Chia-Ying Liu

Effective arterial elastance as index of arterial vascular load in humans.

BackgroundThis study tested whether the simple ratio of ventricular end-systolic pressure to stroke volume, known as the effective arterial elastance (Ea), provides a valid measure of arterial load in humans with normal and aged hypertensive vasculatures. Methods and ResultsVentricular pressure-volume and invasive aortic pressure and flow were simultaneously determined in 10 subjects (four young normotensive and six older hypertensive). Measurements were obtained at rest, during mechanically reduced preload, and after pharmacological interventions. Two measures of arterial load were compared: One was derived from aortic input impedance and arterial compliance data using an algebraic expression based on a three-element Windkessel model of the arterial system [Ea(Z)I, and the other was more simply measured as the ratio of ventricular end-systolic pressure to stroke volume [Ea(PV)]. Although derived from completely different data sources and despite the simplifying assumptions of Ea(PV), both Ea(Z) and Ea(PV) were virtually identical over a broad range of altered conditions: Ea(PV) = 0.97 · Ea(Z) +0.17; n = 33, r2 = 0.98, SEE = 0.09, p < 0.0001. Whereas Ea(PV) also correlated with mean arterial resistance, it exceeded resistance by as much as 25% in older hypertensive subjects (because of reduced compliance and wave reflections), which better indexed the arterial load effects on the ventricle. Simple methods to estimate Ea (PV) from routine arterial pressures were tested and validated. ConclusionsEa(PV) provides a convenient, useful method to assess arterial load and its impact on the human ventricle. These results highlight effects of increased pulsatile load caused by aging or hypertension on the pressure-volume loop and indicate that this load and its effects on cardiac performance are often underestimated by mean arterial resistance but are better accounted for by Ea.

Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants.

BackgroundExperimental studies indicate that in addition to diastolic dysfunction, hypertrophied myocardium can display depressed contractile responses, particularly at rapid heart rates, compounding reserve limitations. This study tests whether such abnormalities exist in intact human subjects at physiological paced rates and, if so, whether they are linked to simultaneous rate-dependent deterioration in diastolic function. Methods and ResultsTen subjects with left ventricular hypertrophy (LVH) and 8 normal control subjects were studied. Most LVH patients presented with dyspnea and/or pulmonary edema and had concentric hypertrophy. Since rapid pacing simultaneously alters cardiac filling volumes and pressures, pressurevolume relation analysis was used to better define changes in contractile response. Patients were instrumented with a conductance catheter and micromanometer for pressure-volume data recording and a balloon occluder at the right atrial-inferior vena caval junction to vary filling and thus generate function relations. Data were obtained at baseline and at three atrial pacing rates (100, 120, 150 min-1). In addition, single-beat force-interval data were used to indirectly examine calcium cycling kinetics. LVH subjects demonstrated baseline diastolic abnormalities, including prolonged relaxation, elevated end-diastolic pressure, and reduced chamber compliance. However, systolic function was similar to that in control subjects. With rapid pacing, normal subjects displayed a positive contractile response, whereas this was markedly diminished in LVH subjects. With abrupt termination of pacing and return to slower sinus rhythm, LVH subjects displayed greater initial potentiation followed by a more rapid decline than control subjects, suggesting abnormalities of calcium handling. Despite contractile abnormalities, diastolic function did not further deteriorate with rapid pacing and thus did not appear to be tightly linked to the systolic changes ConclusionsPacing stress in intact human LVII can result in systolic impairment superimposed on preexisting but not worsened diastolic dysfunction. Abnormal calcium handling probably contributes prominently to this response.

Reduced left ventricular compliance in human mitral stenosis. Role of reversible internal constraint.

