Comparison of Echocardiography and Multi-Planar Gated Acquisition Scans for Predicting Cancer-Treatment-Related Cardiovascular Dysfunction.

BACKGROUND: Current guidelines recommend using sequential cardiac imaging to monitor for cancer treatment-related cardiac dysfunction (CTRCD) in patients undergoing potentially cardiotoxic chemotherapy. Multiple different imaging cardiac modalities are available and there are few prospective head-to-head comparative studies to help guide treatment. OBJECTIVES: To perform an exploratory prospective cohort study of "real-world" CTRCD comparing multigated acquisition nuclear ventriculography (MUGA) at the referring cancer specialist's discretion with a novel echocardiographic strategy at an Australian tertiary hospital. METHOD: Patients were recruited from haematology and oncology outpatient clinics if they were scheduled for treatment with anthracyclines and/or trastuzumab. Patients underwent simultaneous MUGA-based cardiac imaging (conventional strategy) at a frequency according to evidenced-based guidelines in addition to researcher-conducted echocardiographic imaging. The echocardiographic imaging was performed in all patients at time points recommended by international society guidelines. Outcomes included adherence to guideline recommendations, concordance between MUGA and echocardiographic left ventricular ejection fraction (LVEF) measurements, and detection of cardiac dysfunction (defined as >5% LVEF decrement from baseline by three-dimensional [3D]-LVEF). A secondary end point was accuracy of global longitudinal strain in predicting cardiac dysfunction. RESULTS: In total, 35 patients were recruited, including 15 with breast cancer, 19 with haematological malignancy, and one with gastric cancer. MUGA and echocardiographic LVEF measurements correlated poorly with limits of agreement of 30% between 3D-LVEF and MUGA-LVEF and 37% for 3D-LVEF and MUGA-LVEF. Only one case (2.9%) of CTRCD was diagnosed by MUGA, compared with 12 (34.2%) cases by echocardiography. Four (4) patients had >10% decrement in 3D-LVEF that was not detected by MUGA. Global longitudinal strain at 2 months displayed significant ability to predict CTRCD (area under the curve, 0.75, 95% confidence interval, 0.55-0.94). CONCLUSIONS: The MUGA correlates poorly with echocardiographic assessment with substantial discrepancy between MUGA and echocardiography in CTRCD diagnosis. Echocardiographic and MUGA imaging strategies should not be considered equivalent for imaging cancer patients, and a single imaging modality should ideally be used per patient to prevent misdiagnosis by inter-modality variation These findings should be considered hypothesis-generating and require confirmation with larger studies.

Association of Reduced Left Atrial Reserve With Exercise Intolerance and Outcome in Hypertension.

BACKGROUND: Hypertensive heart disease (HHD) is a leading contributor to heart failure with preserved ejection fraction (HFpEF). However the mechanisms behind the transition to the symptomatic phase remain unclear. OBJECTIVES: We sought the association of the exercise response of LA mechanical function with functional capacity, symptoms and outcome across the HF spectrum in hypertension. METHODS: Echocardiography (including LA reservoir [PALS] and contractile strain [PACS], and LA stiffness index) were performed at rest and immediately post-exercise in 139 patients with HHD- 35 with stage A, 48 with stage B and 56 with stage C HFpEF. Patients were followed for HF and atrial fibrillation (AF). RESULTS: Exercise capacity was progressively worse from stage A through stage B to stage C, and accompanied by a gradual impairment of changes in PALS and PACS from rest to exercise, whereas LA stiffness reserve remained unchanged until stage C. PALS and PACS reserves were independently associated with exercise capacity(p=0.017 and 0.008, respectively). LA stiffness reserve and E/e' were the strongest associations of symptomatic HF. Over a median of 25 months, 35 patients developed HF and/or AF. PALS and PACS reserves were associated with the study endpoints after adjusting for age, diabetes, NT-proBNP, LA volume index, resting E/e' and resting PALS/PACS. CONCLUSIONS: Impaired exercise reserve of LA strain and stiffness are associated with reduced functional capacity in hypertension, and LA strain reserve is independently associated with outcome. These parameters appear to be determinants of progression to overt HF in HHD, however their contribution may differ depending on HF stage.

Evolving Applications of Echocardiography in the Evaluation of Left Atrial and Right Ventricular Strain.

