Predicting renal function response to renal artery stenting.

OBJECTIVE: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions Trial found no benefit of renal artery stenting (RAS) over medical therapy, although it was underpowered to detect a benefit among patients with chronic kidney disease (CKD). A post hoc analysis demonstrated improved event-free survival after RAS for patients whose renal function improved by 20% or more. A significant obstacle to achieving this benefit is the inability to predict which patients' renal function will improve from RAS. The objectives of the current study were to identify predictors of renal function response to RAS. METHODS: The Veteran Affairs Corporate Data Warehouse was queried for patients who underwent RAS between 2000 and 2021. The primary outcome was improvement in renal function (estimated glomerular filtration rate [eGFR]) after stenting. Patients were categorized as responders if the eGFR at 30 days or greater after stenting increased by 20% or more compared with before stenting. All others were nonresponders. RESULTS: The study cohort included 695 patients with a median follow-up of 7.1 years (interquartile range, 3.7-11.6 years). Based on postoperative change in eGFR, 202 stented patients (29.1%) were responders, and the remainder (n = 493 [70.9%]) were nonresponders. Before RAS, responders had a significantly higher mean serum creatinine, lower mean eGFR, and higher rate of decline of preoperative GFR in the months before stenting. After stenting, responders had a 26.1% increase in eGFR, compared with before stenting (P < .0001), which remained stable during follow-up. In contrast, nonresponders had a progressive 5.5% decrease in eGFR after stenting. Logistic regression analysis identified three predictors of renal function response to stenting: (1) diabetes (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.44-0.91; P = .013), (2) CKD stages 3b or 4 (OR, 1.80; 95% CI, 1.26-2.57; P = .001), and (3) rate of decline in preoperative eGFR per week before stenting (OR, 1.21; 95% CI, 1.05-1.39; P = .008). CKD stages 3b and 4 and the rate of decline in preoperative eGFR are positive predictors of renal function response to stenting, whereas diabetes is a negative predictor. CONCLUSIONS: Based on our data, patients in CKD stages 3b and 4 (eGFR 15-44 mL/min/1.73 m2) are the only subgroups with a significant probability of improved renal function after RAS. The rate of decline of preoperative eGFR over the months before stenting is a powerful discriminator of patients who are most likely to benefit from RAS. Specifically, patients with a more rapid decrease in eGFR before stenting have a significantly greater probability of improved renal function with RAS. In contrast, diabetes is a negative predictor of improved renal function, so interventionalists should be circumspect about RAS in diabetic patients.

COVID-19 associated mortality and cardiovascular disease outcomes among US women veterans.

The burden of COVID-19 has been noted to be disproportionately greater in minority women, a population that is nevertheless still understudied in COVID-19 research. We conducted an observational study to examine COVID-19-associated mortality and cardiovascular disease outcomes after testing (henceforth index) among a racially diverse adult women veteran population. We assembled a retrospective cohort from a Veterans Affairs (VA) national COVID-19 shared data repository, collected between February and August 2020. A case was defined as a woman veteran who tested positive for SARS-COV-2, and a control as a woman veteran who tested negative. We used Kaplan-Meier curves and the Cox proportional hazards model to examine the distribution of time to death and the effects of baseline predictors on mortality risk. We used generalized linear models to examine 60-day cardiovascular disease outcomes. Covariates studied included age, body mass index (BMI), and active smoking status at index, and pre-existing conditions of diabetes, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and a history of treatment with antiplatelet or anti-thrombotic drug at any time in the 2 years prior to the index date. Women veterans who tested positive for SARS-CoV-2 had 4 times higher mortality risk than women veterans who tested negative (Hazard Ratio 3.8, 95% Confidence Interval CI 2.92 to 4.89) but had lower risk of cardiovascular events (Odds Ratio OR 0.78, 95% CI 0.66 to 0.92) and developing new heart disease conditions within 60 days (OR 0.67, 95% CI 0.58 to 0.77). Older age, obesity (BMI > 30), and prior CVD and COPD conditions were positively associated with increased mortality in 60 days. Despite a higher infection rate among minority women veterans, there was no significant race difference in mortality, cardiovascular events, or onset of heart disease. SARS-CoV-2 infection increased short-term mortality risk among women veterans similarly across race groups. However, there was no evidence of increased cardiovascular disease incidence in 60 days. A longer follow-up of women veterans who tested positive is warranted.

Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER).

BACKGROUND: Low-density lipoproteins (LDLs) are removed by extracorporeal filtration during LDL apheresis. It is mainly used in familial hyperlipidemia. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) evaluated LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. METHODS: We randomized 160 acute coronary syndrome patients at 4 Veterans Affairs centers within 72 hours of percutaneous coronary intervention to intensive lipid-lowering therapy (ILLT) comprising single LDL apheresis and statins versus standard medical therapy (SMT) with no LDL apheresis and statin therapy alone. Trial objectives constituted primary safety and primary efficacy end points and endothelial progenitor cell colony-forming unit mobilization in peripheral blood. RESULTS: Mean LDL reduction at discharge was 53% in ILLT and 17% in SMT groups (P<0.0001) from baseline levels of 116.3±34.3 and 110.7±32 mg/dL (P=0.2979), respectively. The incidence of the primary safety end point of major peri-percutaneous coronary intervention adverse events was similar in both groups (ILLT, 3; SMT, 0). The primary efficacy end point, percentage change in total plaque volume at 90 days by intravascular ultrasound, on average decreased by 4.81% in the ILLT group and increased by 2.31% in the SMT group (difference of means, -7.13 [95% CI, -14.59 to 0.34]; P=0.0611). The raw change in total plaque volume on average decreased more in the ILLT group than in the SMT group (-6.01 versus -0.95 mm3; difference of means, -5.06 [95% CI, -11.61 to 1.48]; P=0.1286). Similar results were obtained after adjusting for participating sites, age, preexisting coronary artery disease, diabetes mellitus, baseline LDL levels, and baseline plaque burden. There was robust endothelial progenitor cell colony-forming unit mobilization from baseline to 90 days in the ILLT group (P=0.0015) but not in SMT (P=0.0844). CONCLUSIONS: PREMIER is the first randomized clinical trial to demonstrate safety and a trend for early coronary plaque regression with LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01004406 and NCT02347098.

The effect of lifelong endurance exercise on cardiovascular structure and exercise function in women.

KEY POINTS: The beneficial effects of sustained or lifelong (>25 years) endurance exercise on cardiovascular structure and exercise function have been largely established in men. The current findings indicate that committed (≥4 weekly exercise sessions) lifelong exercise results in substantial benefits in exercise capacity ( V̇O2max ), cardiovascular function at submaximal and maximal exercise, left ventricular mass and compliance, and blood volume compared to similarly aged or even younger (middle-age) untrained women. Endurance exercise training should be considered a key strategy to prevent cardiovascular disease with ageing in women as well as men. ABSTRACT: This study was a retrospective, cross-sectional analysis of exercise performance and left ventricular (LV) morphology in 70 women to examine whether women who have performed regular, lifelong endurance exercise acquire the same beneficial adaptations in cardiovascular structure and function and exercise performance that have been reported previously in men. Three groups of women were examined: (1) 35 older (>60 years) untrained women (older untrained, OU), (2) 13 older women who had consistently performed four or more endurance exercise sessions weekly for at least 25 years (older trained, OT), and (3) 22 middle-aged (range 35-59 years) untrained women (middle-aged untrained, MU) as a reference control for the appropriate age-related changes. Oxygen uptake ( V̇O2 ) and cardiovascular function (cardiac output ( Q̇ ); stroke volume (SV) acetylene rebreathing) were examined at rest, steady-state submaximal exercise and maximal exercise (maximal oxygen uptake, V̇O2max ). Blood volume (CO rebreathing) and LV mass (cardiac magnetic resonance imaging), plus invasive measures of static and dynamic chamber compliance were also examined. V̇O2max (p < 0.001) and maximal exercise Q̇ and SV were larger in older trained women compared to the two untrained groups (∼17% and ∼27% for Q̇ and SV, respectively, versus MU; ∼40% and ∼38% versus OU, all p < 0.001). Blood volume (mL kg-1 ) and LV mass index (g m-2 ) were larger in OT versus OU (∼11% and ∼16%, respectively, both P ≤ 0.015) Static LV chamber compliance was greater in OT compared to both untrained groups (median (25-75%): MU: 0.065 (0.049-0.080); OU: 0.085 (0.061-0.138); OT: 0.047 (0.031-0.054), P ≤ 0.053). Collectively, these findings indicate that lifetime endurance exercise appears to be extremely effective at preserving or even enhancing cardiovascular structure and function with advanced age in women.

