Background Current approaches fail to separate patients at high versus low risk for ventricular arrhythmias owing to overreliance on a snapshot left ventricular ejection fraction measure. We used ...statistical machine learning to identify important cardiac imaging and time-varying risk predictors. Methods and Results Three hundred eighty-two cardiomyopathy patients (left ventricular ejection fraction ≤35%) underwent cardiac magnetic resonance before primary prevention implantable cardioverter defibrillator insertion. The primary end point was appropriate implantable cardioverter defibrillator discharge or sudden death. Patient characteristics; serum biomarkers of inflammation, neurohormonal status, and injury; and cardiac magnetic resonance-measured left ventricle and left atrial indices and myocardial scar burden were assessed at baseline. Time-varying covariates comprised interval heart failure hospitalizations and left ventricular ejection fractions. A random forest statistical method for survival, longitudinal, and multivariable outcomes incorporating baseline and time-varying variables was compared with (1) Seattle Heart Failure model scores and (2) random forest survival and Cox regression models incorporating baseline characteristics with and without imaging variables. Age averaged 57±13 years with 28% women, 66% white, 51% ischemic, and follow-up time of 5.9±2.3 years. The primary end point (n=75) occurred at 3.3±2.4 years. Random forest statistical method for survival, longitudinal, and multivariable outcomes with baseline and time-varying predictors had the highest area under the receiver operating curve, median 0.88 (95% CI, 0.75-0.96). Top predictors comprised heart failure hospitalization, left ventricle scar, left ventricle and left atrial volumes, left atrial function, and interleukin-6 level; heart failure accounted for 67% of the variation explained by the prediction, imaging 27%, and interleukin-6 2%. Serial left ventricular ejection fraction was not a significant predictor. Conclusions Hospitalization for heart failure and baseline cardiac metrics substantially improve ventricular arrhythmic risk prediction.
Better models to identify individuals at low risk of ventricular arrhythmia (VA) are needed for implantable cardioverter-defibrillator (ICD) candidates to mitigate the risk of ICD-related ...complications. We designed the CERTAINTY study (CinE caRdiac magneTic resonAnce to predIct veNTricular arrhYthmia) with deep learning for VA risk prediction from cine cardiac magnetic resonance (CMR). Using a training cohort of primary prevention ICD recipients (n = 350, 97 women, median age 59 years, 178 ischemic cardiomyopathy) who underwent CMR immediately prior to ICD implantation, we developed two neural networks: Cine Fingerprint Extractor and Risk Predictor. The former extracts cardiac structure and function features from cine CMR in a form of cine fingerprint in a fully unsupervised fashion, and the latter takes in the cine fingerprint and outputs disease outcomes as a cine risk score. Patients with VA (n = 96) had a significantly higher cine risk score than those without VA. Multivariate analysis showed that the cine risk score was significantly associated with VA after adjusting for clinical characteristics, cardiac structure and function including CMR-derived scar extent. These findings indicate that non-contrast, cine CMR inherently contains features to improve VA risk prediction in primary prevention ICD candidates. We solicit participation from multiple centers for external validation.
Left ventricular ejection fraction (LVEF) improves over time in 25%-40% of patients with cardiomyopathy with primary prevention implantable cardioverter-defibrillator (ICD). The determinants of LVEF ...improvement, however, are not well characterized.
We sought to examine the associations of clinical risk factors and cardiac imaging markers with changes in LVEF after ICD implantation.
We conducted a retrospective analysis of cardiac magnetic resonance images in 202 patients who underwent primary prevention ICD implantation to quantify the amount of heterogeneous myocardial tissue (gray zone), dense core, and total scar. LVEF was reassessed at least once after ICD implantation.
Over a mean follow-up of 3 years, LVEF decreased in 43 (21.3%), improved in 88 (43.6%), and was unchanged in 71 (35.1%) of the patients. Baseline LVEF and myocardial scar characteristics were the strongest determinants of LVEF trajectory with high scar burden and increasing lack of myocardial viability associated with a greater decline in LVEF. There was a trend toward an association between both changes in LVEF and scar extent with subsequent appropriate ICD shock. Changes in LVEF were also strongly associated with heart failure hospitalizations.
Scar burden and characteristics were strong determinants, independent of baseline LVEF and other traditional cardiovascular risk factors, of changes in LVEF. Both worsened LVEF and high scar extent were associated with a trend toward increased risk of appropriate shock. These findings suggest that baseline cardiac magnetic resonance imaging of the myocardial substrate may provide important prognostic information on subsequent left ventricular remodeling and adverse events.
