficiency was improved by a remodeling of LD size and subcellular distribution and mitochondrial content. Analysis of LD morphology further revealed that individual organelles were better described as ellipsoids than spheres. Moreover, physical contact between LD and mitochondrial membranes indicated a dysfunctional interplay between organelles in the diabetic state. Taken together, type 2 diabetes should be recognized as a metabolic disease with high cellular heterogeneity in intramuscular lipid storage, underlining the relevance of single-cell technologies in clinical research. Furthermore, HIIT changed intramuscular LD storage toward nondiabetic characteristics.

Acute exercise increases the contact between lipid droplets and mitochondria independently of obesity and type 2 diabetes.

Intramuscular lipid droplets (LDs) and mitochondria are essential organelles in cellular communication and metabolism, supporting local energy demands during muscle contractions. While insulin resistance impacts cellular functions and systems within the skeletal muscle, it remains unclear whether the interaction of LDs and mitochondria is affected by exercise and the role of obesity and type 2 diabetes. By employing transmission electron microscopy (TEM), we aimed to investigate the effects of 1 h of ergometry cycling on LD morphology, subcellular distribution and mitochondrial contact in skeletal muscle fibres of patients with type 2 diabetes and glucose-tolerant lean and obese controls, matched for equal exercise intensities. Exercise did not change LD volumetric density, numerical density, profile size or subcellular distribution. However, evaluated as the magnitude of inter-organelle contact, exercise increased the contact between LDs and mitochondria with no differences between the three groups. This effect was most profound in the subsarcolemmal space of type 1 muscle fibres, and here the absolute contact length increased on average from ∼275 to ∼420 nm. Furthermore, the absolute contact length before exercise (ranging from ∼140 to ∼430 nm) was positively associated with the fat oxidation rate during exercise. In conclusion, we showed that acute exercise did not mediate changes in the LD volume fractions, numbers or size but increased the contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. These data suggest that the increased LD-mitochondria contact with exercise is not disturbed in obesity or type 2 diabetes. KEY POINTS: Type 2 diabetes is associated with altered interactivity between lipid droplets (LDs) and mitochondria in the skeletal muscle. Physical contact between the surface of LDs and the surrounding mitochondrial network is considered favourable for fat oxidation. We show that 1 h of acute exercise increases the length of contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. This contact length between LDs and mitochondria is not associated with a net decrease in the LD volumetric density after the acute exercise. However, it correlates with the fat oxidation rate during exercise. Our data establish that exercise mediates contact between LDs and the mitochondrial network and that this effect is not impaired in individuals with type 2 diabetes or obesity.

Accurate Prediction of Knee Angles during Open-Chain Rehabilitation Exercises Using a Wearable Array of Nanocomposite Stretch Sensors.

In this work, a knee sleeve is presented for application in physical therapy applications relating to knee rehabilitation. The device is instrumented with sixteen piezoresistive sensors to measure knee angles during exercise, and can support at-home rehabilitation methods. The development of the device is presented. Testing was performed on eighteen subjects, and knee angles were predicted using a machine learning regressor. Subject-specific and device-specific models are analyzed and presented. Subject-specific models average root mean square errors of 7.6 and 1.8 degrees for flexion/extension and internal/external rotation, respectively. Device-specific models average root mean square errors of 12.6 and 3.5 degrees for flexion/extension and internal/external rotation, respectively. The device presented in this work proved to be a repeatable, reusable, low-cost device that can adequately model the knee's flexion/extension and internal/external rotation angles for rehabilitation purposes.

Effects of Resistance Training Cessation on Cycling Performance in Well-Trained Cyclists: An Exploratory Study.

