Thomas H. Marwick’s research while affiliated with University of Melbourne and other places

Background Screening for HF may identify asymptomatic abnormalities of LV structure or function, described as stage B heart failure (SBHF) in asymptomatic patients with type 2 diabetes mellitus (T2DM). Sodium-glucose transport protein-2 (SGLT2) inhibitors are associated with reduction of overt HF in T2DM, but the mechanism of their effect in SBHF remains obscure. We sought to assess the response of cardiac function and exercise capacity to dapagliflozin vs placebo in T2DM with stage B HF. Methods The LEAVE-DM (Limiting the progression of Echocardiographically-Assessed left VEntricular dysfunction in Diabetes Mellitus) trial assessed echocardiography and 6-min walk (6MWD) in 262 people with well-controlled T2DM (age 73 ± 7 years; 159 women). Those with LVD (n = 139) were randomized 1:1 to dapagliflozin 10 mg/day or placebo. Follow-up was undertaken at 6 and 24 months and the primary endpoint was global longitudinal strain (GLS). Results Within the randomized group with LV dysfunction, dapagliflozin was associated with reduction of LA volume index (− 2.0 ± 9.0 vs. 0.03 ± 8.6, p = 0.002), and average E/e′ (− 0.1 ± 2.4 vs. 0.7 ± 2.4, p < 0.001), and improved LA reservoir strain (1.8 ± 4.0 vs. − 0.2 ± 4.0, p = 0.02) from baseline to 6 months follow-up. There was an improvement in exercise capacity on dapagliflozin at 6 months follow-up (Δ6MWD 17 ± 46 vs. 2 ± 73 m, p = 0.001). However, although abnormal GLS (< 16%) was less common at 6 months follow-up (41% vs. 49%, p = 0.03), there was no difference in ΔGLS from baseline to 6 months between dapagliflozin and placebo (p = 0.18). There were no significant differences between 6 and 24 months. Conclusions Dapagliflozin showed improvements in diastolic function, atrial function and exercise capacity in in patients with T2DM and SBHF, but no change in GLS. Trial Registration: ACTRN12619001393145 at Australia and New Zealand Clinical Trials registry (https://www.anzctr.org.au/).

Background Familial dilated cardiomyopathy (DCM) is characterized by marked variability in phenotypic penetrance. The extent to which this is determined by patient‐specific environmental factors is unknown. Methods and Results A retrospective longitudinal cohort study was performed in families with DCM‐causing genetic variants. Environmental factors were classified into 2 subsets based on evidence for a causal link to depressed myocardial contractility, termed (1) DCM‐promoting factors and (2) heart failure comorbidities. These factors were correlated with DCM diagnosis and disease trajectory after accounting for relevant confounders and familial relatedness. A total of 105 probands and family members were recruited: 51 genotype positive, phenotype positive, 24 genotype positive, phenotype negative, and 30 genotype negative, phenotype negative. Demographic characteristics were similar between the 3 genotype groups. DCM‐promoting environmental factors (eg, alcohol excess) were enriched in genotype‐positive, phenotype‐positive individuals compared with genotype‐positive, phenotype‐negative ( P <0.001) and genotype‐negative, phenotype‐negative ( P =0.003) individuals and were significantly associated with age at DCM onset (hazard ratio, 2.01; P =0.014). Heart failure comorbidities (eg, diabetes) had a similar prevalence in genotype‐positive, phenotype‐positive and genotype‐negative, phenotype‐negative individuals but were significantly reduced in the genotype‐positive, phenotype‐negative group. Fluctuations in left ventricular ejection fraction during follow‐up were linked to changes in environmental factors in 35 of 45 (78%) of instances: 32 (91%) of these were DCM‐promoting factors. Conclusions We identified distinct subsets of environmental factors that affect DCM penetrance and trajectory. Our data highlight DCM‐promoting environmental factors as key determinants of penetrance and natural history. Collectively, these findings provide a new framework for risk factor assessment in familial DCM and have important implications for clinical management.

