Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial.

Importance: Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains. Objective: To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG. Design, Setting, and Participants: The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 centers across the US, Europe, New Zealand, Australia, and Canada from May 31, 2021, to August 31, 2023. Eligible patients had fasting triglyceride levels in the range of 500 to 4000 mg/dL (to convert to millimoles per liter, multiply by 0.0113) while receiving stable lipid-lowering treatment. Interventions: Participants received 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo on day 1 and at week 12 and were followed up through week 48. Main Outcomes and Measures: The primary end point evaluated the placebo-subtracted difference in means of percentage triglyceride change at week 24. Mixed-model repeated measures were used for statistical modeling. Results: Of 229 patients, 226 (mean [SD] age, 55 [11] years; 176 male [78%]) were included in the primary analysis. Baseline mean (SD) triglyceride level was 897 (625) mg/dL and plasma APOC3 level was 32 (16) mg/dL. Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose. Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) level, which was significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001). However, apolipoprotein B (ApoB) levels did not increase, and non-high-density lipoprotein cholesterol (HDL-C) levels decreased significantly at all doses, with a placebo-adjusted change of -20% at the highest dose. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death. Conclusions and Relevance: In this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute pancreatitis risk in most participants. Other triglyceride-related lipoprotein parameters improved. An increase in LDL-C level was observed but with no change in ApoB level and a decrease in non-HDL-C level. The safety profile was generally favorable at all doses. Additional studies will be required to determine whether plozasiran favorably modulates the risk of sHTG-associated complications. Trial Registration: ClinicalTrials.gov Identifier: NCT04720534.

Characterization and clinical significance of right ventricular mechanics in pulmonary hypertension evaluated with cardiovascular magnetic resonance feature tracking.

BACKGROUND: Prognosis in pulmonary hypertension (PH) is related to right ventricular (RV) function. Quantification of RV mechanics may offer additive value. The objective of our study is to determine the feasibility and clinical and prognostic value of RV strain analysis by cardiovascular magnetic resonance (CMR) based feature tracking (FT) in PH. METHODS: We retrospectively enrolled 116 patients (age 52.2 ± 12 years, 73.6 % women) referred to CMR for PH evaluation who underwent right heart catheterization within 1 month. Using dedicated FT software, peak global longitudinal and circumferential RV strain and strain rates (GLS, GCS, GLSR, and GCSR, respectively) were quantified from standard cine images. Using multivariate regression analysis, we evaluated the associations of strain with a composite endpoint of death, lung transplantation, or functional class deterioration. RESULTS: RV strain analysis was feasible in 110 (95 %) patients. Patients were classified into: Group A (no PH, normal right ventricular ejection fraction [RVEF]; n = 17), Group B (PH, normal RVEF; n = 26), or Group C (PH, abnormal RVEF; n = 67). All strain and strain rate values were reduced in Group C. Furthermore, GCSR was significantly reduced in Group B (-0.92 [-1.0/-0.7]; p < 0.001) compared to Group A (-1.12 [-1.3/-0.9]; p < 0.001). After adjustment for six clinically meaningful covariates, GLS (hazard ratio 1.06; p = 0.026), GLSR (hazard ratio 2.52; p = 0.04), and GCSR (hazard ratio 4.5; p = 0.01) were independently associated with the composite endpoint. GCSR successfully discriminated patients with and without events (p = 0.01). CONCLUSIONS: Quantification of RV strain with CMR-FT is feasible in the majority of patients, correlates with disease severity, and is independently associated with poor outcomes in PH.

Feasibility of intercity and trans-Atlantic telerobotic remote ultrasound: assessment facilitated by a nondedicated bandwidth connection.

We discuss the concept of ultrasound imaging at a distance by presenting the evaluation of a customized, lightweight, human-safe robotic arm for low-force, long-distance, telerobotic ultrasonography. We undertook intercity and trans-Atlantic telerobotic ultrasound simulation from master stations located in New York, New York and Munich, Germany, and imaged a phantom and a human volunteer located at a slave station in Burlington, Massachusetts, using standard Internet bandwidth <100 Mbps and <50 Mbps, respectively. The data from the robotic arm were tracked for understanding the time efficiency of the human interactions at the master stations. Comparison of a beginner in ultrasound operation with a professional sonographer revealed that although proficiency in using ultrasound was not a prerequisite for operating the robotic arm, previous experience in using clinical ultrasound was associated with progressively lower probe maneuvering time and speed due to an enhanced ability of the veteran operator in adjusting the finer angular motions of the probe. These results suggest that long-distance telerobotic echocardiography over a local nondedicated Internet bandwidth is feasible and can be rapidly learned by sonographers for cost-effective resource utilization.