ABSTRACT: Bláfoss, R, Rikardo, J, Andersen, AØ, Hvid, LG, Andersen, LL, Jensen, K, Christensen, PM, Kvorning, T, and Aagaard, P. Effects of resistance training cessation on cycling performance in well-trained cyclists: an exploratory study. J Strength Cond Res 36(3): 796-804, 2022-Supplementary (i.e., concurrent) resistance training can enhance cycling performance among competitive cyclists. However, a lack of knowledge exists about the retention (decay profile) in mechanical muscle function and cycling performance after concurrent resistance and endurance training. The present exploratory intervention study investigated the effect of 6 weeks of resistance training cessation when preceded by 8 weeks of concurrent resistance and endurance training on mechanical muscle function and cycling performance in 9 male well-trained competitive cyclists (V̇o2max = 66 ± 7 ml·min-1·kg-1). Cyclists performed periodized resistance training targeting leg and core muscles for 8 weeks as a supplement to their normal endurance (cycling) training. This was followed by 6 weeks of endurance training only (retention period) leading up to the start of the competitive season. Maximal leg extensor power, isometric leg extensor strength (maximal voluntary contraction [MVC]), rate of force development (RFD), and long-term cycling performance (2-hour submaximal cycling at 55% of Wmax), followed by 5-minute max cycling were evaluated. After 8 weeks of concurrent resistance and endurance training, leg extensor power, MVC, and RFD increased by 12, 15, and 17%, respectively while mean power output (W) during 5-minute max cycling increased by 7% (p < 0.05). Training-induced gains in MVC and 5-minute max cycling power were retained after 6-week cessation of resistance training (p < 0.05). These findings indicate that competitive cyclists can focus on cycling training alone for at least 6 weeks leading up to competition without losing attained gains in maximal muscle strength and cycling performance achieved by preceding periods of concurrent resistance training.

Physiological Performance Characteristics of Danish National Team Handball Players 1990-2016: Implications on Position-Specific Strength and Conditioning Training.

Bøgild, P, Jensen, K, and Kvorning, T. Physiological performance characteristics of Danish National Team Handball players 1990-2016: implications on position-specific strength and conditioning training. J Strength Cond Res 34(6): 1555-1563, 2020-The aims of this study were: (a) to examine the anthropometric and physiological performance characteristics in male and female national team handball (TH) players before and after 2000; and (b) to compare anthropometry and physiological performance characteristics between court playing positions in male and female national TH players. Using a federal database containing physiological test data from 1990 to 2016 of more than 800 national A and U (under 21 years) TH players, data from 175 men and 138 women were extracted by their first appearance for pre- or post-2000 and sorted by playing positions. The level of significance was set at p < 0.05. Pre- vs. post-2000 male A showed no differences, whereas differences were found in male U, female A, and female U. General position-specific differences for both sexes were wings being lowest, lightest, and having lowest fat-free mass (FFM), pivots having higher body mass and FFM than back-court players, and higher %BF than wings. Back-court players and wings had higher jump and reach (JR) than pivots, and wings were faster on 30 m than pivots. Based on these findings, no general differences seem to exist before and after the year 2000 in the observed physiological parameters. The primary differences between playing positions were anthropometric, whereas the physiological performance characteristics, in general, did not differ between playing positions, except for the pivots' lower JR and the wings' faster 30 m, indicating that earlier documented differences in on-court work demands had not, in general, impacted the players' physiological performance characteristics.

Physical exercise in the treatment of alcohol use disorder (AUD) patients affects their drinking habits: A randomized controlled trial.

AIM: The aim of this study is to compare the effect of exercise training on physical capacity and alcohol consumption in alcohol use disorder (AUD) patients. METHODS: One hundred and five AUD patients were randomly assigned to treatment as usual combined with running and brisk walking for 30-45 min twice a week, either in small supervised groups (GR) or individually (IND), or to a control group with no running (C). Assessments were made after 6 and 12 months of training. RESULTS: Training volume was estimated as 36 min per training bout at an intensity of 78% of HRmax with no differences between GR and IND ( p>.05). A highly significant reduction in training frequency was seen in both training groups after the first month ( p<.0001). Only IND increased VO2max, by 5.7% ( p<.05), while no differences were seen between GR, IND and C. Alcohol intake decreased from 219 to 41 units per 30 days as the average for the entire sample with no significant difference of drinking outcomes between groups ( p<.0001). CONCLUSIONS: We saw an effect on drinking habits after running in both groups. However, no additional effect was seen when compared with the control group. A drop in the training frequency during the intervention might have resulted in an insignificant training stimulus.

