James L. Hare

Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab

BACKGROUND Trastuzumab prolongs survival in patients with human epidermal growth factor receptor type 2-positive breast cancer. Sequential left ventricular (LV) ejection fraction (EF) assessment has been mandated to detect myocardial dysfunction because of the risk of heart failure with this treatment. Myocardial deformation imaging is a sensitive means of detecting LV dysfunction, but this technique has not been evaluated in patients treated with trastuzumab. The aim of this study was to investigate whether changes in tissue deformation, assessed by myocardial strain and strain rate (SR), are able to identify LV dysfunction earlier than conventional echocardiographic measures in patients treated with trastuzumab. METHODS Sequential echocardiograms (n = 152) were performed in 35 female patients (51 +/- 8 years) undergoing trastuzumab therapy for human epidermal growth factor receptor type 2-positive breast cancer. Left ventricular EF was measured by 2- and 3-dimensional (2D and 3D) echocardiography, and myocardial deformation was assessed using tissue Doppler imaging and 2D-based (speckle-tracking) strain and SR. Change over time was compared every 3 months between baseline and 12 months. RESULTS There was no overall change in 3D-EF, 2D-EF, myocardial E-velocity, or strain. However, there were significant reductions seen in tissue Doppler imaging SR (P < .05), 2D-SR (P < .001), and 2D radial SR (P < .001). A drop > or =1 SD in 2D longitudinal SR was seen in 18 (51%) patients; 13 (37%) had a similar drop in radial SR. Of the 18 patients with reduced longitudinal SR, 3 had a concurrent reduction in EF > or =10%, and another 2 showed a reduction over 20 months follow-up. CONCLUSIONS Myocardial deformation identifies preclinical myocardial dysfunction earlier than conventional measures in women undergoing treatment with trastuzumab for breast cancer.

Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection

AIMS The variability of ejection fraction (EF) poses a problem in the assessment of left ventricular (LV) function in patients receiving potentially cardiotoxic chemotherapy. We sought to use global longitudinal strain (GLS) to compare LV responses to various cardiotoxic chemotherapy regimens and to examine the response to cardioprotection with beta-blockers (BB) in patients showing subclinical myocardial damage. METHODS AND RESULTS We studied 159 patients (49 ± 14 year, 127 women) receiving anthracycline (group A, n = 53, 46 ± 17 year), trastuzumab (group T, n = 61, 53 ± 12 year), or trastuzumab after anthracyclines (group AT, n = 45, 46 ± 9 year). LV indices [ejection fraction (EF), mitral annular systolic velocity, and GLS] were measured at baseline and follow-up (7 ± 7 months). Patients who decreased GLS by ≥11% were followed for another 6 months; initiation of BB was at the discretion of the clinician. Anthracycline dose was similar between group A and group AT (213 ± 118 vs. 216 ± 47 mg/m(2), P = 0.85). Although ΔEF was similar among the groups, attenuation of GLS was the greatest in group AT (group A, 0.7 ± 2.8% shortening; T, 1.1 ± 2.7%; and AT, 2.0 ± 2.3%; P = 0.003, after adjustment). Of 52 patients who decreased GLS by ≥-11%, 24 were treated with BB and 28 were not. GLS improved in BB groups (from -17.6 ± 2.3 to -19.8 ± 2.6%, P < 0.001) but not in non-BB groups (from -18.0 ± 2.0 to -19.0 ± 3.0%, P = 0.08). Effects of BB were similar with all regimens. CONCLUSIONS GLS is an effective parameter for identifying systolic dysfunction (which appears worst with combined anthracycline and trastuzumab therapy) and responds to cardioprotection in patients administered beta-blockers.