Impact of Prolonged Spaceflight on Orthostatic Tolerance During Ambulation and Blood Pressure Profiles in Astronauts.

BACKGROUND: Astronauts returning to earth usually demonstrate reduced orthostatic tolerance when assessed on a tilt table or quiet standing, but no studies have evaluated postflight orthostatic tolerance during activities of daily living, when it is most clinically relevant. Ambulatory blood pressure (BP) variability also is associated with orthostatic intolerance in certain patient populations and can capture clinically significant orthostatic hypotension during activities of daily living, especially when measured on a beat-to-beat basis. We evaluated the impact of prolonged spaceflight on orthostatic tolerance and BP profiles in astronauts. METHODS: Ambulatory beat-to-beat BP was recorded using a portable device for multiple 24-hour time periods before, during, and after 6 months of spaceflight in 12 astronauts (4 women; age 48±5 [mean±SD] years). BP variability in the time domain was calculated as the SD. Systolic BP distribution during activities of daily living was characterized by skewness and kurtosis. RESULTS: In contrast with results from previous studies that used tilt tables or stand tests, no astronaut experienced orthostatic intolerance/hypotension during activities of daily living before or after spaceflight. Also, 24-hour systolic BP decreased in space (120±10 mm Hg before spaceflight versus 106±9 mm Hg during spaceflight; P<0.01), but it returned to normal upon landing (122±13 mm Hg). Diastolic BP was unchanged during and after spaceflight. Systolic and diastolic BP variability remained the same before, during, and after spaceflight (both P>0.05). The skewness of systolic BP increased in space (0.74±0.51 versus 1.43±1.00; P=0.001), indicating that signal fluctuations became asymmetrical; however, it returned to preflight levels after landing (0.51±0.42). The kurtosis increased in space (5.01±7.67 versus 11.10±11.79; P=0.010), suggesting that fluctuations concentrated around the mean with a narrow distribution; however, it also returned to preflight levels (2.21±2.56) after return to earth. CONCLUSIONS: Given current countermeasures including in-flight exercise training and volume resuscitation on return, no astronauts experienced orthostatic hypotension or intolerance during routine (for landing day) activities in the initial 24 hours after landing following 6 months in space. Prolonged exposure to spaceflight had little impact on systolic BP variability and its distribution, although the latter showed a transient change in space (accompanied by mild relative hypotension), all of which returned to preflight values after return to earth.

Plasma matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs and aging and lifelong exercise adaptations in ventricular and arterial stiffness.

The age-associated increase in cardiac and central arterial stiffness is attenuated with lifelong (>25 years) endurance exercise in a dose-dependent manner. Remodelling of the extracellular matrix of cardiovascular structures may underpin these lifelong exercise adaptations in structural stiffness. The primary aim was to examine whether matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) levels are associated with aging and lifelong exercise-related changes in cardiac and central arterial stiffness. Plasma MMPs and TIMPs, left ventricular (LV) (LV stiffness constant) and central arterial stiffness (pulse wave velocity) were examined in healthy adults stratified into five groups based on age and lifelong weekly exercise frequency: (1) young sedentary adults (28-50 years), and older adults (>60 years) who had performed either: (a) sedentary (0-1 sessions/week), (b) casual (2-3 sessions/week), (c) committed (4-5 sessions/week) or (d) athletic (≥6 sessions/week) frequency of exercise. MMP-1 was significantly lower in young compared to older sedentary (p = 0.049). Except for TIMP-2 (p = 0.018 versus committed) and the ratio of MMP-2/TIMP-4 (p = 0.047 versus committed), MMP and TIMP expression was not significantly different in lifelong exercise groups (≥casual) compared to the older sedentary group. MMP-1, -3 had a weak positive relationship with central PWV (r = 0.17-0.25, p ≤ 0.050) but there were no significant relationships between MMPs or TIMPs and LV stiffness constant (p ≥ 0.148). In conclusion, there was not a clear or consistent difference in plasma MMPs and TIMPs with lifelong exercise dose despite exhibiting lower cardiovascular stiffness at the highest exercise levels.

Impact of Lifelong Exercise Training Dose on Ventricular-Arterial Coupling.