Impaired endothelium-mediated relaxation contributes to vasospasm and myocardial ischemia in patients with coronary artery disease. We hypothesized that cholesterol-lowering therapy with the ...3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis. In a randomized, double-blind, placebo-controlled trial, we studied coronary endothelial responses in 23 patients randomly assigned to either lovastatin (40 mg twice daily; 11 patients) or placebo (12 patients) plus a lipid-lowering diet (American Heart Association Step 1 diet). Patients were studied 12 days after randomization and again at 5 1/2 months. These patients had total cholesterol levels ranging from 160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter) and were undergoing coronary angioplasty. At the initial and follow-up studies, patients received serial intracoronary infusions (in a coronary artery not undergoing angioplasty) of acetylcholine to assess endothelium-mediated vasodilatation. The responses of the coronary vessels were analyzed with quantitative angiography. The patients in the placebo and lovastatin groups had similar responses to acetylcholine at a mean of 12 days of therapy (expressed as the percentage of change in diameter in response to acetylcholine doses of 10(-9) M, 10(-8) M, 10(-7) M, and 10(-6) M). In the placebo group, the respective mean (+/-SE) changes were 1 +/- 2, 0 +/- 2, -2 +/- 4, and -19 +/- 4 percent; in the lovastatin group, they were -2 +/- 2, -4 +/- 4, -12 +/- 5, and -16 +/- 7 percent (P = 0.32). (Coronary-artery constriction is reflected by negative numbers.) The responses to acetylcholine in the placebo group after a mean of 5.5 months of therapy were -3 +/- 3, -1 +/- 2, -8 +/- 4, and -18 +/- 5 percent, respectively; there was significant improvement in the lovastatin group, which had responses of 3 +/- 3, 3 +/- 3, 0 +/- 2, and 0 +/-3 percent (P = 0.004)
1 Department of Health, Nutrition, and Exercise Sciences, and 2 School of Nursing, University of Delaware; and 3 Christiana Care Health System, Inc., Cardiovascular Research, Newark, Delaware
...Submitted 22 February 2006
; accepted in final form 7 June 2006
The purpose of this study was to examine the relationship between osmolality and efferent sympathetic outflow in humans. We hypothesized that increased plasma osmolality would be associated with increases in directly measured sympathetic outflow. Muscle sympathetic outflow was successfully recorded in eight healthy subjects during a 60-min intravenous hypertonic saline infusion (HSI; 3% NaCl) on one day and during a 60-min intravenous isotonic saline (ISO) infusion (0.9% NaCl) on a different day. The HSI provides an osmotic and volume stimulus, whereas the ISO infusion provides a volume-only stimulus. Muscle sympathetic nerve activity was quantified using the technique of peroneal microneurography. Plasma osmolality increased during the HSI but not during the ISO infusion (ANOVA, P < 0.05). Sympathetic outflow differed between the trials (ANOVA, P < 0.05); during the HSI burst, frequency initially increased from 14.6 ± 2.5 to 18.1 ± 1.9 bursts/min; during the ISO infusion, burst frequency initially declined from 14.7 ± 2.5 to 12.0 ± 2.1 bursts/min. Plasma norepinephrine concentration was greater at the end of the HSI compared with the end of the ISO infusion (HSI: 297 ± 64 vs. ISO: 202 ± 49 pg/ml; ANOVA, P < 0.05). We conclude that HSI-induced increases in plasma osmolality are associated with increases in sympathetic activity in humans.
