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BACKGROUND Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, >500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by lonis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.) [ABSTRACT FROM AUTHOR]

Anxious to free Beethoven's compositions from the ideologically driven notion of "lateness" - 'why should it be impossible to look at works at chronologically late points in Beethoven's creative biography without highly loaded historical and aesthetic prejudgements ... ? For Joseph Kerman, the String Quartet in B flat, Op. 130, was Beethoven's "most dissociated composition" ( I The Beethoven Quartets i (London, 1967), 321), the antithesis to the paradigm of "integration" represented by the C sharp minor work, Op. 131. [Extracted from the article]

Background: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods: Adults with non–high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non–HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. Results: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58–69) years, 44% were female, the median non–HDL-C was 132.4 (interquartile range, 118.0–154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4–270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non–HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P <0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P <0.001). The effects on LDL-C and ApoB were more modest (7.9%–16.0% and 6.0%–15.1%, respectively) and without a clear dose-response relationship‚ and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P <0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). Conclusions: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non–HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04516291. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.Results: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3.Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores. [ABSTRACT FROM AUTHOR]

Background: The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients.Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol.Findings: Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61-0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78-0·92]; pinteraction=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73-0·91]) and non-statin treatment (0·67 [0·47-0·95]; pinteraction=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74-0·98]), myocardial infarction (0·80 [0·71-0·90]), stroke (0·73 [0·61-0·87]), and coronary revascularisation (0·80 [0·66-0·96]).Interpretation: In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients.Funding: None. [ABSTRACT FROM AUTHOR]

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk.Methods: We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab.Results: In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50-1.00; P=0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57-1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33-0.88]; P=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53-0.90]; P=0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30-0.89]; P=0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk (Pinteraction 0.087 for HR; Pheterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (Pinteraction=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (Pinteraction=0.04) and absolute VTE reduction (Pheterogeneity=0.009) in comparison with those without high genetic risk.Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors. [ABSTRACT FROM AUTHOR]

Background: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established.Methods: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years.Results: After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (Ptrend=0.005) and major coronary events (Ptrend<0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 1.02; absolute risk reduction [ARR], -0.2%, P=0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75-0.998], P=0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55-0.86], P=0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk (Ptrend for HR=0.017, ARR Ptrend=0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk.Conclusion: Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk. [ABSTRACT FROM AUTHOR]

Background: Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events.Methods: We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters.Results: A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]).Conclusions: In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects. [ABSTRACT FROM AUTHOR]

This article introduces to Schenker scholarship a virtually unknown, unfinished text, 'Der Weg zum Gleichniss' ('The Path to Likeness'). I date it to the decade following 1895, and more specifically to 1902–4: thus, between 'Der Geist der musikalischen Technik' and Harmonielehre (1906). 'Geist' has for more than thirty years been repeatedly re-examined for its negative account of organicism in music; I show that the 'Gleichniss' text both reiterates Schenker's position and argues that, through the controlling concept of 'likeness', music succeeded in elevating itself to the level of 'a distinct, second, artificial and higher nature'. In short, this text may represent the 'missing link' between 'Geist' and the more positively organicist Harmonielehre. Finally, I ponder the context of 'Geist' and the background to Schenker's idiosyncratic use of the term 'Gleichniss': this leads both forwards to the 1933 article 'Was wird aus der Musik?' and backwards to the Old Testament. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Background Right ventricular ( RV) function is significantly impaired in patients with chronic thromboembolic pulmonary hypertension ( CTEPH). Two-dimensional speckle tracking RV strain and strain rate are novel methods to assess regional RV systolic function in CTEPH patients before and after pulmonary thromboendarterectomy ( PTE). Our goal was to (1) assess baseline longitudinal strain and strain rate of the basal RV free wall in CTEPH and (2) measure early changes in RV strain and strain rate after PTE. Methods We performed echocardiography on 30 consecutive patients with CTEPH referred for PTE with adequate pre- and post- PTE strain imaging. Strain and strain rate were assessed 6.4 ± 4.5 days before and 9.1 ± 3.9 after PTE. Results Basal RV free wall strain and time to peak strain-but not basal RV strain rate and time to peak strain rate-changed significantly after PTE. Unexpectedly, basal RV strain became less negative, from −24.3% to −18.9% after PTE (P = 0.005). Time to peak strain decreased from 356 to 287 msec after PTE (P < 0.001). Preoperatively, RV strain correlated with pulmonary vascular resistance (PVR) and mean pulmonary artery pressure ( mPAP) but this relationship was not evident postoperatively. Furthermore, the change in RV strain did not correlate with the change in mPAP or PVR. Conclusions In patients with CTEPH, RV basal strain paradoxically became less negative (i.e., relative systolic shortening decreased) following PTE. This change in RV strain could be due to intraoperative RV ischemia and/or postoperative stunning. Thus, RV basal strain cannot be used as a surrogate marker for surgical success early after PTE. [ABSTRACT FROM AUTHOR]