BACKGROUND: The dynamic Starling mechanism, as assessed by beat-by-beat changes in stroke volume and left ventricular end-diastolic pressure, reflects ventricular-arterial coupling. It deteriorates with age, and is preserved in highly trained masters athletes. Currently, it remains unclear how much exercise over a lifetime is necessary to preserve efficient ventricular-arterial coupling. The purpose of this study was to assess the dose-dependent relationship between lifelong exercise training and the dynamic Starling mechanism in healthy seniors. METHODS: One hundred two seniors were recruited and stratified into 4 groups based on 25 years of exercise training history: sedentary subjects (n=27, <2 sessions/week), casual exercisers (n=25, 2-3 sessions/week), committed exercisers (n=25, 4-5 sessions/week), and competitive Masters Athletes (n=25, 6-7 sessions/week). The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure, a surrogate for left ventricular end-diastolic pressure, and stroke volume index. RESULTS: The transfer function gain of pulmonary artery pressure-stroke volume index was markedly enhanced in committed and competitive exercisers compared with more sedentary seniors and correlated with higher peak oxygen uptake (Vo2) and lower left ventricular stiffness. The power spectral density of pulmonary artery pressure was greater in sedentary adults than in committed and competitive exercisers, whereas the power spectral density of stroke volume index was greater in competitive exercisers than in the other groups. CONCLUSIONS: There is a graded, dose-dependent improvement in ventricular-arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Our data suggest that the optimal dose of lifelong endurance exercise to preserve ventricular-arterial coupling with age appears to be at least 4 to 5 sessions per week.

The effect of lifelong exercise frequency on arterial stiffness.

KEY POINTS: This study examined the effect of different 'doses' of lifelong (>25 years) exercise on arterial stiffening (a hallmark of vascular ageing) in older adults. There are clear dose-dependent effects of lifelong exercise training on human arterial stiffness that vary according to the site and size of the arteries. Similar to what we have observed previously with ventricular stiffening, 4-5 days week-1 of committed exercise over a lifetime are necessary to preserve 'youthful' vascular compliance, especially of the large central arteries. Casual exercise training of two to three times per week may be sufficient for middle-sized arteries like the carotid to minimize arterial stiffening with ageing. However, there is little effect of exercise training on the small-sized peripheral arteries at any dose. ABSTRACT: Central arterial stiffness increases with sedentary ageing. While near-daily, vigorous lifelong (>25 years) endurance exercise training prevents arterial stiffening with ageing, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent 'dose' of lifelong exercise training (four to five sessions per week for > 30 min) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with ageing. A cross-sectional examination of 102 seniors (>60 years old) who had a consistent lifelong exercise history was performed. Subjects were stratified into four groups based on exercise frequency as an index of exercise 'dose': sedentary: fewer than two sessions per week; casual exercisers: two to three sessions per week; committed exercisers: four to five sessions per week; and Masters athletes: six to seven sessions per week plus regular competitions. Detailed measurements of arterial stiffness and left ventricular afterload were collected. Biological aortic age and central pulse wave velocity were younger in committed exercisers and Masters athletes compared to sedentary seniors. Total arterial compliance index (TACi) was lower, while carotid ß-stiffness index and effective arterial elastance were higher in sedentary seniors compared to the other groups. There appeared to be a dose-response threshold for carotid ß-stiffness index and TACi. Peripheral arterial stiffness was not significantly different among the groups. These data suggest that four to five weekly exercise sessions over a lifetime is associated with reduced central arterial stiffness in the elderly. A less frequent dose of lifelong exercise (two to three sessions per week) is associated with decreased ventricular afterload and peripheral resistance, while peripheral arterial stiffness is unaffected by any dose of exercise.

Effects of Prolonged Spaceflight on Atrial Size, Atrial Electrophysiology, and Risk of Atrial Fibrillation.

