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Thomas H Marwick

Publications and source records attributed to Thomas H Marwick.

At least 37 records · Page 2Linked to original sources
PubMed2006

Population-based detection of systolic and diastolic dysfunction with amino-terminal pro-B-type natriuretic peptide.

BACKGROUND: There is limited information regarding the clinical utility of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) for the detection of left ventricular (LV) dysfunction in the community. We evaluated predictors of circulating NT-proBNP levels and determined the utility of NT-proBNP to detect systolic and diastolic LV dysfunction in older adults. METHODS: A population-based sample of 1229 older adults (mean age 69.4 years, 50.1% women) underwent echocardiographic assessment of cardiac structure and function and measurement of circulating NT-proBNP levels. RESULTS: Predictors of NT-proBNP included age, female sex, body mass index, and cardiorenal parameters (diastolic dysfunction [DD] severity; LV mass and left atrial volume; right ventricular overload; decreasing ejection fraction [EF] and creatinine clearance). The performance of NT-proBNP to detect any degree of LV dysfunction, including mild DD, was poor (area under the curve 0.56-0.66). In contrast, the performance of NT-proBNP for the detection of EF < or = 40% and moderate-severe DD was strong with area under the curve of > 0.90 regardless of age and sex; history of hypertension, diabetes, coronary artery disease; or body mass category. The ability of NT-proBNP to detect EF < or = 40% and/or moderate-severe DD was optimized by using age/sex-specific limits. Of "false-positive" tests, 88% (124/141) were explained after considering cardiorenal determinants of NT-proBNP levels. CONCLUSIONS: Amino-terminal pro-B-type natriuretic peptide is a suboptimal marker of mild LV dysfunction, but performs strongly as a marker of EF < or = 40% and/or moderate-severe DD in the community. Most subjects with a positive NT-proBNP test, using age/sex-specific cutoffs, had prognostically significant abnormalities of cardiac structure or function.

Aged↗
PubMed2006

What is the optimal clinical technique for measurement of left ventricular volume after myocardial infarction? A comparative study of 3-dimensional echocardiography, single photon emission computed tomography, and cardiac magnetic resonance imaging.

BACKGROUND: Left ventricular (LV) volumes have important prognostic implications, but are commonly underestimated. We sought accuracy and reproducibility of LV volume measurement by live 3-dimensional (3D) echocardiography (3DE) and TI-201 single photon emission computed tomography (SPECT), compared with cardiac magnetic resonance imaging (MRI). METHODS: In all, 30 patients (age 62 +/- 9 years, 23 men) underwent LV volume assessment with 3DE, SPECT, and cardiac MRI after myocardial infarction. LV volumes were measured using a semiautomated border detection algorithm for 3DE, gated SPECT software for SPECT, and a 3D display for MRI. Results of 3DE and SPECT volumes were compared with MRI as the standard of reference. RESULTS: The 3DE volumes showed excellent correlation with cardiac MRI (end-diastolic volume [EDV], r = 0.90, P = .001; end-systolic volume [ESV], r = 0.94, P = .001), as did SPECT (EDV, r = 0.89, P = .001; ESV, r = 0.95, P = .001). However, both 3DE and SPECT underestimated LV volumes. The mean MRI EDV was 179 +/- 56 mL compared with 3DE (mean difference, -10 +/- 26 mL, P = .04) and SPECT (mean difference, -58 +/- 28 mL, P < .001). There was a significant difference between SPECT EDV and 3DE (mean difference, -48 +/- 31 mL, P < .001). The mean MRI ESV was 96 +/- 54 mL and this was underestimated by SPECT (mean difference, -22 +/- 19 mL, P < .001), but not by 3DE (mean difference, -0.9 +/- 19 mL, P = not significant). ESV was also underestimated when SPECT was compared with 3DE (mean difference, -22 +/- 27 mL, P < .001). The results of 3DE were reproducible with excellent intraobserver (ESV, r = 0.98, -2 +/- 6 mL; EDV, r = 0.98, -1 +/- 6 mL, P = .001) and interobserver (ESV, r = 0.97, -2 +/- 6 mL; EDV, r = 0.95, -3 +/- 10 mL, P = .001) correlation. CONCLUSION: We have shown that 3DE is accurate and reproducible for the measurement of LV volumes for risk assessment in chronic ischemic heart disease and dilated cardiomyopathy. Furthermore, 3DE is more accurate than TI-201 SPECT with less underestimation of LV volumes.