Strength and Conditioning Training by the Danish National Handball Team Before an Olympic Tournament.

Kvorning, T, Hansen, MRB, and Jensen, K. Strength and conditioning training by the Danish national handball team before an Olympic tournament. J Strength Cond Res 31(7): 1759-1765, 2017-The physical demands imposed on national team handball teams during the Olympics imply significant physical preparation to improve performance and reduce incidence of injuries. The purpose of this case report was to describe and analyze the strength and conditioning (S&C) training performed by the Danish national handball team before the Beijing Olympic Games. Eight weeks of S&C was divided into 5 weeks emphasizing muscle hypertrophy and long-interval running followed by 3 weeks emphasizing strength, power, and short-interval running. Body mass increased by 1.6% (p < 0.05), whereas body fat decreased by 1.0% (p < 0.05). No differences were seen in countermovement jump or jump-and-reach height (p > 0.05). Agility performance was evaluated by a T-test and improved by 2.5% (p < 0.05). Changes by 6% and 22% were seen in 1 repetition maximum (1RM) bench press and 1RM back squat, respectively. However, only the 1RM bench press increased significantly (p < 0.05). Running performance was tested by the Yo-Yo intermittent recovery test, level 2, and improved by 25% (p < 0.05). In conclusion, during 8 weeks of S&C training before the Beijing Olympics, body composition changed toward more muscle mass, better upper-body strength, better interval running, and agility performance, whereas no changes were seen in jumping or lower-body muscle strength. This case report may be used as a handy script for handball teams preparing for competition. Detailed and periodized S&C training programs for 8 weeks are provided and can be used by teams ranging from moderately to highly trained.

Polar substitutions in helix 3 of the prion protein produce transmembrane isoforms that disturb vesicle trafficking.

Prion diseases encompass a diverse group of neurodegenerative conditions characterized by the accumulation of misfolded prion protein (PrP) isoforms. Other conformational variants of PrP have also been proposed to contribute to neurotoxicity in prion diseases, including misfolded intermediates as well as cytosolic and transmembrane isoforms. To better understand PrP neurotoxicity, we analyzed the role of two highly conserved methionines in helix 3 on PrP biogenesis, folding and pathogenesis. Expression of the PrP-M205S and -M205,212S mutants in Drosophila led to hyperglycosylation, intracellular accumulation and widespread conformational changes due to failure of oxidative folding. Surprisingly, PrP-M205S and -M205,212S acquired a transmembrane topology (Ctm) previously linked to mutations in the signal peptide (SP) and the transmembrane domain (TMD). PrP-M205,212S also disrupted the accumulation of key neurodevelopmental proteins in lipid rafts, resulting in shortened axonal projections. These results uncover a new role for the hydrophobic domain in promoting oxidative folding and preventing the formation of neurotoxic Ctm PrP, mechanisms that may be relevant in the pathogenesis of both inherited and sporadic prion diseases.

Need to Revise Classification of Physical Activity Intensity in Older Adults? The Use of Estimated METs, Measured METs, and V̇O2 Reserve.