Myocardial mechanics in cardiomyopathies.

Cardiomyopathies are a heterogeneous group of diseases that can be phenotypically recognized by specific patterns of ventricular morphology and function. The authors summarize recent clinical observations that mechanistically link the multidirectional components of left ventricular (LV) deformation with morphological phenotypes of cardiomyopathies for offering key insights into the transmural heterogeneity of myocardial function. Subendocardial dysfunction predominantly alters LV longitudinal shortening, lengthening and suction performance and contributes to the phenotypic patterns of heart failure (HF) with preserved ejection fraction (EF) seen with hypertrophic and restrictive patterns of cardiomyopathy. On the other hand, a more progressive transmural disease results in reduction of LV circumferential and twist mechanics leading to the phenotypic pattern of dilated cardiomyopathy and the clinical syndrome of HF with reduced (EF). A proper characterization of LV transmural mechanics, energetics, and space-time distributions of pressure and shear stress may allow recognition of early functional changes that can forecast progression or reversal of LV remodeling. Furthermore, the interactions between LV muscle and fluid mechanics hold the promise for offering newer mechanistic insights and tracking impact of novel therapies.

Impact of individual and cumulative coronary risk factors on coronary flow reserve assessed by dobutamine stress echocardiography.

Traditional cardiovascular risk factors have been shown to cause microvascular dysfunction. Most studies that have evaluated microcirculation rely on invasive measurement tools. We used dobutamine stress echocardiography, a validated method to measure coronary flow velocity (CFV) and coronary flow reserve (CFR), in a previously unstudied population without known significant coronary artery disease to determine the impact of traditional risk factors on CFR. Consecutive patients who had no evidence of regional wall motion abnormalities at rest or during dobutamine stress echocardiography were studied. Left anterior descending artery CFV was measured at baseline and at peak dobutamine stress and CFR was calculated as the ratio of peak stress CFV to baseline CFV. Fifty-nine consecutive patients (28 men) with mean age of 66.8+/-14.5 years were studied. CFR was lower in patients with diabetes mellitus (DM) compared with those without (1.7+/-0.74 vs 2.48+/-0.98, p<0.007), in patients with hypertension compared with those without (2+/-0.8 vs 2.6+/-0.9, p<0.02), and in obese patients compared with nonobese patients (1.6+/-0.5 vs 2+/-0.6, p<0.02). CFR was further impaired in the presence of DM with hypertension, DM with obesity, DM with a wide pulse pressure (>50 mm Hg), and obesity with a wide pulse pressure. In a multivariate model, DM, obesity, and wide pulse pressure were significantly associated with variation in CFR (p<0.0008). In conclusion, CFR was abnormal in patients with DM, hypertension, and obesity. CFR impairment is exaggerated as the number of risk factors increases. Despite a negative dobutamine stress echocardiographic result, aggressive risk factor assessment and control should be implemented in patients with coronary risk factors due to an underlying abnormal CFR.

Vascular abnormalities in primary amyloidosis.

AIMS: Primary amyloidosis (AL) is a systemic disease; however, there is limited information regarding the presence and character of vascular abnormalities. METHODS AND RESULTS: Validated ultrasound techniques were used to prospectively determine carotid artery intimal-medial thickness (IMT) and brachial artery flow-mediated dilatation (FMD) in 59 consecutive AL patients and 17 age-similar, healthy, asymptomatic volunteers (CON). Carotid IMT was increased in AL when compared with CON (0.07 +/- 0.02 vs. 0.04 +/- 0.01 mm, P < 0.01). Similarly, brachial artery FMD was significantly lower in AL when compared with CON subjects (3 +/- 7 vs. 12 +/- 8%, P < 0.01). Multivariable analysis revealed that AL was associated with larger IMT and lower FMD after controlling for several confounding variables. However, within AL cases, there was not a significant association of cardiac vs. non-cardiac involvement with IMT or FMD (P = 0.1 and 0.2, respectively). CONCLUSION: AL is associated with abnormal vascular morphology and endothelial dysfunction. Vascular abnormalities do not appear to be related to echocardiographic evidence of cardiac involvement.