PURPOSE OF REVIEW: Speckle-tracking echocardiography (STE) can assess myocardial motion in non-LV chambers-including assessment of left atrial (LA) and right ventricular (RV) strain. This review seeks to highlight the diagnostic, prognostic, and clinical significance of these parameters in heart failure, atrial fibrillation (AF), diastolic dysfunction, pulmonary hypertension (PH), tricuspid regurgitation, and heart transplant recipients. RECENT FINDINGS: Impaired LA strain reflects worse LV diastolic function in individuals with and without HF, and this is associated with decreased exercise capacity. Initiating treatments targeting these functional aspects may enhance exercise capacity and potentially prevent heart failure (HF). Impaired LA strain also identifies patients with a high risk of AF, and this recognition may lead to preventive strategies. Impaired RV strain has significant clinical and prognostic implications across various clinical scenarios, including HF, PH, tricuspid regurgitation, or in heart transplant recipients. STE should not be limited to the assessment of deformation of the LV myocardium. The use of LA and RV strain is supported by a substantial evidence base, and these parameters should be used more widely.

Blood Pressure Lowering in Patients With Central Hypertension: A randomized Clinical Trial.

BACKGROUND: Cuff blood pressure (BP) is recommended for guiding hypertension management. However, central BP has been proposed as a superior clinical measurement. This study aimed to determine whether controlling hypertension as measured by central BP was beneficial in reducing left ventricular mass index beyond control of standard cuff hypertension. METHODS: This multicenter, open-label, blinded-end point trial was conducted in individuals treated for uncomplicated hypertension with controlled cuff BP (<140/90 mm Hg) but elevated central BP (≥0.5 SD above age- and sex-specific normal values). Participants were randomized to 24-months intervention with spironolactone 25 mg/day (n=148) or usual care control (n=153). The primary outcome was change in left ventricular mass index measured by cardiac MRI. Cuff and central BPs were measured by clinic, 7-day home and 24-hour ambulatory BPs. RESULTS: At 24-months, there was a greater reduction in left ventricular mass index (-3.2 [95% CI, -5.0 to -1.3] g/m2; P=0.001) with intervention compared with control. Cuff and central BPs were lowered by a similar magnitude across all BP measurement modes (eg, clinic cuff systolic BP, -6.16 [-9.60 to -2.72] mm Hg and clinic central systolic BP, -4.96 [-8.06 to -1.86] mm Hg; P≥0.48 all). Secondary analyses found that changes in left ventricular mass index correlated to changes in BP, with the magnitude of effect nearly identical for BP measured by cuff (eg, 24-hour systolic BP, ß, 0.17 [0.02-0.31] g/m2) or centrally (24-hour systolic BP, ß, 0.16 [0.01-0.32] g/m2). CONCLUSIONS: Among individuals with central hypertension, spironolactone had beneficial effects in reducing LV mass. Secondary analyses showed that changes in LV mass were equally well associated with lower measured standard cuff BP and central BP. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12613000053729.

Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy.

BACKGROUND: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity. OBJECTIVES: The study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2). METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10). CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

Noninvasive Techniques for Tracking Biological Aging of the Cardiovascular System: JACC Family Series.

Population aging is one of the most important demographic transformations of our time. Increasing the "health span"-the proportion of life spent in good health-is a global priority. Biological aging comprises molecular and cellular modifications over many years, which culminate in gradual physiological decline across multiple organ systems and predispose to age-related illnesses. Cardiovascular disease is a major cause of ill health and premature death in older people. The rate at which biological aging occurs varies across individuals of the same age and is influenced by a wide range of genetic and environmental exposures. The authors review the hallmarks of biological cardiovascular aging and their capture using imaging and other noninvasive techniques and examine how this information may be used to understand aging trajectories, with the aim of guiding individual- and population-level interventions to promote healthy aging.