Background The mechanisms of depressed left ventricular (LV) pump performance in human mitral stenosis (MS) remain poorly understood, because reduced filling alone affects many hemodynamic measurements. Therefore, pressure-volume relations were examined in nine subjects with MS and compared with eight age-matched normal controls. Methods and Results Data were obtained by conductance catheter/micromanometer technique with transient inferior vena cava occlusion used to alter load and generate pressure-volume relations. In a subset of patients (n > =5), data were obtained both acutely and at 3 months (n = 4) after balloon valvuloplasty. MS patients had reduced cardiac output (3.3±0.9 versus 5.6±1.7 I/min) and end-diastolic volume (68.0±6.9 versus 115±31 ml) versus controls (p < 0.001), with a mean transvalvular gradient of 14±6 mm Hg and estimated valve area of 0.6±0.2 cm2. Systolic function as assessed by the end-systolic pressure-volume relation was virtually the same in MS and control subjects. In contrast, end-diastolic pressure-volume relations in MS were consistently shifted leftward and had an increased slope (lower compliance) at matched pressure ranges (6.5±3.0 versus 2.2±0.53 ml/mm Hg at a mean diastolic pressure of 8 mm Hg, p < 0.001). This change was not a result of reduced LV filling or probably of increased right heart loading. Valvuloplasty acutely returned chamber compliance to near normal, a change that was sustained at 3-month follow-up. Systolic function was little altered at this time. Conclusions These data indicate an impairment of diastolic function in human MS that can be acutely reversed by balloon valvuloplasty. Lowered LV compliance probably results from a functional restriction caused by ventricular attachment to a thickened and immobile valve apparatus.

Myocardial Structure, Function, and Scar in Patients With Type 1 Diabetes Mellitus

Background— We report relationships between cardiovascular disease risk factors and myocardial structure, function, and scar in patients with type 1 diabetes mellitus in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods and Results— Cardiac magnetic resonance was obtained in 1017 patients with type 1 diabetes mellitus. Gadolinium cardiac magnetic resonance was also obtained in 741 patients. The mean age was 49±7 years; 52% were men; and mean duration of diabetes mellitus was 28±5 years. Associations of cardiovascular disease risk factors with cardiac magnetic resonance parameters were examined with linear and logistic regression models. History of macroalbuminuria was positively associated with left ventricular mass (by 14.8 g), leading to a significantly higher ratio of left ventricular mass to end-diastolic volume (by 8%). Mean hemoglobin A1c levels over the preceding 22 years were inversely associated with end-diastolic volume (−3.0 mL per unit mean hemoglobin A1c percent) and stroke volume (−2.3 mL per unit mean hemoglobin A1c percent) and positively related to the ratio of elevated left ventricular mass to end-diastolic volume (0.02 g/mL per unit). The overall prevalence of myocardial scar was 4.3% by cardiac magnetic resonance and 1.4% by clinical adjudication of myocardial infarction. Both mean hemoglobin A1c (odds ratio, 1.5 [95% confidence interval, 1.0–2.2] per unit) and macroalbuminuria (odds ratio, 3.5 [95% confidence interval, 1.2–9.9]) were significantly associated with myocardial scar and traditional cardiovascular disease risk factors. Conclusions— In addition to traditional cardiovascular disease risk factors, elevated mean hemoglobin A1c and macroalbuminuria were significantly associated with alterations in left ventricular structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00360893 and NCT00360815.

Original ResearchCOPDImpaired Left Ventricular Filling in COPD and Emphysema: Is It the Heart or the Lungs?: The Multi-Ethnic Study of Atherosclerosis COPD Study

BACKGROUND COPD and heart failure with preserved ejection fraction overlap clinically, and impaired left ventricular (LV) filling is commonly reported in COPD. The mechanism underlying these observations is uncertain, but may include upstream pulmonary dysfunction causing low LV preload or intrinsic LV dysfunction causing high LV preload. The objective of this study is to determine if COPD and emphysema are associated with reduced pulmonary vein dimensions suggestive of low LV preload. METHODS The population-based Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50 to 79 years who were free of clinical cardiovascular disease. COPD was defined by spirometry. Percent emphysema was defined as regions < -910 Hounsfield units on full-lung CT scan. Ostial pulmonary vein cross-sectional area was measured by contrast-enhanced cardiac magnetic resonance and expressed as the sum of all pulmonary vein areas. Linear regression was used to adjust for age, sex, race/ethnicity, body size, and smoking. RESULTS Among 165 participants, the mean (± SD) total pulmonary vein area was 558 ± 159 mm2 in patients with COPD and 623 ± 145 mm2 in control subjects. Total pulmonary vein area was smaller in patients with COPD (-57 mm2; 95% CI, -106 to -7 mm2; P = .03) and inversely associated with percent emphysema (P < .001) in fully adjusted models. Significant decrements in total pulmonary vein area were observed among participants with COPD alone, COPD with emphysema on CT scan, and emphysema without spirometrically defined COPD. CONCLUSIONS Pulmonary vein dimensions were reduced in COPD and emphysema. These findings support a mechanism of upstream pulmonary causes of underfilling of the LV in COPD and in patients with emphysema on CT scan.