Female↗
PubMed2006

Accuracy and feasibility of online 3-dimensional echocardiography for measurement of left ventricular parameters.

BACKGROUND: The availability of automated online software may increase the feasibility of real-time 3-dimensional (3D) echocardiography (3DE) for left ventricular (LV) volume calculation in clinical practice. We sought to compare offline and online approaches with magnetic resonance imaging (MRI). METHODS: Patients who presented to the clinical laboratory for evaluation of LV parameters (n = 110, 94 men, age 63 +/- 10 years) were studied with 2-dimensional echocardiography, online and offline 3DE, and MRI. The 3DE measurements were obtained by a semiautomated LV border detection based on tracing (online) and edge detection (offline). MRI images were obtained using true free induction steady-state precession during breath hold, with measurement of 3D volumes and ejection fraction (EF). RESULTS: All echocardiographic techniques underestimated LV volumes, but EF estimations were similar. The best correlation was between MRI versus offline 3DE. The correlation of online 3DE with MRI was significantly better than 2-dimensional echocardiography (end-diastolic volume (EDV) z = 4.2, end-systolic volume (ESV) z = 4.44, EF z = 4.32; all P < .01). However, correlation of offline 3DE with MRI was significantly better than online 3DE (EDV z = 2.57, P < .05; ESV z = 2.42, P < .05; EF z = 3.82, P < .01). Images were considered to be good quality (endocardium visualized in all walls) in 49 patients; discrepancies between online and offline 3DE and MRI were similar in good- and poor-quality images. Wall-motion abnormalities were present in 98 patients; discrepancies with MRI were similar in patients with and without abnormal wall motion. CONCLUSIONS: Online measurement of LV volumes is feasible and more accurate than with 2-dimensional echocardiography. Although the offline approach is more accurate, it is also more time-consuming.

Computer Systems↗
PubMed2006

Cardiac contributions to exercise training responses in patients with chronic heart failure: a strain imaging study.

The improvement of exercise capacity due to exercise training in heart failure has been associated with peripheral adaptation, but the contribution of cardiac responses is less clear. We sought the extent to which the improvement of functional capacity in patients undergoing exercise training for heart failure was related to myocardial performance. Thirty-seven patients (35 men, age 64 +/- 11) with symptomatic heart failure and left ventricular ejection fraction < or = 35% (29 +/- 9%) were studied during a 16-week exercise training program. LV function was assessed by resting and exercise 2D-echocardiography, tissue Doppler derived myocardial strain, and strain rate. Peak oxygen consumption (VO2) and LV function were measured at baseline and follow-up, and the contribution of LV function at baseline and its response to training to the change of each parameter was sought. Baseline peak VO2 (12.4 +/- 4.6) increased by 9% at 8 weeks (13.5 +/- 4.2, P = 0.26), and by 21% at 16 weeks (15.0 +/- 4.9, P < 0.001). Although there were no overall changes in myocardial parameters in this study, change in peak VO2 at 16 weeks was significantly correlated with baseline strain (r = 0.51, P = 0.003) and the improvement of strain at 8 weeks (r = 0.44, P = 0.01), independent of baseline functional capacity and clinical variables. Thus, change in peak VO2 following 16 weeks exercise training is related to myocardial function at baseline.

Aged↗
PubMed2005

Incremental value of strain rate analysis as an adjunct to wall-motion scoring for assessment of myocardial viability by dobutamine echocardiography: a follow-up study after revascularization.