Safety of exercise stress testing in patients with abnormal concentrations of serum potassium.

The objective of this study was to determine the safety of performing exercise stress testing in patients with abnormal serum potassium concentrations. Data were reviewed from 9,084 patients (mean age 63 +/- 12 years) referred for exercise echocardiography who had serum potassium measured <48 hours before the test were reviewed, and the occurrence of arrhythmias during stress testing was determined. Of 10,272 studies, 9,067 (88%) were in patients with normokalemia and 1,205 (12%) were in patients with abnormal serum potassium concentrations: 309 (26%) with hypokalemia (mean 3.4 +/- 0.16 mmol/L) and 896 (74%) with hyperkalemia (mean 5.1 +/- 0.19 mmol/L). Ventricular and supraventricular ectopy were common during exercise. Only 1 patient (potassium 4.9 mmol/L) had sustained ventricular tachycardia; all other episodes were nonsustained. Although ventricular and supraventricular ectopy are common during exercise testing, life-threatening arrhythmias are not. Exercise testing is generally safe despite mild to moderate hypokalemia or hyperkalemia.

Two-dimensional acoustic pattern derived strain parameters closely correlate with one-dimensional tissue Doppler derived strain measurements.

BACKGROUND: Two-dimensional strain echocardiography (2D-SE) calculates tissue velocities via frame-to-frame tracking of unique acoustic markers within the image and provides strain parameters in two dimensions. Novel 2D-SE software allows semi-automated strain measurements and increased averaging capabilities optimizing signal-noise ratio. AIM: We tested whether 2D-SE and the currently used and well-validated tissue Doppler derived strain echocardiography (TD-SE) yield similar information in the clinical setting. METHODS AND RESULTS: We performed 2D-SE and TD-SE on 17 patients with amyloid cardiomyopathy and 10 age-matched healthy volunteers. Single walls from standard apical views (2- and 4-chamber) were acquired at high frame rates ( approximately 200fps). Offline analysis was performed by observers blinded to clinical data using the EchoPAC program with custom 2D-SE software. Longitudinal strain rate and strain from the basal, mid and apical segments of the septal and lateral walls were determined by each method (TD-SE and 2D-SE). Ejection fraction was >0.55 in healthy volunteers and ranged from 0.30 to 0.80 in cardiomyopathy group. A total of 54 walls (162 segments) were examined. Acceptable quality strain data was available in 92% and 85% segments by 2D-SE and TD-SE, respectively. Two-dimensional strain echocardiography values correlated closely with TD-SE values (r=0.94 and 0.96 for strain rate and strain, respectively). CONCLUSIONS: Deformation analysis by 2D-SE is feasible in a clinical setting and 2D-SE values correlate closely with TD-SE measurements over a wide range of global systolic function. Two-dimensional strain echocardiography may help to facilitate the routine clinical implementation of deformation analysis.

Doppler derived coronary flow reserve during dobutamine stress echocardiography further improves detection of myocardial ischemia.

BACKGROUND: The coronary flow velocity (CFV) has been used to estimate coronary flow reserve (CFR) during dobutamine stress echocardiography (DSE). However, the relationship of the CFR to myocardial wall thickening (WT) has not been investigated. OBJECTIVES: The aims of this study were: (1) to assess the feasibility of obtaining systolic and diastolic CFV and thus CFR during DSE and (2) to assess the relation between CFR and stress induced WT. METHODS: Distal left anterior descending CFV was recorded by transthoracic Doppler echocardiography during DSE. Systolic and diastolic velocities were measured at rest, low and peak dobutamine doses, simultaneously, WT of distal anteroseptal segment was assessed by 2D-guided M-mode. The CFV and CFR of patients with normal WT defined as thickening of >50% (group 1) at peak stress were compared to that of patients with abnormal WT (group 2). RESULTS: A total of 67 patients, 34 females and 33 males (mean age of 66.5+/-14.5 years) were studied. The feasibility of assessing the CFR was 97% from peak diastolic velocity, 91% from diastolic time velocity integral, 91% from peak systolic velocity, and 90% from systolic time velocity integral. Contrast agent was used in 6 patients (7%) to obtain the CFV. Twenty-five of 67 patients demonstrated abnormal wall thickening. The percentage of WT was 30.9+/-15.7% in group 2 compared to 80.8+/-24.3% in group 1 (p<0.0001). The 25 patients in group 2, who developed abnormal WT, demonstrated significantly lower CFR at low dose, as well as at peak dobutamine dose compared to patients in group 1 (1.55+/-0.5 vs. 2.03+/-0.6, p<0.008). CONCLUSION: CFV and CFR assessments are feasible during DSE with second harmonic imaging in most patients without use of contrast agent. CFR assessment during DSE correlates well with wall thickening and was able to detect ischemia early before development of wall motion abnormality.

