Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains ...of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes.
We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 pT181, pT217) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated.
The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R
= 0.31) and 59% in plasma p-tau217 (Adj. R
= 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm
was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm
was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R
= 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously.
Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration.
Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesised that women with a history of ...hypertensive pregnancy would have altered LV geometry and function when compared with women with only normotensive pregnancies.
In this cohort study, we analysed echocardiograms of 2637 women who participated in the Family Blood Pressure Program. We compared LV mass and function in women with hypertensive pregnancies with those with normotensive pregnancies.
Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared with women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42; 95% CI 1.01 to 1.99, p=0.05), after adjusting for age, race, research network of the Family Blood Pressure Program, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19; CI 0.08 to 1.78, p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups.
A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy.
GENOA- NCT00005269; HyperGEN- NCT00005267; Sapphire- NCT00005270; GenNet- NCT00005268.
Cardiac resynchronization therapy (CRT) benefits patients with advanced heart failure. The role of atrioventricular nodal (AVN) ablation in improving CRT outcomes, including survival benefit in CRT ...recipients with atrial fibrillation, is uncertain.
The purpose of this study was to assess the impact of AVN ablation on clinical and survival outcomes in a large atrial fibrillation and heart failure population that met the current indication for CRT and to determine whether AVN ablation is an independent predictor of survival in CRT recipients.
Of 154 patients with atrial fibrillation who received CRT-D, 45 (29%) underwent AVN ablation (+AVN-ABL group), whereas 109 (71%) received drug therapy for rate control during CRT (-AVN-ABL group). New York Heart Association (NYHA) class, electrocardiogram, and echocardiogram were assessed before and after CRT. Survival data were obtained from the national death and location database (Accurint).
CRT comparably improved left ventricular ejection fraction (8.1% +/- 10.7% vs 6.8% +/- 9.6%, P = .49) and left ventricular end-diastolic diameter (-2.1 +/- 5.9 mm vs -2.1 +/- 6.7 mm, P = .74) in both +AVN-ABL and -AVN-ABL groups. Improvement in NYHA class was significantly greater in the +AVN-ABL group than in -AVN-ABL group (-0.7 +/- 0.8 vs -0.4 +/- 0.8, P = .04). Survival estimates at 2 years were 96.0% (95% confidence interval CI 88.6%-100%) for +AVN-ABL group and 76.5% (95% CI 68.1%-85.8%) for-AVN-ABL group (P = .008). AVN ablation was independently associated with survival benefit from death (hazard ratio HR 0.13, 95% CI 0.03-0.58, P = .007) and from combined death, heart transplant, and left ventricular assist device (HR 0.19, 95% CI 0.06-0.62, P = .006) after CRT.
Among patients with atrial fibrillation and heart failure receiving CRT, AVN ablation for definitive biventricular pacing provides greater improvement in NYHA class and survival benefit. Larger-scale randomized trials are needed to assess the clinical and survival outcomes of this therapy.
Cardiac resynchronization therapy (CRT) has a symptomatic and survival benefit for patients with heart failure (HF), but the percentage of nonresponders remains relatively high. The aims of this ...study were to assess the clinical significance of baseline tricuspid regurgitation (TR) or worsening TR after implantation of a CRT device on the response to therapy. This is a multicenter retrospective analysis of prospectively collected databases that includes 689 consecutive patients who underwent implantation of CRT. The patients were divided into groups according to baseline TR grade and according to worsening TR within 15 months after device implantation. Outcome was assessed by clinical and echocardiographic response within 15 months and by estimated survival for a median interquartile range follow-up time of 3.3 years (1.6, 4.6). TR worsening after CRT implantation was documented in 104 patients (15%). These patients had worse clinical and echocardiographic response to CRT, but worsening of TR was not a significant predictor of mortality (p = 0.17). According to baseline echocardiogram, 620 patients (90%) had some degree of TR before CRT implant. Baseline TR was an independent predictor of worse survival (p <0.001), although these patients had significantly better clinical and echocardiographic response compared with patients without TR. In conclusion, worsening of TR after CRT implantation is a predictor of worse clinical and echocardiographic response but was not significantly associated with increased mortality. Baseline TR is associated with reduced survival despite better clinical and echocardiographic response after CRT implantation.
Refining the criteria for patient selection for cardiac resynchronization therapy (CRT) may improve its outcomes. The study objective was to determine the effect of scar location, scar burden, and ...left ventricular (LV) lead position on CRT outcomes.