BACKGROUND: Multiples of resting metabolic rate (RMR) are often used to classify physical activity intensity, a concept known as the metabolic equivalent of task (MET). However, the METs metrics may misclassify physical activity intensity in older adults because of age-related changes in RMR and maximal aerobic capacity (V˙O2max). This study aimed to (i) compare classifications of activity intensity by estimated (METsestimated) and measured (METsmeasured) METs and (ii) compare physical activity classified by absolute (METsmeasured) versus relative intensity (%V˙O2Reserve) in older adults. METHODS: Ninety-eight adults aged 75-90 years participated in the study. RMR and V˙O2 during sitting, standing, daily activities, and 6-minute walking test were measured. V˙O2Reserve was defined as the difference between V˙O2max and RMR. Moderate and vigorous intensity was classified as 3 and 6 METs and 40% and 60% of V˙O2Reserve, respectively. Paired t tests and a confusion matrix were used to investigate aims 1 and 2, respectively. RESULTS: METsmeasured was 24% lower than the standard 1 MET of 3.5 mL O2·min-1·kg-1. METsestimated underestimated the intensity during daily and walking activities when compared to METsmeasured. Nevertheless, when comparing METsmeasured to percentages of V˙O2Reserve, a mismatch was shown for moderate intensity in 47%-67% of the participants during daily activities and 21% of the participants during self-selected gait speed. CONCLUSIONS: Applying METsestimated for older adults leads to potential underestimation of physical activity intensity, suggesting that current classification metrics should be revised for older adults. V˙O2Reserve is a candidate metric for establishing precise physical activity intensity cut points for older adults. Clinical Trials Registration Number: NCT04821713.

High-intensity interval training combining rowing and cycling improves but does not restore beta-cell function in type 2 diabetes.

Aim: We investigated whether a high-intensity interval training (HIIT) protocol could restore beta-cell function in type 2 diabetes compared with sedentary obese and lean individuals. Materials and methods: In patients with type 2 diabetes, and age-matched, glucose-tolerant obese and lean controls, we examined the effect of 8 weeks of supervised HIIT combining rowing and cycling on the acute (first-phase) and second-phase insulin responses, beta-cell function adjusted for insulin sensitivity (disposition index), and serum free fatty acid (FFA) levels using the Botnia clamp (1-h IVGTT followed by 3-h hyperinsulinemic-euglycemic clamp). Results: At baseline, patients with type 2 diabetes had reduced insulin sensitivity (~40%), acute insulin secretion (~13-fold), and disposition index (>35-fold), whereas insulin-suppressed serum FFA was higher (⁓2.5-fold) compared with controls (all P < 0.05). The HIIT protocol increased insulin sensitivity in all groups (all P < 0.01). In patients with type 2 diabetes, this was accompanied by a large (>200%) but variable improvement in the disposition index (P < 0.05). Whereas insulin sensitivity improved to the degree seen in controls at baseline, the disposition index remained markedly lower in patients with type 2 diabetes after HIIT (all P < 0.001). In controls, HIIT increased the disposition index by ~20-30% (all P < 0.05). In all groups, the second-phase insulin responses and insulin-suppressed FFA levels were reduced in response to HIIT (all P < 0.05). No group differences were seen in these HIIT-induced responses. Conclusion: HIIT combining rowing and cycling induced a large but variable increase in beta-cell function adjusted for insulin sensitivity in type 2 diabetes, but the disposition index remained severely impaired compared to controls, suggesting that this defect is less reversible in response to exercise training than insulin resistance. Trial registration: ClinicalTrials.gov (NCT03500016).

A Maximal Rowing-Ergometer Protocol to Predict Maximal Oxygen Uptake in Female Rowers.

BACKGROUND: Laboratory assessment of maximal oxygen uptake (V˙O2max) is physically and mentally draining for the athlete and requires expensive laboratory equipment. Indirect measurement of V˙O2max could provide a practical alternative to laboratory testing. PURPOSE: To examine the relationship between the maximal power output (MPO) in an individualized 7 × 2-minute incremental test (INCR-test) and V˙O2max and to develop a regression equation to predict V˙O2max from MPO in female rowers. METHODS: Twenty female club and Olympic rowers (development group) performed the INCR-test on a Concept2 rowing ergometer to determine V˙O2max and MPO. A linear regression analysis was used to develop a prediction of V˙O2max from MPO. Cross-validation analysis of the prediction equation was performed using an independent sample of 10 female rowers (validation group). RESULTS: A high correlation coefficient (r = .94) was found between MPO and V˙O2max. The following prediction equation was developed: V˙O2max (mL·min-1) = 9.58 × MPO (W) + 958. No difference was found between the mean predicted V˙O2max in the INCR-test (3480 mL·min-1) and the measured V˙O2max (3530 mL·min-1). The standard error of estimate was 162 mL·min-1, and the percentage standard error of estimate was 4.6%. The prediction model only including MPO, determined during the INCR-test, explained 89% of the variability in V˙O2max. CONCLUSION: The INCR-test is a practical and accessible alternative to laboratory testing of V˙O2max.