Use of the energy waveform electrocardiogram to detect subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Recent guidelines propose N-terminal pro-B-type natriuretic peptide (NT-proBNP) for recognition of asymptomatic left ventricular (LV) dysfunction (Stage B Heart Failure, SBHF) in type 2 diabetes mellitus (T2DM). Wavelet Transform based signal-processing transforms electrocardiogram (ECG) waveforms into an energy distribution waveform (ew)ECG, providing frequency and energy features that machine learning can use as additional inputs to improve the identification of SBHF. Accordingly, we sought whether machine learning model based on ewECG features was superior to NT-proBNP, as well as a conventional screening tool-the Atherosclerosis Risk in Communities (ARIC) HF risk score, in SBHF screening among patients with T2DM. METHODS: Participants in two clinical trials of SBHF (defined as diastolic dysfunction [DD], reduced global longitudinal strain [GLS ≤ 18%] or LV hypertrophy [LVH]) in T2DM underwent 12-lead ECG with additional ewECG feature and echocardiography. Supervised machine learning was adopted to identify the optimal combination of ewECG extracted features for SBHF screening in 178 participants in one trial and tested in 97 participants in the other trial. The accuracy of the ewECG model in SBHF screening was compared with NT-proBNP and ARIC HF. RESULTS: SBHF was identified in 128 (72%) participants in the training dataset (median 72 years, 41% female) and 64 (66%) in the validation dataset (median 70 years, 43% female). Fifteen ewECG features showed an area under the curve (AUC) of 0.81 (95% CI 0.787-0.794) in identifying SBHF, significantly better than both NT-proBNP (AUC 0.56, 95% CI 0.44-0.68, p < 0.001) and ARIC HF (AUC 0.67, 95%CI 0.56-0.79, p = 0.002). ewECG features were also led to robust models screening for DD (AUC 0.74, 95% CI 0.73-0.74), reduced GLS (AUC 0.76, 95% CI 0.73-0.74) and LVH (AUC 0.90, 95% CI 0.88-0.89). CONCLUSIONS: Machine learning based modelling using additional ewECG extracted features are superior to NT-proBNP and ARIC HF in SBHF screening among patients with T2DM, providing an alternative HF screening strategy for asymptomatic patients and potentially act as a guidance tool to determine those who required echocardiogram to confirm diagnosis. Trial registration LEAVE-DM, ACTRN 12619001393145 and Vic-ELF, ACTRN 12617000116325.

A novel approach to accurately measuring the burden of hospitalisations for cardiovascular disease in people with diabetes: A pilot study.

AIM: To determine the reliability of hospital discharge codes for heart failure (HF), acute myocardial infarction (AMI) and stroke compared with adjudicated diagnosis, and to pilot a scalable approach to adjudicate records on a population-based sample. METHODS: A population-based sample of 685 people with diabetes admitted (1274 admissions) to one of three Australian hospitals during 2018-2020 were randomly selected for this study. All medical records were reviewed and adjudicated. RESULTS: Cardiovascular diseases were the most common primary reason for hospitalisation in people with diabetes, accounting for ~17% (215/1274) of all hospitalisations, with HF as the leading cause. ICD-10 codes substantially underestimated HF prevalence and had the lowest agreement with the adjudicated diagnosis of HF (Kappa = 0.81), compared with AMI and stroke (Kappa ≥ 0.91). While ICD-10 codes provided suboptimal sensitivity (72%) for HF, the performance was better for AMI (sensitivity 84%; specificity 100%) and stroke (sensitivity 85%; specificity 100%). A novel approach to screen possible HF cases only required adjudicating 8% (105/1274) of records, correctly identified 78/81 of HF admissions and yielded 96% sensitivity and 98% specificity. CONCLUSIONS: While ICD-10 codes appear reliable for AMI or stroke, a more complex diagnosis such as HF benefits from a two-stage process to screen for suspected HF cases that need adjudicating. The next step is to validate this novel approach on large multi-centre studies in diabetes.

Influence of Repeated Plaque Visualization on Cardiovascular Risk Reduction after 3 years; a randomized controlled trial.