Anthracycline-Associated T1 Mapping Characteristics Are Elevated Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors.

Background—Cardiovascular magnetic resonance T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. Methods and Results—We performed blinded cardiovascular magnetic resonance analyses of left ventricular T1 and extracellular volume (ECV) fraction in 327 individuals (65% women, aged 64±12 years). Thirty-seven individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors who received either anthracycline-based (n=37) or nonanthracycline-based (n=17) chemotherapy 2.8±1.3 years earlier were compared with 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058±7 ms) and post- (1040±7 ms) receipt of anthracycline chemotherapy versus comparators (965±3 ms; P<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4±0.7%) compared with either pretreatment cancer (27.8±0.7%; P<0.01) or cancer-free comparators (26.9±0.2%; P<0.0001). T1 and ECV of nonanthracycline survivors were no different than pretreatment survivors (P=0.17 and P=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and left ventricular ejection fraction or myocardial mass index (P<0.0001 for all). Conclusions—Three years after anthracycline-based chemotherapy, elevations in myocardial T1 and ECV occur independent of underlying cancer or cardiovascular comorbidities, suggesting that imaging biomarkers of interstitial fibrosis in cancer survivors are related to prior receipt of a potentially cardiotoxic cancer treatment regimen.

Pulmonary Hyperinflation and Left Ventricular Mass

Background— Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2–12; P =0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3–11; P <0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume ( P =0.02) and with hyperinflation measured as residual volume to total lung capacity ratio ( P =0.009). Conclusions— Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass. # Clinical Perspective {#article-title-62}Background— Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2–12; P=0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3–11; P<0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume (P=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009). Conclusions— Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.

Prevalence of Cancer at Baseline Screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort

Importance Establishment of an optimal cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with Li-Fraumeni syndrome, a rare, highly penetrant cancer predisposition syndrome. Objective To determine the feasibility and efficacy of a comprehensive cancer screening regimen in Li-Fraumeni syndrome, using multiple radiologic techniques, including rapid whole-body magnetic resonance imaging (MRI) and laboratory measurements. Design, Setting, and Participants Baseline evaluation of a prospective cancer screening study was conducted from June 1, 2012, to July 30, 2016, at the National Cancer Institute, National Institutes of Health (an academic research facility). Participants included 116 individuals with Li-Fraumeni syndrome with a germline TP53 pathogenic variant who were aged 3 years or older at the time of baseline screening and had not received active cancer therapy at least 6 months prior to screening. Main Outcomes and Measures Detection of prevalent cancer with multimodal screening techniques and the need for additional evaluation. Results Of the 116 study participants, 77 (66.4%) were female; median age was 37.6 years (range, 3-68 years). Baseline cancer screening led to the diagnosis of cancer in 8 (6.9%) individuals (2 lung adenocarcinomas, 1 osteosarcoma, 1 sarcoma, 1 astrocytoma, 1 low-grade glioma, and 2 preinvasive breast cancers [ductal carcinoma in situ]); all but 1 required only resection for definitive treatment. A total of 40 (34.5%) participants required additional studies to further investigate abnormalities identified on screening, with 32 having incidental, benign, or normal findings, resulting in a false-positive rate of 29.6%. Non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer in our cohort. Conclusions and Relevance This study describes the establishment and feasibility of an intensive cancer surveillance protocol for individuals with Li-Fraumeni syndrome. Prevalent cancers were detected at an early stage with baseline whole-body, brain, and breast MRI. Prospective screening of the participants is under way.