BACKGROUND: The prevalence of atrial fibrillation (AF) in active astronauts is ≈5%, similar to the general population but at a younger age. Risk factors for AF include left atrial enlargement, increased number of premature atrial complexes, and certain parameters on signal-averaged electrocardiography, such as P-wave duration, root mean square voltage for the terminal 20 ms of the signal-averaged P wave, and P-wave amplitude. We aimed to evaluate changes in atrial structure, supraventricular beats, and atrial electrophysiology to determine whether spaceflight could increase the risk of AF. METHODS: Thirteen astronauts underwent cardiac magnetic resonance imaging to assess atrial structure and function before and after 6 months in space and high-resolution Holter monitoring for multiple 48-hour time periods before flight, during flight, and on landing day. RESULTS: Left atrial volume transiently increased after 6 months in space (12±18 mL; P=0.03) without changing atrial function. Right atrial size remained unchanged. No changes in supraventricular beats were noted. One astronaut had a large increase in supraventricular ectopic beats but none developed AF. Filtered P-wave duration did not change over time, but root mean square voltage for the terminal 20 ms decreased on all fight days except landing day. No changes in P-wave amplitude were seen in leads II or V1 except landing day for lead V1. CONCLUSIONS: Six months of spaceflight may be sufficient to cause transient changes in left atrial structure and atrial electrophysiology that increase the risk of AF. However, there was no definite evidence of increased supraventricular arrhythmias and no identified episodes of AF.

A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation.

OBJECTIVES: This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. BACKGROUND: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. METHODS: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. RESULTS: The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CONCLUSIONS: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172).

Left Ventricular Volume-Time Relation in Patients With Heart Failure With Preserved Ejection Fraction.

Elevated left ventricular (LV) filling pressures are commonly reported in patients with heart failure with preserved ejection fraction (HFpEF) and are associated with impaired relaxation in diastole. Relaxation has been assessed by Doppler, but the methods for doing so are indirect and heavily influenced by loading conditions. The aim of this study is to assess LV volume-time relation in patients with HFpEF, when correcting for left atrial driving pressure and chamber size, using cardiac magnetic resonance imaging (cMRI). Cine short-axis views by cMRI (1.5T-magnet) at 26 Hz were used for measurement of LV volume. We compared the following diastolic parameters: peak filling rate/end-diastolic volume (PFR/EDV); PFR/EDV/pulmonary capillary wedge pressure (PFR/EDV/PCWP); time to PFR (TPFR); and %TPFR for cardiac cycle calculated by cMRI between patients with HFpEF (n = 10, 73 ± 7 years) and age-matched controls (n = 12, 70 ± 3 years). PCWP was significantly greater in the HFpEF group than in controls (HFpEF vs controls: 15.6 ± 5.2 vs 11.2 ± 1.3 mmHg, p = 0.0092). PFR/EDV was significantly slower in the HFpEF group than in controls (2.68 ± 0.85 vs 3.59 ± 0.87/s, p = 0.03), and was nearly 50% slower when corrected for left atrial driving pressure: PFR/EDV/PCWP (0.18 ± 0.07 vs 0.33 ± 0.10/s/mmHg, p = 0.002). In addition, TPFR (246 ± 17.2 vs 188 ± 15.7 ms, p = 0.04) and %TPFR of cardiac cycle (36.4 ± 10.4 vs 25.6 ± 5.9%, p = 0.012) were significantly longer in the HFpEF group than in controls. Patients with HFpEF have an abnormal volume-time relation, including lower PFR/EDV (PFR/EDV/PCWP) and prolonged TPFR, due to the impairment of active relaxation during early diastole.

Percutaneous Coronary Intervention of Coronary Chronic Total Occlusions Improves Peak Oxygen Uptake During Cardiopulmonary Exercise Testing.

OBJECTIVES: Although coronary chronic total occlusions (CTOs) are treated with percutaneous coronary intervention (PCI) to improve symptoms, studies demonstrating symptom improvement have been mostly limited to questionnaire responses. The current study assessed for changes in peak oxygen uptake during cardiopulmonary exercise testing after CTO-PCI. METHODS: Patients with heart failure or angina symptoms referred for CTO-PCI were prospectively enrolled. The primary outcome of the study was improvement in peak oxygen uptake during cardiopulmonary exercise (CPX) testing 5 months after CTO-PCI. Secondary outcomes included improvement in physical capacity, angina, and self perception of health as assessed by questionnaires, and in plasma brain natriuretic peptide (BNP) levels. RESULTS: CTO-PCI was attempted in 32 men (mean age, 62 ± 6 years; CTO vessel: 47% right coronary, 44% left anterior descending). CTO-PCI was unsuccessful in 1 patient, and 3 patients had restenosis of their CTO vessel at follow-up. In the 28 patients with patent CTO vessel at follow-up, significant improvements were noted in self-reported physical capacity, angina, and several aspects of health perception. In the 25 patients who underwent baseline and follow-up CPX testing, peak oxygen uptake significantly improved from 17.7 ± 4.3 mL/kg/min to 19.1 ± 4.0 mL/kg/min (P=.02). Plasma BNP levels significantly decreased from 143 ± 138 pg/mL to 102 ± 123 pg/mL (P=.01). CONCLUSIONS: CTO-PCI in symptomatic patients was associated with improvements in cardiovascular exercise capacity, as assessed by peak oxygen uptake. These results suggest that in symptomatic patients with CTOs, PCI appears clinically beneficial.