Genetic testing, hypercholesterolemia, myocardial infarction, phytosterols, hyperlipoproteinemia type II B I Patient presentation (continued): i The patient was diagnosed with hypercholesterolemia in her 20s but did not carry a diagnosis of FH. Keywords: genetic testing; hypercholesterolemia; hyperlipoproteinemia type II; myocardial infarction; phytosterols EN genetic testing hypercholesterolemia hyperlipoproteinemia type II myocardial infarction phytosterols 1843 1847 5 06/09/23 20230613 NES 230613 I Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Marston), who responds to the information and shares his reasoning with the reader (regular type). The belief of some cardiologists that genetic testing will not change how they treat a patient is the final barrier to the widespread appropriate use of genetic testing. [Extracted from the article]

Background: Impaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE). Methods: Forty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters. Results: Pre-op LAVI (mean 19.0 ± 7 mL/m2) correlated significantly with pre-op PVR (R = −0.45, p = 0.001), mPAP (R = −0.28, p = 0.05) and cardiac index (R = 0.38, p = 0.006). Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR (765 to 311 dyne-s/cm5, p = 0.01), cardiac index (2.6 to 3.2 L/min/m2, p = 0.02), and E/A (.95 to 1.44, p = 0.002). Conclusion: In CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: A normal preoperative myocardial perfusion-imaging (MPI) test in advance of vascular surgery predicts a low risk of postoperative clinical events at 30 days. Among patients undergoing vascular surgery with a normal preoperative MPI, cardiac troponin I (cTnI) elevations are common and predictive of a poor long-term outcome. Methods: The study cohort comprised 182 patients. Between January 2005 and December 2009, we studied these patients, who had no evidence of myocardial ischemia on preoperative MPI and were undergoing vascular surgery. Blood was obtained in all of the patients in the first 2 days following vascular surgery, and cTnI levels were measured. The values that exceeded the upper reference limit (URL) were categorized as either low (+) (greater than or equal to the URL but less than three times the URL) or high (+) (greater than or equal to three times the URL). Long-term survival was determined from the time of the vascular operation. Results: The mean age of the population was 69 ± 8 years, and the mean revised cardiac risk index was 1.80 ± 0.77. The most common indication for vascular intervention was an expanding abdominal aortic aneurysm (n = 96, 52.5%). Within 48 hours of surgery, 58 patients (32%) had a typical rise and fall in TnI, with at least one value exceeding the URL. Of these patients, 17 (9%) were classified as high (+) and 41 (22.5%) as low (+). At 1 year post-vascular surgery, mortality was 8% for the overall cohort. A high (+) Tn elevation was an identifier of decreased 1 -year survival (29%) relative to normal (3%) and low (+) (14%; P < 0.001). Stratified cTn was an independent predictor of the long-term risk of death. Conclusions: Among patients undergoing vascular procedures without evidence of myocardial ischemia on MPI, an elevation in TnI is common and predictive of long-term mortality risk. [ABSTRACT FROM AUTHOR]