High-intensity interval training combining rowing and cycling efficiently improves insulin sensitivity, body composition and VO2max in men with obesity and type 2 diabetes.

Aims: Non-weight-bearing high-intensity interval training (HIIT) involving several muscle groups may efficiently improve metabolic health without compromising adherence in obesity and type 2 diabetes. In a non-randomized intervention study, we examined the effect of a novel HIIT-protocol, recruiting both lower and upper body muscles, on insulin sensitivity, measures of metabolic health and adherence in obesity and type 2 diabetes. Methods: In 15 obese men with type 2 diabetes and age-matched obese (n=15) and lean (n=18) glucose-tolerant men, the effects of 8-weeks supervised HIIT combining rowing and cycling on ergometers (3 sessions/week) were examined by DXA-scan, incremental exercise test and hyperinsulinemic-euglycemic clamp combined with indirect calorimetry. Results: At baseline, insulin-stimulated glucose disposal rate (GDR) was ~40% reduced in the diabetic vs the non-diabetic groups (all p<0.01). In response to HIIT, insulin-stimulated GDR increased ~30-40% in all groups (all p<0.01) entirely explained by increased glucose storage. These changes were accompanied by ~8-15% increases in VO2max, (all p<0.01), decreased total fat mass and increased lean body mass in all groups (all p<0.05). There were no correlations between these training adaptations and no group-differences in these responses. HbA1c showed a clinically relevant decrease in men with type 2 diabetes (4±2 mmol/mol; p<0.05). Importantly, adherence was high (>95%) in all groups and no injuries were reported. Conclusions: A novel HIIT-protocol recruiting lower and upper body muscles efficiently improves insulin sensitivity, VO2max and body composition with intact responses in obesity and type 2 diabetes. The high adherence and lack of injuries show that non-weight-bearing HIIT involving several muscle groups is a promising mode of exercise training in obesity and type 2 diabetes.

Histone H2A.Z acid patch residues required for deposition and function.

The incorporation of histone variants is one mechanism used by the eukaryotic cell to alter the generally repressive chromatin template. However, the exact molecular mechanisms that direct this incorporation are not well understood. The SWR1 chromatin remodeling complex that binds to and directs incorporation of histone variant H2A.Z into chromatin has been characterized, but significantly less information is available concerning the requirements on the H2A.Z target molecule. We performed an unbiased mutagenic screen designed to elucidate the function of H2A.Z in Saccharomyces cerevisiae. The screen identified residues within the conserved acidic patch of H2A.Z as being important for the function of the variant. We characterized single point mutations in the patch that are phenotypically sensitive to a variety of growth conditions and are expressed at lower protein levels, but are functionally defective (htz1-D99A, htz1-D99K, and htz1-E101K). The mutants were significantly less detectable by chromatin immunoprecipitation at PHO5, a gene previously described to be enriched for H2A.Z. These results identify acidic patch residues of H2A.Z that are critical for mediating deposition and function in chromatin, and represent potential candidates for the interaction of H2A.Z with its deposition and/or targeting machinery.

Diffusion-weighted MRI for verification of electroporation-based treatments.