Analysis of the interaction between segmental relaxation patterns and global diastolic function by strain echocardiography.

BACKGROUND: Strain echocardiography can depict segmental mechanical activity with high temporal and spatial accuracy, and may allow assessment of segmental relaxation not possible with conventional echocardiography. METHODS: Conventional and strain echocardiography were performed in healthy volunteers (young [group 1] and old [group 2]) and patients with normal 2-dimensional and stress echocardiography, with either normal global diastolic function (group 3a) or grade I or II global diastolic dysfunction (DD) (group 3b). Standard echocardiography criteria were used to define global DD. Early to late diastolic strain rate ratio less than 1.1 was defined as altered segmental relaxation. RESULTS: All participants had normal wall motion and ejection fraction. Participants of group 1 had normal segmental and global diastolic function. Participants of groups 2 and 3a demonstrated a wide range of altered segmental relaxation in the absence of global DD. All patients of group 3b had 12 or more segments with altered relaxation and global DD. Age and hypertension were associated with a larger number of altered segments, a lower mean early to late diastolic strain rate ratio, and global DD. CONCLUSIONS: A wide range of altered segmental relaxation can exist in the absence of global DD. Age and hypertension are associated with altered segmental relaxation and global DD. Assessment of segmental relaxation may be beneficial in the elderly and patients with hypertension.

Left atrial myopathy in cardiac amyloidosis: implications of novel echocardiographic techniques.

AIMS: To assess left atrial (LA) function and determine the prevalence of LA dysfunction in AL amyloidosis (AL) using conventional and strain echocardiography. METHODS AND RESULTS: LA ejection fraction, LA filling fraction, LA ejection force, peak LA systolic strain rate (LAsSR), and LA systolic strain (LA epsilon) were determined in 95 AL patients (70 with and 25 without echocardiographic evidence of cardiac involvement, abbreviated CAL and NCAL, respectively), 30 age-matched controls (CON), and 20 patients with diastolic dysfunction and LA dilatation (DD). Peak LAsSR >2 standard deviations below mean CON value was used as the cut-off for normal LA function. LA ejection fraction was lower in CAL when compared with CON (40.4+/-13.6 vs. 67.0+/-6%, P=0.01). Left atrial septal strain rate and strain were lower in CAL (0.8+/-0.5 s(-1) and 5.5+/-4%, respectively) compared with CON (1.8+/-0.8 s(-1) and 14+/-4%, respectively, P=<0.0001), NCAL (1.6+/-0.8 s(-1) and 13+/-7%, respectively, P<0.0001) and DD (1.3+/-0.4 s(-1) and 10+/-2%, respectively, P<0.0001). Based on peak LA systolic strain rate criteria, the cut-off values for normal LA function were -1.1 s(-1) and -1.05 s(-1) for lateral and septal walls. Using these criteria, LA dysfunction was identified in 32% (lateral LA criteria) and 60% (septal LA criteria) of CAL patients. Lateral and septal LAsSR were lower in CAL patients with vs. those without symptoms of heart failure. Inter- and intra-observer agreement was high for LA strain echocardiography. CONCLUSION: LA function assessment using strain echocardiography is feasible with low intra- and inter-observer variability. LA dysfunction is observed in AL patients without other echocardiographic features of cardiac involvement and may contribute to cardiac symptoms in CAL.

Factors associated with progression of carcinoid heart disease.