Diffuse myocardial fibrosis in hypertrophic cardiomyopathy can be identified by cardiovascular magnetic resonance, and is associated with left ventricular diastolic dysfunction

BackgroundThe presence of myocardial fibrosis is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) sequences can detect regional, but not diffuse myocardial fibrosis. Post-contrast T1 mapping is an emerging CMR technique that may enable the non-invasive evaluation of diffuse myocardial fibrosis in HCM. The purpose of this study was to non-invasively detect and quantify diffuse myocardial fibrosis in HCM with CMR and examine its relationship to diastolic performance.MethodsWe performed CMR on 76 patients - 51 with asymmetric septal hypertrophy due to HCM and 25 healthy controls. Left ventricular (LV) morphology, function and distribution of regional myocardial fibrosis were evaluated with cine imaging and LGE. A CMR T1 mapping sequence determined the post-contrast myocardial T1 time as an index of diffuse myocardial fibrosis. Diastolic function was assessed by transthoracic echocardiography.ResultsRegional myocardial fibrosis was observed in 84% of the HCM group. Post-contrast myocardial T1 time was significantly shorter in patients with HCM compared to controls, consistent with diffuse myocardial fibrosis (498 ± 80 ms vs. 561 ± 47 ms, p < 0.001). In HCM patients, post-contrast myocardial T1 time correlated with mean E/e’ (r = −0.48, p < 0.001).ConclusionsPatients with HCM have shorter post-contrast myocardial T1 times, consistent with diffuse myocardial fibrosis, which correlate with estimated LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic function in HCM.

Histological validation of cardiac magnetic resonance analysis of regional and diffuse interstitial myocardial fibrosis

AIM Myocardial fibrosis is fundamental in the pathogenesis of heart failure. Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging is commonly assumed to represent myocardial fibrosis; however, comparative human histological data are limited, especially in non-ischaemic cardiac disease. Diffuse interstitial myocardial fibrosis is increasingly recognized as central in the pathogenesis of cardiomyopathy and can be quantified using newer CMR techniques such as T1 mapping. We evaluated the relationship of CMR assessment of regional and diffuse fibrosis with human histology. METHODS AND RESULTS Eleven patients on the waiting list for heart transplantation (43.5 ± 7.6 years, 64% male) and eight patients undergoing surgical myectomy for obstructive hypertrophic cardiomyopathy (57.1 ± 8.6 years, 63% male) were recruited and underwent CMR prior to cardiac transplantation or myectomy. Quantification of fibrosis in explanted hearts using digitally analysed Masson-trichrome-stained slides was validated against picrosirius red-stained slides analysed using Image J, with an excellent correlation (R = 0.95, P < 0.0001). Significant correlations were observed between LGE and histological fibrosis across a range of signal intensity thresholds in the explanted hearts (range: 2-10 standard deviations above reference myocardium), with maximal accuracy at a threshold of 6 SD (R = 0.91, P < 0.001). Assessment of interstitial myocardial fibrosis with post-contrast T1 times demonstrated a significant correlation on both segmental (R = -0.64, P = 0.002) and per-patient (R = -0.78, P = 0.003) analyses. CONCLUSION CMR provides accurate, non-invasive assessment of regional myocardial fibrosis using LGE, while diffuse interstitial myocardial fibrosis is accurately assessed with post-contrast T1 mapping.

Feasibility and clinical decision-making with 3D echocardiography in routine practice

Objective: To assess the feasibility and potential impact of routine three-dimensional (3D) echocardiographic assessment of left ventricular (LV) ejection fraction and volumes on clinical decision-making. Methods: Patients referred to three hospital-based echocardiography laboratories underwent 2D echocardiography (2DE) and 3D echocardiography (3DE). Feasibility was assessed in a group of 168 unselected patients and decision-making assessed within an expanded group of 220 patients. The time for acquisition and measurement was obtained. Feasibility was defined by ability to measure LV parameters. The potential of 3DE to alter clinical decisions based on 2DE was evaluated by the ability to identify four clinically relevant measurement thresholds: (1) LV end-systolic volume (LVESV) >50 ml/m2 (indication for surgery in regurgitant valve disease); (2) LVESV >30 ml/m2 (prognosis after infarction); (3) LV ejection fraction (LVEF) <35% (indication for implantable defibrillator); and (4) LVEF <40% (indication for heart failure treatment). Results: 3DE was technically feasible in 83% of unselected patients. The additional time for 3D acquisition and measurement was available in 184 patients and was 5.4 (SD 2.0) minutes. The use of 3DE changed categorisation in between 6–11% of patients. Within threshold categories, 3D reallocated 17.5% (11/63) of patients with LVEF <35%, 16.1% (13/81) for LVEF <40%, 12.4% (13/105) for LVESV >30 ml/m2 and 8.5% (5/59) for LVESV >50 ml/m2. Most of the impact of 3D was within 10 ml/m2 of selected volume thresholds (⩾75%) and 10% of EF thresholds (>80%). Conclusion: Measurement of LV volumes and EF by 3DE is clinically feasible and has the potential to significantly alter clinical decision-making.