The study included 213 consecutive CRT recipients with radionuclide myocardial perfusion imaging before CRT between January 2002 and December 2008. Scar localization and myocardial viability were analyzed using a 17-segment model and a 5-point semiquantitative scale. New York Heart Association (NYHA) class and echocardiography were assessed before and after CRT. The anatomic LV lead location in the 17-segment model was assessed by review of fluoroscopic cinegrams in right and left anterior oblique views. As in published studies, clinical response was defined as an absolute improvement in LV ejection fraction of ≥5 percentage points after CRT.
A total of 651 scar segments was identified in 213 patients. Eighty-three percent of scar segments were located in the LV anterior, posterior, septal, and apical regions, whereas 84% of LV leads were in the lateral wall. Only 11% of LV leads were positioned in scar segments. The extent of scarring was significantly higher in nonresponders than in responders (18.0% vs. 6%, P = 0.001). Compared with patients with scarring >22%, patients ≤70 y with scarring ≤22% of the left ventricle had a greater increase in LV ejection fraction (10.1% ± 10.5% vs. 0.8% ± 6.1%; P < 0.001) and improvement in NYHA class (-0.9 ± 0.7 vs. -0.5 ± 0.8; P = 0.02).
LV leads were often located in viable myocardial regions. Less scar burden was associated with a greater improvement in heart failure but only in relatively younger CRT recipients.
We sought to determine the clinical and survival outcomes of cardiac resynchronization therapy (CRT) associated with left ventricular (LV) lead location. The lateral left ventricle has been ...considered the optimal LV lead location for CRT.
Left ventricular lead cinegrams taken in 30° right and left anterior oblique views were evaluated in 457 recipients of CRT with a pacemaker or a defibrillator from 1 January 2002 to 31 December 2008 in this retrospective study. Left ventricular lead placement was prioritized at implantation into posterolateral (PL), anterolateral (AL), middle cardiac, and anterointerventricular coronary veins. Using echocardiographic LV 16-segment analysis, we grouped the leads as anterior, AL, PL, and posterior locations. New York Heart Association (NYHA) class and echocardiography were assessed before and after CRT. Clinical and survival outcomes after CRT were compared among the four LV lead locations. Patient baseline demographic characteristics were similar among these four groups. Improvement in NYHA class was significantly greater in the AL (P= 0.04) and PL (P= 0.03) locations than in the anterior location. There was a tendency for greater improvement in LV ejection fraction among the AL (P= 0.11) and PL (P= 0.08) locations than the anterior location. Kaplan-Meier survival estimate at 4 years varied for location: AL, 72%; anterior, 48%; PL, 62%; and posterior, 72% (P= 0.003).
Cardiac resynchronization therapy recipients are profiting from all lead positions. However, LV lead placed in the AL and PL positions is more preferential for achieving optimal CRT benefit than leads placed in the anterior position.
To examine neurodegenerative imaging biomarkers in Alzheimer disease (AD) dementia from middle to old age.
Persons with AD dementia and elevated brain β-amyloid with Pittsburgh compound B (PiB)-PET ...imaging underwent (18)F-fluorodeoxyglucose (FDG)-PET and structural MRI. We evaluated 3 AD-related neurodegeneration biomarkers: hippocampal volume adjusted for total intracranial volume (HVa), FDG standardized uptake value ratio (SUVR) in regions of interest linked to AD, and cortical thickness in AD-related regions of interest. We examined associations of each biomarker with age and evaluated age effects on cutpoints defined by the 90th percentile in AD dementia. We assembled an age-, sex-, and intracranial volume-matched group of 194 similarly imaged clinically normal (CN) persons.
The 97 participants with AD dementia (aged 49-93 years) had PiB SUVR ≥1.8. A nonlinear (inverted-U) relationship between FDG SUVR and age was seen in the AD group but an inverse linear relationship with age was seen in the CN group. Cortical thickness had an inverse linear relationship with age in AD but a nonlinear (flat, then inverse linear) relationship in the CN group. HVa showed an inverse linear relationship with age in both AD and CN groups. Age effects on 90th percentile cutpoints were small for FDG SUVR and cortical thickness, but larger for HVa.