Lifelong Physical Activity Regardless of Dose Is Not Associated With Myocardial Fibrosis.

BACKGROUND: Recent reports have suggested that long-term, intensive physical training may be associated with adverse cardiovascular effects, including the development of myocardial fibrosis. However, the dose-response association of different levels of lifelong physical activity on myocardial fibrosis has not been evaluated. METHODS AND RESULTS: Seniors free of major chronic illnesses were recruited from predefined populations based on the consistent documentation of stable physical activity over >25 years and were classified into 4 groups by the number of sessions/week of aerobic activities ≥30 minutes: sedentary (group 1), <2 sessions; casual (group 2), 2 to 3 sessions; committed (group 3), 4 to 5 sessions; and Masters athletes (group 4), 6 to 7 sessions plus regular competitions. All subjects underwent cardiopulmonary exercise testing and cardiac magnetic resonance imaging, including late gadolinium enhancement assessment of fibrosis. Ninety-two subjects (mean age 69 years, 27% women) were enrolled. No significant differences in age or sex were seen between groups. Median peak oxygen uptake was 25, 26, 32, and 40 mL/kg/min for groups 1, 2, 3, and 4, respectively. Cardiac magnetic resonance imaging demonstrated increasing left ventricular end-diastolic volumes, end-systolic volumes, stroke volumes, and masses with increasing doses of lifelong physical activity. One subject in group 2 had late gadolinium enhancement in a noncoronary distribution, and no subjects in groups 3 and 4 had evidence of late gadolinium enhancement. CONCLUSIONS: A lifelong history of consistent physical activity, regardless of dose ranging from sedentary to competitive marathon running, was not associated with the development of focal myocardial fibrosis.

The effect of 1 year of Alagebrium and moderate-intensity exercise training on left ventricular function during exercise in seniors: a randomized controlled trial.

Sedentary aging leads to left ventricular (LV) and vascular stiffening due in part to advanced glycation end-products (AGEs) cross-linking of extracellular matrix proteins. Vigorous lifelong exercise ameliorates age-related cardiovascular (CV) stiffening and enhances exercise LV function, although this effect is limited when exercise is initiated later in life. We hypothesized that exercise training might be more effective at improving the impact of age-related CV stiffening during exercise when combined with an AGE cross-link breaker (Alagebrium). Sixty-two seniors (≥60 yr) were randomized into four groups: sedentary + placebo, sedentary + Alagebrium, exercise + placebo, and exercise + Alagebrium for 1 yr. Moderate-intensity aerobic exercise was performed 3-4 sessions/wk; controls underwent similar frequency of yoga/balance training. Twenty-four similarly-aged, lifelong exercisers (4-5 sessions/wk) served as a comparator for the effect of lifelong exercise on exercising LV function. Oxygen uptake (Douglas bags), stroke index (SI; acetylene rebreathing), and effective arterial elastance (Ea) were collected at rest and submaximal and maximal exercise. Maximum O2 uptake (23 ± 5 to 25 ± 6 ml·kg(-1)·min(-1)) increased, while SI (35 ± 11 to 39 ± 12 ml/m(2)) and Ea (4.0 ± 1.1 to 3.7 ± 1.2 mmHg·ml(-1)·m(-2)) were improved across all conditions with exercise, but remained unchanged in controls (exercise × time, P ≤ 0.018). SI or Ea were not affected by Alagebrium (medication × time, P ≥ 0.468) or its combination with exercise (interaction P ≥ 0.252). After 1 yr of exercise plus Alagebrium, exercise SI and Ea remained substantially below that of lifelong exercisers (15-24 and 9-22%, respectively, P ≤ 0.415). In conclusion, Alagebrium plus exercise had no synergistic effect on exercise LV function and failed to achieve levels associated with lifelong exercise, despite a similar exercise frequency.