This article draws on the rich resources of Heinrich Schenker's Nachlass in the Ernst Oster Collection ( New York Public Library) to construct the development of interruption ( Unterbrechung), a vital aspect of Schenker's mature understanding of musical form. In §90 of Der freie Satz (1935) Schenker makes a crucial distinction between the structural weight of the two configurations in an interrupted Ursatz, and gives priority to the first one: the effect of interruption depends on the sense that this will be succeeded by , rather than by the return to that is actually forthcoming. Subsequently, in §93, Schenker claims that the reasserted connects back to its first appearance, prior to the first arrival of . The article explores the tension between these two claims in relation to and Ursätze and reconstructs preliminary versions of the text relating to interruption in Der freie Satz. It concludes by suggesting that Schenker's shifting notation of interrupted structures reflects a continuing uneasiness with his own definition of interruption as a theoretical concept. [ABSTRACT FROM AUTHOR]

Although it has long been known that Beethoven began composing a piano trio in F minor in 1816, scholarly examination of the extant sources for this unfinished project has only recently progressed beyond Nottebohm's brief remarks in the 1880s. The present article reveals the existence of numerous new sources evidently unknown to Nottebohm, including a leaf which forms the continuation of the draft score (Concept) of the first movement, the principal source for the trio. (Transcriptions of this score, including the new continuation, and of a newly identified draft which preceded it, accompany the article.) The trio project is contextualized in relation to other compositions, in particular the String Quartet in F minor, op. 95, the 'Archduke' Trio and the Piano Sonata in A, op. 101, and an attempt is made to understand the failure of the trio project in relation to Beethoven's limited compositional activity at this much-discussed point in his career. [ABSTRACT FROM AUTHOR]

Explores the metaphorical identification of the tonic key as 'home' in relation to the first movement of Schubert's Piano Sonata. Assimilation of a foreign or alien element into the home sphere; Success in doing the reverse, rendering the tonic unhomely in the recapitulation; Fragmentary continuity draft for the movement.

Focuses on 'The Beethoven Sketchbooks.' Importance of the sequence of sketches in a sketchbook; Description on the sketchbook Landsberg 5 prepared by scholar Clemens Brenneis; Classification of the sketchbook project.

Focuses on Ludwig van Beethoven's Hammerklavier sonata. Reason Hammerklavier sonata is pointing and puzzling; First movement of the Hammerklavier; Conclusion.

Highlights the premiere of Ludwig van Beethoven's major works 'Piano Concerto' and 'Second Symphony' at the Theater an der Wien in Vienna, Austria on April 5, 1803. Comparison of the third continuity draft and the final version of the finale of 'Second Symphony'; Basic element of the underlying idea.

Discusses Robert Schumann's essay in sonata form `Fantasie.' Tripartite segmentation of the first movement of the `Fantasie'; Revelation of the `Stichvorlage' for the `Fantasie'; Role of the `Im Legendenton' section; Confusion over the status of `Im Legendenton' as a separate movement from `Stichvorlage'; Interpretation; Disjunction between `Im Legendenton' and its flanking sections; Links to be observed in the three.

Background: Elevated triglycerides (TGs) have been associated with an increased risk of cardiovascular (CV) events. Whether TGs remain a predictor of CV events in patients with well-treated LDL-C and after adjusting for traditional risk factors and atherogenic lipoprotein particles remains debated. Hypothesis: When adjusted for clinical variables and apolipoprotein B (apoB), TGs do not independently predict CV events. Methods: We divided 13,779 pts with stable atherosclerosis, LDL-C ≥70 mg/dL (or non-HDL-C ≥ 100 mg/dl), and TG <400 mg/dL enrolled in the placebo arm of the FOURIER trial into 5 groups by baseline fasting TG level: <100, 100-149, 150-199, 200-249, ≥250 mg/dL. All pts had baseline apoB levels drawn. The primary endpoint was a composite of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Pts were followed for a median of 2.2 years. Models adjusted for traditional clinical risk factors (age, sex, race, region, prior MI, stroke, PAD, HTN, DM, smoking, eGFR, HDL-C, hs-CRP, waist size, fasting glucose) and then for apoB. Results: The unadjusted risk of CV events significantly increased with higher baseline TGs (Table; HR 1.16 for TG ≥250 vs. <100; P-trend 0.033). When adjusted for clinical variables, the trend was no longer present (P=0.21). When baseline apoB was added to the model, the pattern reversed , with significantly lower CV risk with higher TGs (HR 0.75 for TG ≥250 vs. <100; P-trend 0.021). Conclusion: Although higher TGs were associated with CV events in the unadjusted analysis, no such trend was present when adjusting for clinical risk factors, and a reverse association was found when adding apoB. Thus: (1) the concentration of apoB-containing particles appears to determine CV risk rather than cholesterol or triglyceride content carried by the particles, and (2) for a given apoB concentration, risk may be higher with relatively more LDL than VLDL. [ABSTRACT FROM AUTHOR]