BACKGROUND: Assessment of myocardial viability based on wall-motion scoring (WMS) during dobutamine echocardiography (DbE) is difficult and subjective. Strain-rate imaging (SRI) is quantitative, but its incremental value over WMS for prediction of functional recovery after revascularization is unclear. METHODS AND RESULTS: DbE and SRI were performed in 55 stable patients (mean age, 64+/-10 years; mean ejection fraction, 36+/-8%) with previous myocardial infarction. Viability was predicted by WMS if function augmented during low-dose DbE. SR, end-systolic strain (ESS), postsystolic strain (PSS), and timing parameters were analyzed at rest and with low-dose DbE in abnormal segments. Regional and global functional recovery was defined by side-by-side comparison of echocardiographic images before and 9 months after revascularization. Of 369 segments with abnormal resting function, 146 showed regional recovery. Compared with segments showing functional recovery, those that failed to recover had lower low-dose DbE SR, SR increment (DeltaSR), ESS, and ESS increment (DeltaESS) (each P<0.005). After optimal cutoffs for the strain parameters were defined, the sensitivity of low-dose DbE SR (78%, P=0.3), DeltaSR (80%, P=0.1), ESS (75%, P=0.6), and DeltaESS (74%, P=0.8) was better though not significantly different from WMS (73%). The specificity of WMS (77%) was similar to the SRI parameters. Combination of WMS and SRI parameters augmented the sensitivity for prediction of functional recovery above WMS alone (82% versus 73%, P=0.015; area under the curve=0.88 versus 0.73, P<0.001), although specificities were comparable (80% versus 77%, P=0.2). CONCLUSIONS: The measurement of low-dose DbE SR and DeltaSR is feasible, and their combination with WMS assessment improves the sensitivity of viability assessment with DbE.

Aged↗
PubMed2005

Myocardial and vascular dysfunction and exercise capacity in the metabolic syndrome.

The metabolic syndrome (MS) is associated with cardiovascular risk exceeding that expected from atherosclerotic risk factors, but the mechanism of this association is unclear. We sought to determine the effects of the MS on myocardial and vascular function and cardiorespiratory fitness in 393 subjects with significant risk factors but no cardiovascular disease and negative stress echocardiographic findings. Myocardial function was assessed by global strain rate, strain, and regional systolic velocity (s(m)) and diastolic velocity (e(m)) using tissue Doppler imaging. Arterial compliance was assessed using the pulse pressure method, involving simultaneous radial applanation tonometry and echocardiographic measurement of stroke volume. Exercise capacity was measured by expired gas analysis. Significant and incremental variations in left ventricular systolic (s(m), global strain, and strain rate) and diastolic (e(m)) function were found according to the number of components of MS (p <0.001). MS contributed to reduced systolic and diastolic function even in those without left ventricular hypertrophy (p <0.01). A similar dose-response association was present between the number of components of the MS and exercise capacity (p <0.001) and arterial compliance. The global strain rate and e(m) were independent predictors of exercise capacity. In conclusion, subclinical left ventricular dysfunction corresponded to the degree of metabolic burden, and these myocardial changes were associated with reduced cardiorespiratory fitness. Subjects with MS who also have subclinical myocardial abnormalities and reduced cardiorespiratory fitness may have a higher risk of cardiovascular disease events and heart failure.

Blood Pressure↗
PubMed2005

Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease.

BACKGROUND: Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease. METHODS: We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a and C1-Inhibitor (C1 inh.) were measured enzymatically. RESULTS: Patients with UAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r=0.27, p<0.02), C3a (r=0.32, p<0.001) and C1 INH.(r=0.41, p<0.003), but not with flow mediated dilatation (r=0.09, P=0.41). Hs-CRP and C1 INH.were found to be independent predictors of UAP in a backward stepwise logistic regression model. CONCLUSIONS: We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP.

Aged↗
PubMed2005

The prognostic value of a nomogram for exercise capacity in women.