BACKGROUND: By releasing vasoactive substances into the circulation, carcinoid tumors can cause right-sided valvular heart disease. Factors associated with the progression of carcinoid heart disease are poorly understood. We conducted a retrospective study to identify such factors. METHODS: Our sample included 71 patients with the carcinoid syndrome who underwent serial echocardiographic studies performed more than one year apart and 32 patients referred directly for surgical intervention after an initial echocardiographic evaluation. A score for carcinoid heart disease was determined on the basis of an assessment of valvular anatomy and function and the function of the right ventricle. An increase of more than 25 percent in the score between studies was considered suggestive of disease progression. Tumor progression was assessed on the basis of abdominal computed tomographic scans and changes in the level of urinary 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin. RESULTS: Of the patients with serial echocardiographic studies, 25 (35 percent) had an increase of more than 25 percent in the cardiac score. As compared with patients whose score changed by 25 percent or less, these patients had higher urinary peak 5-HIAA levels (median, 265 mg per 24 hours [interquartile range, 209 to 593] vs. 189 mg per 24 hours [interquartile range, 75 to 286]; P=0.004) and were more likely to have biochemical progression (10 of 25 patients vs. 9 of 46, P=0.05) and to have received chemotherapy (13 of 25 vs. 10 of 46, P=0.009). Logistic-regression analysis showed that a higher peak urinary 5-HIAA level and previous chemotherapy were predictors of an increase in the cardiac score that exceeded 25 percent (odds ratio for each increase in 5-HIAA of 25 mg per 24 hours, 1.08 [95 percent confidence interval, 1.03 to 1.13]; P=0.009); odds ratio associated with chemotherapy, 3.65 [95 percent confidence interval, 1.74 to 7.48]; P=0.001). CONCLUSIONS: Serotonin is related to the progression of carcinoid heart disease, and the risk of progressive heart disease is higher in patients who receive chemotherapy than in those who do not.

Prediction of mortality in patients with left ventricular hypertrophy by clinical, exercise stress, and echocardiographic data.

OBJECTIVES: This study evaluated the clinical, exercise stress test, and echocardiographic predictors of mortality and cardiac events in patients with left ventricular hypertrophy (LVH). BACKGROUND: Left ventricular hypertrophy is associated with an increased risk of cardiovascular morbidity and mortality. METHODS: Symptom-limited treadmill exercise echocardiography was performed for evaluation of coronary artery disease in 483 patients (age, 66 +/- 11 years; 281 men) with LVH. End points during follow-up were all-cause mortality and hard cardiac events (cardiac death and nonfatal myocardial infarction [MI]). RESULTS: Forty-six patients died and 14 had nonfatal MI. The cumulative mortality rate was higher in patients with abnormal exercise echocardiography (3% vs. 0.4% at one year, 11.7% vs. 3.7% at three years, and 18.3% vs. 9.5% at five years, p < 0.001). In a sequential multivariate analysis model of clinical, exercise test, and rest and exercise echocardiographic data, incremental predictors of mortality were workload (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3 to 0.9), rate pressure product (HR, 0.7; 95% CI, 0.5 to 0.9), left ventricular (LV) mass index (HR, 1.4; 95% CI, 1.1 to 1.8), and failure to increase ejection fraction (EF) with exercise (HR, 2.1; 95% CI, 1.1 to 3.8). Predictors of cardiac events were history of coronary artery bypass grafting (HR, 2.6; 95% CI, 1.2 to 5.4), lower exercise rate-pressure product (HR, 0.6; 95% CI, 0.5 to 0.8), resting wall motion score index (HR, 1.4; 95% CI, 1.1 to 1.8), and failure to increase EF with exercise (HR, 3.3; 95% CI, 1.6 to 6.9). CONCLUSIONS: In patients with LVH, LV mass index and EF response to exercise are independent predictors of mortality, incremental to clinical and exercise test data and resting LV function. A normal exercise echocardiogram predicts a relatively low mortality rate during the following three years.

Mycotic aneurysm of the left ventricle: echocardiographic diagnosis.

We report an unusual case of myocardial mycotic aneurysm of the left ventricle resulting from a healed myocardial abscess caused by an aortic regurgitant jet lesion. The diagnosis was made during intraoperative transesophageal echocardiography and confirmed by surgical inspection. The echocardiographic features are described.