Clinical electroporation (EP) is a rapidly advancing treatment modality that uses electric pulses to introduce drugs or genes into, e.g., cancer cells. The indication of successful EP is an instant plasma membrane permeabilization in the treated tissue. A noninvasive means of monitoring such a tissue reaction represents a great clinical benefit since, in case of target miss, retreatment can be performed immediately. We propose diffusion-weighted magnetic resonance imaging (DW-MRI) as a method to monitor EP tissue, using the concept of the apparent diffusion coefficient (ADC). We hypothesize that the plasma membrane permeabilization induced by EP changes the ADC, suggesting that DW-MRI constitutes a noninvasive and quick means of EP verification. In this study we performed in vivo EP in rat brains, followed by DW-MRI using a clinical MRI scanner. We found a pulse amplitude-dependent increase in the ADC following EP, indicating that (1) DW-MRI is sensitive to the EP-induced changes and (2) the observed changes in ADC are indeed due to the applied electric field.

Intracoronary compared to intravenous bolus abciximab during primary percutaneous coronary intervention in ST-segment Elevation Myocardial Infarction (STEMI) patients reduces 30-day mortality and target vessel revascularization: a randomized trial.

BACKGROUND: Abciximab is beneficial in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). However, the optimal administration route of the initial bolus of abciximab, that is, intravenous (IV) versus intracoronary (IC), has been questioned. Preliminary studies suggest that IC-bolus is superior, probably due to high local concentration. In this study, we assess the short-term efficacy and safety of IC compared to IV bolus of abciximab in patients with STEMI during pPCI. METHODS: In 2006-2008, we randomized 355 STEMI patients who underwent pPCI and had indication for abciximab to either IV or IC bolus followed by a 12-hour IV infusion. Primary end-points at 30 days were target vessel revascularization (TVR), recurrent myocardial infarction (MI) or death, and the composite of the three. Secondary end-points were bleeding complications. RESULTS: The two groups (IV n = 170;IC n = 185) were similar with respect to baseline characteristics. Mortality at 30 days was 5.3% in the IV group compared to only 1.1% in the IC group (P = 0.02). TVR was performed in 9.4% in the IV group compared to 3.8% in the IC group (P = 0.03). No significant difference in MI rates was seen (IV 4.7% vs. IC 2.7%; P = 0.32). We found a significant reduction in the composite end-point (IV 19.4% vs. IC 7.6%; P = 0.001) in favor of IC use. Major bleeding complications were similar (IV 2.4% vs. IC 1.6%; P = 0.62). Neither difference was observed in minor bleedings (IV 14.1% vs. IC 9.7%; P = 0.20). CONCLUSION: IC administration of bolus abciximab in STEMI patients undergoing pPCI reduces 30-day mortality and TVR and tends to reduce MI, compared to IV-bolus.

A Maximal Rowing Ergometer Protocol to Predict Maximal Oxygen Uptake.

PURPOSE: To examine the relationship between the maximal power output (MPO) in an individualized 7 × 2-minute incremental (INCR) test, average power in a 2k (W2k) rowing ergometer test, and maximal oxygen uptake (V˙O2max) and to develop a regression equation to predict V˙O2max. METHODS: A total of 34 male club rowers (age 18-30 y) performed a 2k and an INCR test in a Concept2 rowing ergometer to determine and compare MPO, W2k, and V˙O2max. RESULTS: No significant difference was found between V˙O2max measured during INCR or 2k test (P = .73). A very high correlation coefficient (r = .96) was found between MPO and V˙O2max and between W2k and V˙O2max (r = .93). Linear regression analyses were developed for predicting V˙O2max from MPO: (1) V˙O2max (mL·min-1) = 11.49 × MPO + 810 and V˙O2max from W2k: (2) V˙O2max = 10.96 × W2k + 1168. Cross-validation analyses were performed using an independent sample of 14 rowers. There was no difference between the mean predicted V˙O2max in the INCR test (4.41 L·min-1) or the 2k test (4.39 L·min-1) and the observed V˙O2max (4.40 L·min-1). Technical error of measurement was 3.1% and 3.6%, standard error of estimate was 0.136 and 0.157 mL·min-1, and validation coefficients (r) were .95 and .94 using Equation (1) and (2), respectively. CONCLUSION: A prediction model only including MPO or W2k explains 88% to 90% of the variability in V˙O2max and is suggested for practical use in male club rowers.

Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy.

BACKGROUND: The currently recommended treatment for chronic thromboembolic pulmonary hypertension is pulmonary thromboendarterectomy (PTE). No convincing evidence for the use of pulmonary hypertensive medical therapy (PHT) exists in operable candidates. We sought to determine the prevalence of the use of PHT on referral for PTE and the effects on pre-PTE hemodynamics and post-PTE outcomes/hemodynamics. METHODS AND RESULTS: We performed a retrospective analysis of chronic thromboembolic pulmonary hypertension patients referred for PTE during 2005-2007. The prevalence of PHT was determined for all patients referred to our institution. Hemodynamic and outcomes analysis involved only those undergoing PTE. Data included baseline demographics, PHT medication(s), dosage, duration of therapy, and time to referral. Hemodynamic data were acquired from the time of diagnosis, the time of referral visit, and after PTE. Outcomes included intensive care unit, hospital, and ventilator days; bleeding and infection rates; incidence of reperfusion lung injury; and in-hospital mortality. The control group (n=244) was compared with the PHT group (n=111); subgroups included monotherapy with bosentan, sildenafil, or epoprostenol and combination therapy. The prevalence of PHT significantly increased from 19.9% in 2005 to 37% in 2007. There was minimal benefit of treatment with PHT on pre-PTE mean pulmonary artery pressure, but its use was associated with a significant delay in time to referral for PTE. Both groups experienced significant improvements in hemodynamic parameters after PTE. The 2 groups did not differ significantly in any post-PTE outcome. Similar results were obtained for each subgroup. CONCLUSIONS: Our results suggest that PHT use has minimal effect on pre-PTE hemodynamics and no effect on post-PTE outcomes/hemodynamics.

Absence of Coronary Artery Calcium During Positron Emission Tomography Stress Testing in Patients Without Known Coronary Artery Disease Identifies Individuals With Very Low Risk of Cardiac Events.

BACKGROUND: Myocardial perfusion imaging, including positron emission tomography/computed tomography (PET/CT), is often used to assess for high-grade coronary artery disease (CAD) requiring revascularization. The use of coronary artery calcium (CAC) to predict risk of major adverse cardiovascular events in asymptomatic patients is accepted. However, little is known regarding the use of CAC in PET/CT patients without known CAD in identifying patients unlikely to need revascularization. Here, we determined whether the absence of CAC, using low-dose attenuation correction CT obtained during the PET/CT, identifies patients unlikely to undergo coronary revascularization within 90 days of a PET/CT. METHODS: Patients, without a history of CAD and no elevation in troponin, referred for PET/CT at Intermountain Medical Center were studied (n=5528). The presence of CAC was visually assessed using low-dose attenuation correction CT. The association between CAC and 90-day high-grade CAD and revascularization were assessed. Longer-term (up to 4 years) major adverse cardiovascular events, including all-cause death, myocardial infarction, and late revascularization (>90 days), were examined. RESULTS: There were 2510 (45.4%) patients in CAC-present group and 3018 (54.6%) patients in CAC-absent group. The CAC-absent group, compared with the CAC-present group, was less likely to undergo coronary angiography (3.4% versus 10.2%, P<0.0001), have high-grade CAD (0.5% versus 6.5%, P<0.0001), and receive revascularization (0.4% versus 5.8%, [adjusted odds ratio =0.09; 95% CI, 0.05-0.16]; P<0.0001). In patients with an ischemic burden >10%, the CAC-absent group was associated with reduced revascularization (P<0.0001). Longer-term major adverse cardiovascular events were lower in the CAC-absent (2.4%) compared with the CAC-present (6.9%) group (adjusted hazard ratio, 0.45 [95% CI, 0.34-0.60]; P<0.0001). CONCLUSIONS: The absence of CAC on low-dose attenuation correction CT identifies PET/CT patients unlikely to have high-grade CAD or require revascularization within 90 days and unlikely to experience longer-term major adverse cardiovascular events. The prognostic value of CAC, beyond ischemic burden, suggests its potential as a first-step screening tool in intermediate-risk patients to identify those who do not need coronary revascularization.