BACKGROUND: Recent studies have demonstrated that exercise capacity is an independent predictor of mortality in women. Normative values of exercise capacity for age in women have not been well established. Our objectives were to construct a nomogram to permit determination of predicted exercise capacity for age in women and to assess the predictive value of the nomogram with respect to survival. METHODS: A total of 5721 asymptomatic women underwent a symptom-limited, maximal stress test. Exercise capacity was measured in metabolic equivalents (MET). Linear regression was used to estimate the mean MET achieved for age. A nomogram was established to allow the percentage of predicted exercise capacity to be estimated on the basis of age and the exercise capacity achieved. The nomogram was then used to determine the percentage of predicted exercise capacity for both the original cohort and a referral population of 4471 women with cardiovascular symptoms who underwent a symptom-limited stress test. Survival data were obtained for both cohorts, and Cox survival analysis was used to estimate the rates of death from any cause and from cardiac causes in each group. RESULTS: The linear regression equation for predicted exercise capacity (in MET) on the basis of age in the cohort of asymptomatic women was as follows: predicted MET = 14.7 - (0.13 x age). The risk of death among asymptomatic women whose exercise capacity was less than 85 percent of the predicted value for age was twice that among women whose exercise capacity was at least 85 percent of the age-predicted value (P<0.001). Results were similar in the cohort of symptomatic women. CONCLUSIONS: We have established a nomogram for predicted exercise capacity on the basis of age that is predictive of survival among both asymptomatic and symptomatic women. These findings could be incorporated into the interpretation of exercise stress tests, providing additional prognostic information for risk stratification.

Adult↗
PubMed2005

Comparison of specificity of quantitative myocardial contrast echocardiography for diagnosis of coronary artery disease in patients with versus without diabetes mellitus.

Impaired coronary flow reserve is widely reported in diabetes mellitus (DM) but its effect on myocardial contrast echocardiography (MCE) is unclear. We sought to identify whether DM influences the accuracy of qualitative and quantitative assessment of coronary artery disease (CAD) using MCE in 83 patients who underwent coronary angiography (60 men, 27 with DM; 56 +/- 11 years;). Destruction replenishment imaging was performed at rest and after combined dipyridamole-exercise stress testing. Ischemia was identified by the development of new wall motion abnormalities, qualitative MCE (new perfusion defects apparent 1 second after flash during hyperemia), and quantitative MCE (myocardial blood flow reserve <2.0 in the anterior circulation). Qualitative and quantitative assessment of perfusion was feasible in 100% and 92% of patients, respectively. Significant left anterior descending coronary stenosis (>50% by quantitative angiography) was present in 28 patients (including 8 with DM); 55 patients had no CAD (including 19 with DM). The myocardial blood flow reserve was reduced in patients with coronary stenosis compared with those with no CAD (1.6 +/- 1.1 vs 3.8 +/- 2.5, p <0.001). Among patients with no CAD, those with DM had an impaired flow reserve compared with control patients without DM (2.4 +/- 1.0 vs 4.5 +/- 2.8, p = 0.003). In conclusion, DM significantly influenced the quantitative, but not the qualitative, assessment of MCE, with a marked reduction in specificity in patients with DM.

Aged↗
PubMed2005

Derivation and validation of a disease-specific risk score for cardiac risk stratification in chronic kidney disease.

OBJECTIVE: Cardiac events (CE; cardiac death, non-fatal myocardial infarction and acute coronary syndrome) are the principal causes of death in patients with chronic kidney disease (CKD). We sought to devise and validate a cardiac risk score to risk-stratify patients with CKD. METHODS: Clinical history and biochemical data were obtained in 167 CKD patients. CE were recorded over a median follow-up of 22 months. The hazard ratio (HR) of each independent variable using Cox regression analysis was used to derive a cardiac risk score for the prediction of events. The cardiac risk score was then applied to a validation population of 99 CKD patients to confirm its validity in predicting CE. RESULTS: CE occurred in 20 patients in the derivation group. The independent predictors of CE were cardiac history (HR 9.83, P = 0.001), body mass index (BMI; HR 1.15, P = 0.002), dialysis duration (HR 1.24, P = 0.004) and serum phosphate (HR 4.29, P = 0.001). The resulting cardiac risk score (range 26-67) gave an area under the receiver operating characteristic curve of 0.86. CE occurred in 25 patients in the validation group; the ROC curve area was similar (0.84, P = 0.11). An optimal cardiac risk score cut-off of 50 assigned high risk to 29% of the derivation and 35% of the validation group (P = 0.26). CE occurred in 35 and 57% of the high-risk derivation and validation groups, respectively (P = 0.09), and in 2 and 8% of the low-risk groups (P = 0.15). CONCLUSION: Application of a cardiac risk score using cardiac history, dialysis duration, BMI and phosphate identifies CKD patients at risk of future CE.