Association of masked hypertension and left ventricular remodeling with the hypertensive response to exercise

BACKGROUND A hypertensive response to exercise (HRE; defined as normal clinic blood pressure (BP) and exercise systolic BP (SBP) ≥210 mm Hg in men or ≥190 mm Hg in women, or diastolic BP (DBP) ≥105 mm Hg) independently predicts mortality. The mechanisms remain unclear but may be related to masked hypertension. This study aimed to assess the prevalence of masked hypertension and its association with cardiovascular risk factors, including left ventricular (LV) mass, in patients with a HRE. METHODS Comprehensive clinical and echocardiographic evaluation (including central BP, aortic pulse wave velocity by tonometry) and 24-h ambulatory BP monitoring (ABPM) were performed in 72 untreated patients with HRE (aged 54 ± 9 years; 60% male; free from coronary artery disease confirmed by exercise stress echocardiography). Masked hypertension was defined according to guidelines as daytime ABPM ≥135/85 mm Hg and clinic BP <140/90 mm Hg. RESULTS Masked hypertension was present in 42 patients (58%). These patients had higher LV mass index (41.5 ± 8.7 g/m(2.7) vs. 35.9 ± 8.5 g/m(2.7); P = 0.01), LV relative wall thickness (RWT; 0.42 ± 0.09 vs. 0.37 ± 0.06; P = 0.004) and exercise SBP (222 ± 17 mm Hg vs. 212 ± 14 mm Hg; P = 0.01), but no significant difference in aortic pulse wave velocity or central pulse pressure (P > 0.05 for both). The strongest independent determinant of LV mass index was the presence of masked hypertension (unstandardized β = 5.6; P = 0.007), which was also independently related to LV RWT (unstandardized β = 0.04; P = 0.03). CONCLUSIONS Masked hypertension is highly prevalent in HRE patients with a normal resting office BP and is associated with increased LV mass index and RWT. Clinicians should consider measuring ABPM or home BP in HRE patients.

A comprehensive evaluation of myocardial fibrosis in hypertrophic cardiomyopathy with cardiac magnetic resonance imaging: linking genotype with fibrotic phenotype

AIMS In hypertrophic cardiomyopathy (HCM), attempts to associate genotype with phenotype have largely been unsuccessful. More recently, cardiac magnetic resonance (CMR) imaging has enhanced myocardial fibrosis characterization, while next-generation sequencing (NGS) can identify pathogenic HCM mutations. We used CMR and NGS to explore the link between genotype and fibrotic phenotype in HCM. METHODS AND RESULTS One hundred and thirty-nine patients with HCM and 25 healthy controls underwent CMR to quantify regional myocardial fibrosis with late gadolinium enhancement (LGE) and diffuse myocardial fibrosis with post-contrast T1 mapping. Collagen content of myectomy specimens from nine HCM patients was determined. Fifty-six HCM patients underwent NGS for 65 cardiomyopathy genes, including 36 HCM-associated genes. Post-contrast myocardial T1 time correlated histologically with myocardial collagen content (r = -0.70, P = 0.03). Compared with controls, HCM patients had more LGE (4.6 ± 6.1 vs. 0%, P < 0.001) and lower post-contrast T1 time (483 ± 83 vs. 545 ± 49 ms, P < 0.001). LGE negatively correlated with left-ventricular (LV) ejection fraction and outflow tract obstruction, whereas lower post-contrast T1 time, suggestive of more diffuse myocardial fibrosis, was associated with LV diastolic impairment and dyspnoea. Patients with identifiable HCM mutations had more LGE (7.9 ± 8.6 vs. 3.1 ± 4.3%, P = 0.03), but higher post-contrast T1 time (498 ± 81 vs. 451 ± 70 ms, P = 0.03) than patients without. CONCLUSION In HCM, contrast-enhanced CMR with T1 mapping can non-invasively evaluate regional and diffuse patterns of myocardial fibrosis. These patterns of fibrosis occur independently of each other and exhibit distinct clinical associations. HCM patients with recognized genetic mutations have significantly more regional, but less diffuse myocardial fibrosis than those without.