Interstitial Fibrosis, Left Ventricular Remodeling and Myocardial Mechanical Behavior in a Population-Based Multi-ethnic Cohort: MESA Study

Background—Tagged cardiac magnetic resonance provides detailed information on regional myocardial function and mechanical behavior. T1 mapping by cardiac magnetic resonance allows noninvasive quantification of myocardial extracellular expansion (ECE), which has been related to interstitial fibrosis in previous clinical and subclinical studies. We assessed sex-associated differences in the relation of ECE to left ventricular (LV) remodeling and myocardial systolic and diastolic deformation in a large community-based multiethnic population. Methods and Results—Midventricular midwall peak circumferential shortening and early diastolic strain rate and LV torsion and torsional recoil rate were determined using cardiac magnetic resonance tagging. Midventricular short-axis T1 maps were acquired in the same examination pre- and postcontrast injection using Modified Look-Locker Inversion-Recovery sequence. Multivariable linear regression (estimated regression coefficient, B) was used to adjust for risk factors and subclinical disease measures. Of 1230 participants, 114 had a visible myocardial scar by late gadolinium enhancement. Participants without a visible myocardial scar (n=1116) had no history of previous clinical events. In the latter group, multivariable linear regression demonstrated that lower postcontrast T1 times, reflecting greater ECE, were associated with lower circumferential shortening (B=−0.1; P=0.0001), lower LV end-diastolic volume index (B=0.6; P=0.0001), and lower LV end-diastolic mass index (B=0.4; P=0.0001). In addition, lower postcontrast T1 times were associated with lower early diastolic strain rate (B=0.01; P=0.03) in women only and lower LV torsion (B=0.005; P=0.03) and lower LV ejection fraction (B=0.2, P=0.01) in men only. Conclusions—Greater ECE is associated with reduced LV end-diastolic volume index and LV end-diastolic mass index in a large multiethnic population without history of previous cardiovascular events. In addition, greater ECE is associated with reduced circumferential shortening, lower early diastolic strain rate, and a preserved ejection fraction in women, whereas in men, greater ECE is associated with greater LV dysfunction manifested as reduced circumferential shortening, reduced LV torsion, and reduced ejection fraction.

Chronic Obstructive Pulmonary Disease (COPD) is associated with pulmonary artery stiffness - the MESA COPD study

Background This study seeks to evaluate indices of pulmonary artery (PA) stiffness in patients with COPD and compare with normal controls. We hypothesize that patients with COPD would have increased pulmonary artery stiffness. To test this we determine the pulmonary artery area change (distensibility in %) by cardiac MRI and relate the distensibility to a wide range of severity of COPD. Methods The MESA COPD Study recruited 290 patients (135 patients of various COPD severity and 155 controls) from four field centers in the US, age 50-79 years with ≥10 pack-years of smoking, all free of clinical cardiovascular disease. COPD was defined on post-bronchodilator spirometry by GOLD criteria (FEV1/FVC 80% = mild, 50-80%=moderate, <50%=severe). All participants underwent full-lung CTs. Percent emphysema was defined as the percentage of total voxels within the lung field that fell below -910 Hounsfield units. MRI studies were performed using 1.5T scanners. To measure ventricular function, the entire heart was imaged in short-axis orientation using a retrospectively gated steady-state free precession sequence. Phase-contrast images of the pulmonary arteries were obtained using a segmented fast gradient echo sequence with free breathing and analyzed quantitatively using dedicated software (FLOW, Medis). Distensibility of the pulmonary vessels (in %) are measured by the following formula, 100×(maximum PA area-minimum PA area)/minimum PA area. The base model (model 1) was adjusted for age, gender, height, weight, race/ethnicity and cohort of selection, given relationships of COPD severity to the pulmonary distensibility. We then additionally adjusted for smoking status, pack-years, diabetes mellitus, hypertension, oxygen saturation, LDL, HDL and statin use (model 2).