Adult↗
PubMed2005

Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I.

OBJECTIVES: To explore whether aldosterone excess can induce adverse cardiovascular effects independently of effects on blood pressure (BP), we sought evidence of disturbed cardiovascular structure or function in normotensive individuals with primary aldosteronism. METHODS: Eight normotensive subjects with genetically proven familial hyperaldosteronism type I (FH-I) were compared with 24 age- and sex-matched normotensive controls in terms of BP, biochemical parameters, pulse wave velocity, and echocardiographic characteristics. RESULTS: Subjects with FH-I demonstrated higher serum aldosterone levels and aldosterone/renin ratios than controls, as expected. Despite having similar 24-h ambulatory BPs, subjects with FH-I demonstrated evidence of concentric remodeling with greater septal (mean +/- sd, 9.4 +/- 1.1 vs. 7.9 +/- 0.9 mm; P < 0.001), posterior wall (9.2 +/- 1.7 vs. 7.7 +/- 1.0 mm; P < 0.01), and relative wall (0.29 +/- 0.03 vs. 0.24 +/- 0.02; P < 0.001) thicknesses, and lower mitral early peak velocities (0.74 +/- 0.10 vs. 0.90 +/- 0.16 m/sec; P < 0.05), ratios of early to late peak diastolic transmitral flow velocity (1.56 +/- 0.24 vs. 2.06 +/- 0.41; P < 0.01), and myocardial early peak velocities (8.3 +/- 1.8 vs. 10.3 +/- 2.6 cm/sec; P < 0.05). There were no significant differences in pulse wave velocity or left ventricular ejection fraction, long axis strain rate, peak systolic strain, cyclic variation of integrated backscatter, or posterior wall calibrated integrated backscatter. CONCLUSIONS: Aldosterone excess is associated with increased left ventricular wall thicknesses and reduced diastolic function, even in the absence of hypertension.

Adolescent↗
PubMed2005

Can we justify the cost of echocardiography? Lessons from outcomes research.

The inexorable growth in the performance of cardiac imaging studies has led to a significant reduction in reimbursement for these services, which are already being reimbursed at levels that are quite similar to their cost. This paper seeks to apply the principles of analysis of cost-effectiveness to echocardiography. Opportunities are summarized for reducing cost and maximizing effectiveness, and different approaches to defining cost-effectiveness are examined for valvular, myocardial and ischemic indications.

Clinical Trials as Topic↗
PubMed2005

Impact of gender on risk stratification by exercise and dobutamine stress echocardiography: long-term mortality in 4234 women and 6898 men.

AIMS: Prior research is limited with regard to the diagnostic and prognostic accuracy of commonplace cardiac imaging modalities in women. The aim of this study was to examine 5-year mortality in 4234 women and 6898 men undergoing exercise or dobutamine stress echocardiography at three hospitals. METHODS AND RESULTS: Univariable and multivariable Cox proportional hazards models were used to estimate time to cardiac death in this multi-centre, observational registry. Of the 11 132 patients, women had a greater frequency of cardiac risk factors (P<0.0001). However, men more often had a history of coronary disease including a greater frequency of echocardiographic wall motion abnormalities (P<0.0001). During 5 years of follow-up, 103 women and 226 men died from ischaemic heart disease (P<0.0001). Echocardiographic estimates of left ventricular function (P<0.0001) and the extent of ischaemic wall motion abnormalities (P<0.0001) were highly predictive of cardiac death. Risk-adjusted 5-year survival was 99.4, 97.6, and 95% for exercising women with no, single, and multi-vessel ischaemia (P<0.0001). For women undergoing dobutamine stress, 5-year survival was 95, 89, and 86.6% for those with 0, 1, and 2-3 vessel ischaemia (P<0.0001). Exercising men had a 2.0-fold higher risk at every level of worsening ischaemia (P<0.0001). Significantly worsening cardiac survival was noted for the 1568 men undergoing dobutamine stress echocardiography (P<0.0001); no ischaemia was associated with 92% 5-year survival as compared with death rates of >/=16% for men with ischaemia on dobutamine stress echocardiography (P<0.0001). CONCLUSION: Echocardiographic measures of inducible wall motion abnormalities and global and regional left ventricular function are highly predictive of long-term outcome for women and men alike.