blood pressure; salt sensitivity; hypertension
Address for reprint requests and other correspondence: W. B. Farquhar, 541 South College Ave., Fred Rust Arena, Office 143/HPL, Newark, DE 19716 (email: wbf{at}udel.edu )
1 Department of Health, Nutrition, and Exercise Sciences, University of Delaware, Newark; and 2 Christiana Care Health System, Inc., Cardiovascular Research, Newark, Deleware
Submitted 19 April 2006
...; accepted in final form 23 June 2006
Venous compliance is lower in older adults compared with younger adults. It is possible that alterations in venous smooth muscle tone and responsiveness may contribute to the age-related differences in venous compliance. To determine the effects of sympathetic activation cold pressor test (cold pressor test); rhythmic ischemic handgrip (rhythmic ischemic handgrip) and endothelium-independent decreases in smooth muscle tone sublingual nitroglycerin (nitroglycerin) on venous compliance in young and older adults, forearm and calf venous compliance was measured in 12 young (22 ± 1 yr) and 12 old (65 ± 1 yr) supine subjects using venous occlusion plethysmography. Venous compliance was assessed at baseline, during the cold pressor test and rhythmic ischemic handgrip tests, and after nitroglycerin administration. All pressure-volume relationships were modeled with a quadratic regression equation, and 1 and 2 were used as indexes of venous compliance. A repeated-measures ANOVA was used to determine the effect of the age and trial on venous compliance. Calf regression parameters 1 (0.0639 ± 0.0126 vs. 0.0503 ± 0.0059, young vs. older; P < 0.05) and 2 (0.00054 ± 0.00011 vs. 0.00041 ± 0.00005, young vs. older; P < 0.05) were significantly less in older adults at baseline. Similarly, forearm regression parameters, 1 and 2 were lower in older adults at baseline. Venous compliance was not effected by the cold pressor test test, rhythmic ischemic handgrip, or sublingual nitroglycerin in either group. Data suggest that forearm and calf venous compliance is lower in older adults compared with young. However, this difference probably cannot be explained by alterations in smooth muscle tone or responsiveness.
aging; nitroglycerin; venous capacitance
Address for reprint requests and other correspondence: W. B. Farquhar, 541 South College Ave., Fred Rust Arena-Office #143/HPL, Newark, DE 19716 (e-mail: wbf{at}udel.edu )
1 Department of Health, Nutrition, and Exercise Sciences, University of Delaware, Newark, Delaware; 2 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri; ...and 3 Christiana Care Health Services, Cardiovascular Clinical Trials, Newark, Delaware
Submitted 25 April 2008
; accepted in final form 12 July 2008
Hypertensive (HTN) animal models demonstrate lower venous compliance as well as increased venous tone and responsiveness compared with normotensive (NTN) controls. However, the extent to which findings in experimental animals can be extended to humans is unknown. Forearm and calf venous compliance were quantified in 9 NTN (23 ± 1 yr) and 9 HTN (24 ± 1 yr) men at baseline, after administration of nitroglycerin (NTG), during a cold pressor test (CP), and post-handgrip exercise ischemia (PEI). Individual pressure-volume relationships from a cuff deflation protocol (1 mmHg/s) were modeled with a quadratic regression. Regression parameters β 1 and β 2 were used to calculate compliance. A one-way ANOVA was used to compare the beta parameters and a repeated-measures ANOVA was used to compare volumes across all pressures (between groups at baseline and within groups during perturbations). Limb venous compliance was similar between groups (forearm: NTN β 1 = 0.11 ± 0.01 and β 2 = –0.00097 ± 0.0001, HTN β 1 = 0.10 ± 0.01 and β 2 = –0.00088 ± 0.0001; calf: NTN β 1 = 0.12 ± 0.01 and β 2 = –0.00102 ± 0.0001, HTN β 1 = 0.11 ± 0.01 and β 2 = –0.00090 ± 0.0001). However, at baseline, volume across all pressures (i.e., capacitance) was lower in the forearm ( P 0.01) and tended to be lower in the calf ( P = 0.08) in HTN subjects. Venous compliance was not altered by any perturbation in either group. Forearm volume was increased during NTG in HTN subjects only. While venous compliance was similar between NTN and HTN adults, HTN adults have lower forearm venous capacitance (volume) which is increased with NTG. These data suggest that young HTN adults may have augmented venous smooth muscle tone compared with NTN controls.