Background Cardiac rehabilitation (CR) programs are effective, but they are underutilized. Digitally enabled CR programs (DeCR) offer alternative means of healthcare delivery. We aimed to assess the effects of a DeCR program on cardiovascular risk factors and healthcare utilization. Methods In this observational cohort study that used propensity score matching, privately insured Australian patients, recruited nationally following a cardiac hospitalization, were given a digital app and received weekly telehealth consultations. Risk factors were assessed before and after the intervention. Propensity scoring methods were used to compare differences in 30-day, 90-day and 12-month rehospitalizations, hospital-days and mortality rates in the DeCR group with patients who undertook: a) usual care (n=266) or b) face-to-face CR (F2F-CR, n=115). Results Overall, 172 intervention patients (70% men, age 68±10 years, 36% living in regional/remote areas) were enrolled (59% agreed to participate, 91% completed final follow-up). The DeCR group had significant improvements in most risk factors. Rehospitalization and mortality rates were similar between the DeCR group and both comparison groups at all time points (all p>0.05). Patients in the DeCR group spent significantly fewer days in hospital compared to usual care within 30-days (p=0.026), 90-days (p=0.003) and 12-months (p=0.04) post-discharge. Cardiac-related rehospitalization bed days were reduced at 30-days (p=0.005) and 90-days (p=0.017) but not 12-months (p=0.20). There were no group differences between DeCR and F2F-CR across any outcomes (all p>0.05). Conclusions DeCR was associated with lower healthcare utilization than usual care, yet comparable compared to F2F-CR. DeCR represents a suitable option for cardiac patients post discharge.

Importance Coronary artery calcium (CAC) scoring provides prognostic information, especially in patients at intermediate risk for coronary artery disease (CAD). However, the benefit of combining CAC score with a primary prevention strategy has not been tested in a randomized trial. Objective To assess whether combining the CAC score with a prevention strategy can be used to limit plaque progression in intermediate-risk patients with a family history of premature CAD. Design, Setting, and Participants Prospective, randomized, open-blinded end point clinical trial in 7 hospitals across Australia (between 2013 and 2020; the last date of follow-up was June 5, 2021). Asymptomatic people aged 40 to 70 years with a first-degree relative with CAD onset at younger than 60 years old or second-degree relative with onset at younger than 50 years old were recruited from the community. Interventions Intermediate-risk participants underwent CAC scoring. Those with a CAC score greater than 0 but less than 400 underwent coronary computed tomography angiography (CCTA) and were randomized to CAC score–informed prevention or usual care. Main Outcomes and Measures Follow-up CCTA was obtained at 3 years, with plaque volume measured by an independent core laboratory. The primary outcome was total plaque volume, with further analysis for calcified and noncalcified plaque volume. Results This study included 365 participants (mean [SD] age, 58 [6] years; 57.5% male); 179 in the CAC score–informed and 186 in the usual care groups. Compared with usual care, the CAC score–informed group showed a sustained reduction in total (mean [SD], −3 [31] mg/dL vs −56 [38] mg/dL; P < .001) and LDL (mean [SD], −2 [31] vs −51 [36] mg/dL; P < .001) cholesterol levels at 3 years, which was associated with a reduction in pooled cohort equation risk calculation (mean [SD], 2.1% [2.9%] vs 0.5% [2.9%]; P < .001). Plaque progression was greater in usual care than CAC score–informed participants for total plaque volume (mean [SD], 24.9 [37.7] mm ³ vs 15.4 [30.9] mm ³ ; P = .009), noncalcified plaque volume (mean [SD], 15.7 [32.2] mm ³ vs 5.6 [28.5] mm ³ ; P = .002), and fibrofatty and necrotic core plaque volume (mean [SD], 4.5 [25.8] mm ³ vs −0.8 [12.6] mm ³ ; P = .02). These plaque volume changes were independent of other risk factors including baseline plaque volume, blood pressure, and lipid profile. Conclusions and Relevance The combination of CAC score with a primary prevention strategy in intermediate-risk patients with a family history of CAD was associated with reduction of atherogenic lipids and slower plaque progression compared with usual care. These data support the use of CAC score to assist intensive preventive strategies in intermediate-risk patients. Trial Registration anzctr.org.au Identifier: ACTRN12614001294640