Coronary Artery Disease↗
PubMed2005

Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: Consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association.

Cardiovascular disease is the leading cause of mortality for women in the United States. Coronary heart disease, which includes coronary atherosclerotic disease, myocardial infarction, acute coronary syndromes, and angina, is the largest subset of this mortality, with >240,000 women dying annually from the disease. Atherosclerotic coronary artery disease (CAD) is the focus of this consensus statement. Research continues to report underrecognition and underdiagnosis of CAD as contributory to high mortality rates in women. Timely and accurate diagnosis can significantly reduce CAD mortality for women; indeed, once the diagnosis is made, it does appear that current treatments are equally effective at reducing risk in both women and men. As such, noninvasive diagnostic and prognostic testing offers the potential to identify women at increased CAD risk as the basis for instituting preventive and therapeutic interventions. Nevertheless, the recent evidence-based practice program report from the Agency for Healthcare Research and Quality noted the paucity of women enrolled in diagnostic research studies. Consequently, much of the evidence supporting contemporary recommendations for noninvasive diagnostic studies in women is extrapolated from studies conducted predominantly in cohorts of middle-aged men. The majority of diagnostic and prognostic evidence in cardiac imaging in women and men has been derived from observational registries and referral populations that are affected by selection and other biases. Thus, a better understanding of the potential impact of sex differences on noninvasive cardiac testing in women may greatly improve clinical decision making. This consensus statement provides a synopsis of available evidence on the role of the exercise ECG and cardiac imaging modalities, both those in common use as well as developing technologies that may add clinical value to the diagnosis and risk assessment of the symptomatic and asymptomatic woman with suspected CAD.

Coronary Artery Disease↗
PubMed2005

Determinants of functional capacity in patients with chronic heart failure: role of filling pressure and systolic and diastolic function.

BACKGROUND: Previous work suggesting a better correlation of diastolic than systolic function with exercise capacity in heart failure may reflect the relative insensitivity and load-dependence of ejection fraction (EF). We sought the correlation of new and more sensitive methods of quantifying systolic and diastolic function and filling pressure with functional capacity. METHODS: We studied 155 consecutive exercise tests on 95 patients with congestive heart failure (81 male, aged 62 +/- 10 years), who underwent resting 2-dimensional echocardiography and tissue Doppler imaging before and after measurement of maximum oxygen uptake (peak VO2). RESULTS: The resting EF was 31% +/- 10% and a peak VO2 was 13 +/- 5 mL/kg.min; the majority of these patients (80%) had an ischemic cardiomyopathy. Resting EF (r = 0.14, P = .09) correlated poorly with peak VO2 and mean systolic (r = 0.23, P = .004) and diastolic tissue velocities (r = 0.18, P = .02). Peak EF was weakly correlated with the mean systolic (r = 0.18, P = .02) and diastolic velocities (r = 0.16, P < .04). The mean sum of systolic and diastolic velocities in both annuli (r = 0.30, P < .001) and E/Ea ratio (r = -0.31, P < .001) were better correlated with peak VO2 . Prediction of peak VO2 was similar with models based on models of filling pressure (R = 0.61), systolic factors (R = 0.63), and diastolic factors (R = 0.59), although a composite model of filling pressure, systolic and diastolic function was a superior predictor of peak VO2 (R = 0.69; all P < .001). CONCLUSIONS: The reported association of diastolic rather than systolic function with functional capacity may have reflected the limitations of EF. Functional capacity appears related not only to diastolic function, but also to systolic function and filling pressure, and is most closely associated with a combination of these factors.

Aged↗