Association of Myocardial Strain With Left Ventricular Geometry and Progression of Hypertensive Heart Disease

Different patterns of abnormal left ventricular (LV) geometry are associated with variations in prognosis, but the mechanisms of these effects remain undefined. We investigated the association of myocardial deformation with these findings and their evolution. Two-dimensional echocardiography was performed in 85 hypertensive patients referred for serial evaluation (age 58 +/- 13 years, 48% male). LV mass index and regional wall thickness were used to assign patients into groups with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Septal strain and strain rate were measured using velocity vector imaging. The evolution of morphological changes was followed over 2.7 +/- 1.3 years. Analysis of LV geometry revealed normal geometry in 13 patients (15%), concentric remodeling in 20 (24%), concentric hypertrophy in 42 (49%), and eccentric hypertrophy in 10 (12%). Overall strain was -13.6 +/- 4.5%, and strain rate was -0.65 +/- 0.24/second. Strain was significantly lower in patients with concentric remodeling (-12.8 +/- 4.2%) or concentric hypertrophy (-12.5 +/- 4.1%) compared with patients with normal geometry (-17.5 +/- 5.5%, p < or =0.05), and these associations were independent of blood pressure. Strain rate was also significantly reduced in patients with concentric hypertrophy (p < or =0.01). There were no significant differences in baseline strain, wall stress, blood pressure, or age between patients who changed LV geometric class and those who did not. In conclusion, baseline myocardial tissue deformation, but not evolution, is associated with LV geometry in treated hypertensive patients.

Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus

Objective New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. Methods In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (≥50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. Results On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4±2.6 years (range 0.6–9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37%; normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10; p=0.04), as was systolic blood pressure (HR=1.02; p<0.001) and levels of glycosylated haemoglobin (HR=1.28; p=0.011). Patients with LVD had significantly worse outcome than those without (χ2=4.73; p=0.030). Conclusions Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. Trial registration number Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831).

Masked hypertension is "unmasked" by low-intensity exercise blood pressure.

Abstract Purpose: Masked hypertension (MH) independently predicts mortality but cannot be diagnosed from clinic blood pressure (BP) taken under resting conditions. We sought to determine if MH could be identified from BP taken during a single bout of low-intensity exercise. Methods. BP was recorded at rest and during brief low-level cycling exercise (60–70% of age-predicted maximal heart rate) in 75 untreated subjects with a hypertensive response to exercise (aged 54 ± 9 years). All subjects underwent 24-h ambulatory BP monitoring (ABPM) and MH was defined as clinic BP < 140/90 mmHg and ABPM BP ≥ 130/80 mmHg. Results. There were 42 (56%) patients with MH, and at rest systolic (SBP) was higher in subjects with MH compared with those without MH (127 ± 9 vs 120 ± 9 mmHg; p < 0.05). During exercise, MH subjects had significantly higher SBP (188 ± 22 vs 168 ± 15 mmHg; p < 0.05), with a greater change from baseline (61 ± 21 vs 48 ± 15 mmHg; p < 0.05). Low-level exercise SBP was independently associated with MH, and if ≥175 mmHg, identified MH with 74% sensitivity and 67% specificity (p < 0.001). Conclusion. MH can be identified in untreated individuals from low-intensity exercise SBP. Further research on the diagnostic value of BP during early phases of exercise stress testing is needed.