AIMS: Helping people to understand their cardiovascular (CV) risk can influence the choices they make for risk reduction, including medication adherence and lifestyle modification. This study sought whether repeated visualization of coronary artery calcium (CAC) images was effective in sustaining long-term risk control in primary prevention, independent of a risk reduction program. METHODS: Asymptomatic, statin-naïve participants, 40-70 years, with a family history of premature coronary artery disease and a CAC score from 1-400 were randomised to a nurse-led CV risk reduction program or standard care with bi-annual reviews. Only the intervention group (220 of 449 participants) visualised their CAC image (with repeat exposure in the first 3 months) and were initiated on statin therapy. The primary outcome was change in Framingham Risk Score (FRS) at 36 months, and the impact of CAC image recall on CV risk was assessed. RESULTS: The reduction in FRS (difference in differences (DID): -3.4% [95%CI: -4.4% to -2.4%], p=<0.001 and low-density-lipoprotein-cholesterol -1.2mmol/L [95%CI: -1.4 to -1.0], p=<0.001)) over 36 months was greater in the intervention than the control group. Within the intervention group, sustained recall of CAC images at 24 months was associated with lower systolic blood pressure (DID -4.3mmHg [95%CI: -7.7 to-0.9], p=0.01) and waist circumference (DID -2.0cm [95% CI: -3.9 to -0.1], p=0.03) at 36 months compared to unsustained recall. CONCLUSION: A nurse-led program, combining personalized patient visualization of CAC imaging with statin therapy, is beneficial for improving CV risk. Recalling the presentation of CAC images through repeated visual exposure may influence risk reduction.

This trial sought to determine whether visualization of coronary artery calcium (CAC) images influences behaviour change and cardiovascular risk reduction within a structured nurse-led program versus standard care. Intervention participants visualized their personalized CAC images within the first three months and commenced statin therapy. Control participants were blinded to their CAC images and were not provided statin therapy. Intervention participants had a greater absolute reduction in the Framingham Risk Score (Difference in differences: -3.4% [95% CI: -4.4% to -2.4%], p=<0.001) compared to controls. Those with sustained recollection of their CAC images within the intervention group also had greater reductions in systolic blood pressure and waist circumference.

Use of Clinical and Echocardiographic Evaluation to Assess the Risk of Heart Failure.

BACKGROUND: Clinical and echocardiographic features predict incident heart failure (HF), but the optimal strategy for combining them is unclear. OBJECTIVES: This study sought to define an effective means of using echocardiography in HF risk evaluation. METHODS: The same clinical and echocardiographic evaluation was obtained in 2 groups with HF risk factors: a training group (n = 926, followed to 7 years) and a validation group (n = 355, followed to 10 years). Clinical risk was categorized as low, intermediate, and high using 4-year ARIC (Atherosclerosis Risk In Communities) HF risk score cutpoints of 9% and 33%. A risk stratification algorithm based on clinical risk and echocardiographic markers of stage B HF (SBHF) (abnormal global longitudinal strain [GLS], diastolic dysfunction, or left ventricular hypertrophy) was developed using a classification and regression tree analysis and was validated. RESULTS: HF developed in 12% of the training group, including 9%, 18%, and 73% of low-, intermediate-, and high-risk patients. HF occurred in 8.6% of stage A HF and 19.4% of SBHF (P < 0.001), but stage A HF with clinical risk of ≥9% had similar outcome to SBHF. Abnormal GLS (HR: 2.92 [95% CI: 1.95-4.37]; P < 0.001) was the strongest independent predictor of HF. Normal GLS and diastolic function reclassified 61% of the intermediate-risk group into the low-risk group (HF incidence: 12%). In the validation group, 11% developed HF over 4.5 years; 4%, 17%, and 39% of low-, intermediate-, and high-risk groups. Similar results were obtained after exclusion of patients with known coronary artery disease. The echocardiographic parameters also provided significant incremental value to the ARIC score in predicting new HF admission (C-statistic: 0.78 [95% CI: 0.71-0.84] vs 0.83 [95% CI: 0.77-0.88]; P = 0.027). CONCLUSIONS: Clinical risk assessment is adequate to classify low and high HF risk. Echocardiographic evaluation reclassifies 61% of intermediate-risk patients.

Use of Imaging-guided Decongestion for Reducing Heart Failure Readmission and Death in High-risk Patients: A Multi-site Randomized Trial of a Nurse-led Strategy at the Point of Care.