Association between left ventricular diastolic function and right ventricular function and morphology in asymptomatic aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is a progressive disease in which left ventricular (LV) diastolic dysfunction is common. However, the association between diastolic dysfunction and right ventricular (RV) loading conditions and function has not been investigated in asymptomatic AS patients. METHODS AND FINDINGS: A total of 41 patients underwent right heart catheterization and simultaneous echocardiography at rest and during maximal supine exercise, stratified according to resting diastolic function. Cardiac chamber size and morphology was assessed using cardiac magnetic resonance imaging (cMRI). RV stroke work index, pulmonary artery (PA) compliance, PA elastance, PA pulsatility index, and right atrial pressure (RAP) were calculated at rest and maximal exercise. Ten patients (24%) had normal LV filling pattern, 20 patients (49%) had grade 1, and 11 patients (27%) had grade 2 diastolic dysfunction. Compared to patients with normal diastolic filling pattern, patients with diastolic dysfunction had lower RV end-diastolic volume (66 ± 11 ml/m2 vs. 79 ± 15 ml/m2, p = 0.02) and end-systolic volume (25 ± 7 ml/m2 vs. 32 ± 9 ml/m2, p = 0.04). An increase in mean RAP to ≥15 mmHg following exercise was not seen in patients with normal LV filling, compared to 4 patients (20%) with mild and 7 patients (63%) with moderate diastolic dysfunction (p = 0.003). PA pressure and PA elastance was increased in grade 2 diastolic dysfunction and correlated with RV volume and maximal oxygen consumption (r = -0.71, p < 0.001). CONCLUSIONS: Moderate diastolic dysfunction is associated with increased RV afterload (elastance), which is compensated at rest, but is associated with increased RAP and inversely related to maximal oxygen consumption during maximal exercise.

Surgical revascularization is associated with improved long-term outcomes compared with percutaneous stenting in most subgroups of patients with multivessel coronary artery disease: results from the Intermountain Heart Registry.

BACKGROUND: Coronary artery bypass surgery (CABG) and percutaneous coronary intervention with stenting (PCI-S) are both safe and effective approaches for revascularization in patients with multivessel coronary artery disease. However, conflicting information exists when comparing the efficacy of the two methods. In this study, we examined the outcomes of major adverse cardiovascular events and death for subgroups of typical "real-world" patients undergoing coronary revascularization in the modern era. METHODS AND RESULTS: Patients were included if they were revascularized by CABG or PCI-S, had > or = 5 years of follow-up, and had > or = 2-vessel disease. Patients were followed for an average of 7.0+/-3.2 years for incidence of death and major adverse cardiovascular events (death, myocardial infarction, or repeat revascularization). Multivariate regression models were used to correct for standard cardiac risk factors including age, sex, hyperlipidemia, diabetes mellitus, family history of coronary artery disease, smoking, hypertension, heart failure, and renal failure. Subgroup analyses were also performed, stratified by age, sex, diabetes, ejection fraction, and history of PCI-S, CABG, or myocardial infarction. A total of 6369 patients (CABG 4581; PCI-S 1788) were included. Age averaged 66+/-10.9 years, 76% were male, and 26% were diabetic. Multivariate risk favored CABG over PCI-S for both death (hazard ratio 0.85; P=0.001) and major adverse cardiovascular events (hazard ratio 0.51; P<0.0001). A similar advantage with CABG was also found in most substrata, including diabetes. CONCLUSIONS: In this large observational study of patients undergoing revascularization for multivessel coronary artery disease, a long-term benefit was found, in relationship to both death and major adverse cardiovascular events, for CABG over PCI-S regardless of diabetic status or other stratifications.