In persons with AD dementia with elevated PiB SUVR, values of each neurodegeneration biomarker were associated with age. Cortical thickness had the smallest differences in 90th percentile cutpoints from middle to old age, and HVa the largest differences.
Up to one-third of the patients who undergo cardiac resynchronization therapy (CRT) are not responders.
To demonstrate that delayed lateral left ventricular activation time determined through time to ...intrinsicoid deflection onset (ID) predicts response after CRT.
The ID in leads I, aVL, V₁ and V₂, and V₅ and V₆ were measured in 135 patients who underwent CRT. A CRT response was defined as a decrease in left ventricular end-systolic volume (LVESV) exceeding 15% at 6 months.
In patients with left bundle branch block or nonspecific intraventricular conduction delay, response was predicted by longer ID in lead I (odds ratio OR 3.23; 95% confidence interval (CI) 1.4-7.4; per 20-ms increase), in lead aVL (OR 3.0; 95% CI 1.2-7.3; per 20-ms increase), and in lead I minus lead V₁ (OR 2.4; 95% CI 1.2-4.7) adjusting for baseline QRS duration and LVESV. Results were similar after adjusting for postimplant or change in QRS duration. The ID parameters were better predictors of response than QRS duration parameters. ID in lead I/QRS duration ratio (OR 3.1; 95% CI 1.6-5.9) also increased the odds of response after adjusting for baseline LVESV. Cutoff values for ID in leads--I, 110 ms; aVL, 130 ms; I minus V₁, 90 ms--and ID in lead I/QRS duration ratio of 0.69 yielded a sensitivity and a specificity as high as 83% and 81%.
Measurement of ID on surface electrocardiography permits a preimplant, noninvasive means of determining left ventricle activation delay; is a good predictor of CRT response; and represents a promising alternative to QRS duration parameters.
Objective Hyperhomocysteinemia is associated with an elevated cardiovascular disease risk. We examined whether women with a history of hypertension in pregnancy are more likely to have a high level ...of serum homocysteine decades after pregnancy. Study Design Serum homocysteine was measured at a mean age of 60 years in nulliparous women (n = 216), and women with a history of normotensive (n = 1825) or hypertensive (n = 401) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Relationships between homocysteine and pregnancy history were examined by linear and logistic regression, controlling for multiple covariates including personal and family history of hypertension, diabetes, obesity, tobacco use, and demographics. Results A history of hypertension in pregnancy, when compared with normotensive pregnancy, was associated with a 4.5% higher serum homocysteine level ( P = .015) and 1.60-fold increased odds of having an elevated homocysteine (95% confidence interval, 1.15–2.21; P = .005) after adjusting for potentially confounding covariates. In contrast, a history of normotensive pregnancy, as compared with nulliparity, was associated with a 6.1% lower serum homocysteine level ( P = .005) and a 0.49-fold reduced odds of elevated homocysteine levels (95% confidence interval, 0.32–0.74; P < .001). Conclusion Homocysteine levels decades after pregnancy are higher in women with a history of pregnancy hypertension, even after controlling for potential confounders. Thus, pregnancy history may prompt homocysteine assessment and risk modification in an attempt at primary prevention of cardiovascular disease.
Abstract Background An ankle-brachial index (ABI) (the ratio of ankle to brachial artery systolic blood pressure) value ≤0.9 identifies patients with peripheral arterial disease (PAD) and elevated ...cardiovascular event risk. This study examined whether women with a history of hypertension in pregnancy are more likely to have an ABI ≤0.9 decades after pregnancy. Methods and results ABI was measured in nulliparous women ( n = 144), and women with a history of normotensive ( n = 1272) or hypertensive ( n = 281) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study non-Hispanic white (39%) and black (61%) women, 60 (mean) ± 10 (SD) years of age. Relationships between PAD and pregnancy history were examined by logistic regression. Compared to women with a history of normotensive pregnancy, women with a history of hypertensive pregnancy had greater odds of PAD (1.61 (odds ratio); 1.04–2.49 (95% confidence interval), p = 0.03, adjusted for age, race, height and heart rate). Additional adjustment for ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education did not attenuate this relationship (1.63; 1.02–2.62, p = 0.04). PAD risk did not differ between women with a history of normotensive pregnancy and nulliparous women (1.06; 0.52–2.14, p = 0.87). Conclusions Hypertension in pregnancy is an independent risk factor for PAD decades after pregnancy after adjusting for race, age, height, heart rate, ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education.
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