BACKGROUND: Nurse-led disease management programs (DMPs) decrease readmission after acute decompensated heart failure (HF). We sought whether readmissions could be further reduced by lung ultrasound (LUS)-guided decongestion before discharge and during DMP. METHODS AND RESULTS: Of 290 patients hospitalized with acute decompensated HF, 122 at high risk for readmission or mortality were randomized to receive usual care (UC) (n = 64) or UC plus intervention (DMP-Plus) (n = 58), comprising LUS-guided management before discharge and during at-home follow-up. Residual congestion was identified by ≥10 B-lines detected in 8 lung zones. The outcomes included a composite of readmission and/or mortality at 30 and 90 days, and 90-day HF readmission. Residual congestion was detected equally among the patient groups. The 30-day composite outcome occurred in 28% DMP-plus patients and 22% UC patients (odd ratio [OR], 1.36; 95% confidence interval [CI], 0.59-3.1; P = .5) and the 90-day HF readmission outcome occurred in 22% and 31%, respectively (odds ratio, 0.63; 95% CI, 0.28-1.43; P = .3). Residual congestion, identified at predischarge LUS examination in high-risk patients, was associated with early (<14-day) HF readmission (relative risk, 1.19; 95% CI, 1.06-1.32; P = .002) and multiple (≥2) readmissions over 90 days of follow-up (relative risk, 1.09; 95% CI, 1.01-1.16; P = .012), independent of demographics and comorbidities. CONCLUSIONS: Readmission in patients with incomplete decongestion before discharge occurs within the first 2 weeks. However, our DMP-plus strategy did not improve the primary outcome.

Cardiovascular magnetic resonance imaging for sequential assessment of cardiac fibrosis in mice: technical advancements and reverse translation.

Cardiovascular magnetic resonance (CMR) imaging has become an essential technique for the assessment of cardiac function and morphology, and is now routinely used to monitor disease progression and intervention efficacy in the clinic. Cardiac fibrosis is a common characteristic of numerous cardiovascular diseases and often precedes cardiac dysfunction and heart failure. Hence, the detection of cardiac fibrosis is important for both early diagnosis and the provision of guidance for interventions/therapies. Experimental mouse models with genetically and/or surgically induced disease have been widely used to understand mechanisms underlying cardiac fibrosis and to assess new treatment strategies. Improving the appropriate applications of CMR to mouse studies of cardiac fibrosis has the potential to generate new knowledge, and more accurately examine the safety and efficacy of antifibrotic therapies. In this review, we provide 1) a brief overview of different types of cardiac fibrosis, 2) general background on magnetic resonance imaging (MRI), 3) a summary of different CMR techniques used in mice for the assessment of cardiac fibrosis including experimental and technical considerations (contrast agents and pulse sequences), and 4) provide an overview of mouse studies that have serially monitored cardiac fibrosis during disease progression and/or therapeutic interventions. Clinically established CMR protocols have advanced mouse CMR for the detection of cardiac fibrosis, and there is hope that discovery studies in mice will identify new antifibrotic therapies for patients, highlighting the value of both reverse translation and bench-to-bedside research.

Contribution of reduced skeletal muscle perfusion reserve to exercise intolerance in heart failure with preserved ejection fraction.

BACKGROUND: Skeletal muscle (SM)-associated mechanisms of exercise intolerance in HFpEF are insufficiently defined, and inadequate augmentation of SM blood flow during physical effort may be one of the contributors. Therefore, we sought to investigate the association of SM perfusion response to exertion with exercise capacity in this clinical condition. METHODS: Echocardiography and SM microvascular perfusion by contrast-enhanced ultrasound were performed at rest and immediately post-exercise test in 77 HFpEF patients in NYHA class II and III, and in 25 subjects with normal exercise tolerance (stage B). Exercise reserve of cardiac function and SM perfusion was calculated by subtracting resting value from exercise value. RESULTS: In addition to decreased cardiac functional reserve, HFpEF patients demonstrated significantly reduced SM perfusion reserve as compared to HF stage B, with the degree of impairment being greater in the subgroup with more profound left ventricular (LV) diastolic abnormalities (E/e' > 15 and TRV > 2.8 m/s). SM perfusion reserve was significantly associated with exercise capacity (beta = 0.33; SE 0.11; p = 0.003), cardiac output reserve (beta = 0.24; SE 0.12; p = 0.039), resting E/e' (beta = -0.33; SE 0.11; p = 0.006), and patient frailty expressed by the PRISMA 7 score (beta = -0.30; SE 0.11; p = 0.008). In multivariable analysis including clinical, demographic and cardiac functional variables, SM perfusion reserve was in addition to patient frailty, sex and LV longitudinal strain reserve among the independent correlates of exercise capacity. CONCLUSIONS: SM perfusion reserve is impaired in HFpEF, and is associated with reduced exercise capacity independent of clinical, demographic and "central" cardiac factors. This supports the need to consider the SM domain in patient management strategies in HFpEF.