nitroglycerin; cold pressor test; postexercise ischemia; venous smooth muscle tone
Address for reprint requests and other correspondence: W. B. Farquhar, 541 S. College Ave., Fred Rust Arena-Office #143/HPL, Newark, DE 19716 (e-mail: wbf{at}udel.edu )
1 Department of Health, Nutrition, and Exercise Sciences and 2 College of Health Sciences, University of Delaware; and 3 Christiana Care Health Systems, Cardiovascular Research, Newark, Delaware
...Submitted 20 December 2006
; accepted in final form 11 July 2007
The purpose of this study was to determine if plasma osmolality alters baroreflex control of sympathetic activity when controlling for a change in intravascular volume; we hypothesized that baroreflex control of sympathetic activity would be greater during a hyperosmotic stimulus compared with an isoosmotic stimulus when intravascular volume expansion was matched. Seven healthy subjects (25 ± 2 yr) completed two intravenous infusions: a hypertonic saline infusion (HSI; 3% NaCl) and, on a separate occasion, an isotonic saline infusion (ISO; 0.9% NaCl), both at a rate of 0.15 ml·kg –1 ·min –1 . To isolate the effect of osmolality, comparisons between HSI and ISO conditions were retrospectively matched based on hematocrit; therefore, baroreflex control of sympathetic outflow was determined at 20 min of a HSI and 40 min of an ISO. Muscle sympathetic outflow (MSNA) was directly measured using the technique of peroneal microneurography; osmolality and blood pressure (Finometer) were assessed. The baroreflex control of sympathetic outflow was estimated by calculating the slope of the relationship between MSNA and diastolic blood pressure during controlled breathing. Plasma osmolality was greater during the HSI compared with the ISO (HSI: 292 ± 0.9 mosmol/kg and ISO: 289 ± 0.8 mosmol/kg, P < 0.05). Hematocrits were matched (HSI: 39.1 ± 1% and ISO: 39.1 ± 1%, P > 0.40); thus, we were successful in isolating osmolality. The baroreflex control of sympathetic outflow was greater during the HSI compared with the ISO (HSI: –8.3 ± 1.2 arbitrary units·beat –1 ·mmHg –1 vs. ISO: –4.0 ± 0.8 arbitrary units·beat –1 ·mmHg –1 , P = 0.01). In conclusion, when controlling for intravascular volume, increased plasma osmolality enhances baroreflex control of sympathetic activity in humans.
baroreceptor; muscle sympathetic nerve activity; intravascular volume
Address for reprint requests and other correspondence: W. B. Farquhar, 541 S. College Ave., Fred Rust Arena, Office #143/HPL, Newark, DE 19716 (e-mail: wbf{at}udel.edu )
Departments of 1 Health, Nutrition, and Exercise Sciences, and 2 Nursing, University of Delaware, Newark; and 3 Christiana Care Health Services, Cardiovascular Research, Newark, Delaware
Submitted 7 ...March 2005
; accepted in final form 20 June 2005
The purpose of this study was to investigate the acute blood pressure (BP) and hemodynamic effects of sodium chloride (3% intravenous solution). Although many studies link a change in dietary sodium to a change in BP, few consider the effects of sodium concentration in the blood on BP. We hypothesized that an intravenous sodium load would increase BP, and we quantified alterations in cardiac output ( c) and peripheral vascular resistance (PVR). Thirteen subjects (age 27 ± 2 yr) underwent a 60-min 3% saline infusion (0.15 ml·kg 1 ·min 1 ). BP was assessed on a beat-to-beat basis with a Finometer, c was assessed via the CO 2 rebreathing technique, and PVR was derived. Serum sodium and osmolality increased, and hematocrit declined during the infusion (ANOVA, P < 0.01). Mean arterial pressure (MAP) increased continuously during the infusion from 81.8 ± 3.4 to 91.6 ± 3.6 mmHg (ANOVA, P < 0.01). BP responsiveness to sodium was expressed as the slope of the serum sodium-MAP relationship and averaged 1.75 ± 0.34 mmHg·mmol 1 ·l 1 . BP responsiveness to the volume change was expressed as the slope of the hematocrit-MAP relationship and averaged 2.2 ± 0.35 mmHg/%. The early change in MAP was mediated by an increase in c and the late change by an increase in PVR ( P < 0.05), corresponding to a 30% increase in plasma norepinephrine. In conclusion, an acute infusion of hypertonic saline was effective in increasing BP, and both sodium and volume appear to be involved in this increase; acute BP responsiveness to serum sodium can be quantified using a MAP-sodium plot.
cardiac output; peripheral vascular resistance; salt sensitivity; hypertension
Address for reprint requests and other correspondence: W. B. Farquhar, 541 South College Ave., Fred Rust Arena-Office #143/HPL, Newark, DE 19716 (e-mail: wbf{at}udel.edu )
CONTEXT High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not ...well defined. OBJECTIVE To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI. DESIGN, SETTING, AND PATIENTS Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety GRAVITAS) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010. INTERVENTIONS High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months. MAIN OUTCOME MEASURES The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days. RESULTS At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio HR, 1.01; 95% confidence interval CI, 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 1.4% vs 25 2.3%, HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001). CONCLUSIONS Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00645918
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