Introduction: Use of high-sensitivity troponin (hsTn) in stable patients (pts) with established ischemic heart disease (SIHD) is an emerging application to identify heightened risk of major cardiovascular (CV) events. However, appropriate decision-limits are not yet defined. Methods: We measured serum hsTnI (Abbott ARCHITECT, limit-of-detection 2 ng/L, MI cut-point 26 ng/L) in a prospective nested cohort of 8,635 pts enrolled in the PEGASUS-TIMI 54 trial. All patients had SIHD with a myocardial infarction (MI) 1-3 years prior to enrollment. Previous studies have proposed 6 ng/L as a decision-limit for risk stratification. Pts were categorized based on baseline hsTnI: undetectable (<2), low (2-6), and high (>6 ng/L). The primary endpoint (PEP) was a composite of CV death, MI, or stroke. Pts were followed for a median of 33 months. Results: The median value of hsTnI was 4.2 ng/L (25th, 75th: 2.7, 7.2 ng/L) and 89.3% of pts had detectable hsTnI (≥2 ng/L) with 31.1% >6 ng/L. The 3y PEP rates for the undetectable, low, and high hsTnI groups were 2.8, 6.0, and 13.5%, respectively (Fig). Adjusting for age, diabetes, smoking, hypertension, stroke, CABG, peripheral artery disease, history of heart failure and chronic kidney disease, there remained a 2 and 4-fold higher risk for the PEP in the low and high hsTnI groups(Fig). Rates of MI in the undetectable, low, and high groups were 2.5, 4.3, and 8.7%, respectively, with adjusted HRs of 1.9 (95% CI 1.2-3.2, p=0.009) in the low and 3.6 (95% CI 2.2-6.0, p<0.0001) in the high group. No CV deaths occurred in pts with undetectable troponin. There was no significant interaction with efficacy of ticagrelor. Conclusion: hsTn demonstrates a strong independent graded association with recurrent major cardiovascular events in pts with SIHD. The increased risk is present in the low detectable range and progresses with higher levels. A single hsTnI >6 ng/L was present in nearly 1/3 of patients, identifying a 4-fold higher risk of recurrent cardiac event. [ABSTRACT FROM AUTHOR]

The article introduces the thirteenth volume of the publication "Beethoven Forum" in 2006.

Background: Impaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE).Methods: Forty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters.Results: Pre-op LAVI (mean 19.0 ± 7 mL/m2) correlated significantly with pre-op PVR (R = -0.45, p = 0.001), mPAP (R = -0.28, p = 0.05) and cardiac index (R = 0.38, p = 0.006). Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR (765 to 311 dyne-s/cm5, p = 0.01), cardiac index (2.6 to 3.2 L/min/m2, p = 0.02), and E/A (.95 to 1.44, p = 0.002).Conclusion: In CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction. [ABSTRACT FROM AUTHOR]

The article discusses reports published within the issue including one by Robert Pascall on the last movement of the Ninth Symphony and another by David Levy on the composition "Grosse Fuge."

The article discusses various reports published within the issue, including essays by Sarah Clemmens Waltz and William Drabkin regarding myths about Beethoven and his music, and a review-essay by Michael Spitzer on James Hepokoski and Warren Darcy's "Elements of Sonata Theory."