Optical coherence tomography findings after chronic total occlusion interventions: Insights from the "AngiographiC evaluation of the everolimus-eluting stent in chronic Total occlusions" (ACE-CTO) study (NCT01012869).

BACKGROUND: There is limited information on optical coherence tomography (OCT) findings after percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). OCT allows high resolution imaging that can enhance understanding of the vascular response after stenting of chronically occluded vessels. METHODS: The Angiographic Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO) study collected angiographic and clinical outcomes from 100 patients undergoing CTO PCI with the everolimus-eluting stent (EES). OCT was performed 8-months post stenting in 62 patients. Every third frame was analyzed throughout the course of the stented arterial segment. Lumen contours were semi-automatically traced and stent struts were manually delineated, with automatic measurement of the strut to lumen distance. Struts on the luminal side of the lumen contour were classified as malapposed if the distance to the lumen contour exceeded 0.108mm. RESULTS: A total of 44,450 struts in 6047 frames were analyzed, of which 4113 9.3%, 95% confidence intervals [CI] 9.0% to 9.5%) were malapposed and 1230 (2.8%, 95% CI 2.6% to 2.9%) were uncovered. Fifty-five of 62 patients (88.7%, 95% CI 78.5% to 98.4%) had at least one malapposed stent strut and 50 patients (80.7%, 95% CI 69.2% to 88.6%) had at least one uncovered stent strut. Mean strut-intimal thickness of the apposed and malapposed struts was 0.126±0.140mm and -0.491±0.440mm, respectively. CONCLUSION: High rates of stent strut malapposition and incomplete stent strut coverage were observed after CTO PCI using EES, highlighting unique challenges associated with stent implantation in CTOs.

Transient Ischemic Dilatation during Stress Echocardiography: An Additional Marker of Significant Myocardial Ischemia.

AIM: Left ventricular (LV) transient ischemic dilatation (TID) is not clear how it relates to inducible myocardial ischemia during stress echocardiography (SE). METHODS AND RESULTS: Eighty-eight SEs were examined from the site certification phase of the ISCHEMIA Trial. LV end-diastolic volume (EDV) and end-systolic volume (ESV) were measured at rest and peak stages and the percent change calculated. Moderate or greater ischemia was defined as ≥3 segments with stress-induced severe hypokinesis or akinesis. Optimum cut points in stress-induced percent EDV and ESV change that identified moderate or greater myocardial ischemia were analyzed. Analysis from percentage distribution identified a > 13% LV volume increase in EDV or a > 9% LV volume increase in ESV as the optimum cutoff points for moderate or greater ischemia. Using these definitions for TID, there were 27 (31%) with TIDESV and 12 (14%) with TIDEDV . By logistic regression analysis and receiver operating characteristic curves, the percent change in ESV had a stronger association with moderate or greater myocardial ischemia than that of EDV change. Compared to those without TIDESV , cases with TIDESV had larger extent of inducible wall-motion abnormalities, lower peak stress LVEF, and higher likelihood of moderate or grater ischemia. For moderate or greater myocardial ischemia detection, TIDESV had a sensitivity of 46%, specificity of 83%, positive predictive value of 70%, and negative predictive value of 64%. CONCLUSION: Transient ischemic dilatation by SE is a marker of extensive myocardial ischemia and can be used as an additional marker of higher risk.

The AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusion (ACE-CTO) Study.

BACKGROUND: There are limited data on outcomes after implantation of second-generation drug-eluting stents in coronary chronic total occlusions (CTOs). We aimed to evaluate the frequency of angiographic restenosis and clinical outcomes after implantation of the everolimus-eluting stent (EES) in coronary CTOs. METHODS: One hundred patients undergoing successful CTO percutaneous coronary intervention using EES at our institution between 2009 and 2012 were enrolled. The primary study endpoint was binary in-segment restenosis at 8-month follow-up quantitative coronary angiography. Secondary endpoints included death, myocardial infarction, target-lesion and target-vessel revascularization, and symptom improvement. RESULTS: Mean age was 64 ± 7 years and 99% of the patients were men. The successful crossing technique was antegrade wiring in 51 patients, antegrade dissection/reentry in 24 patients, and retrograde in 25 patients. Binary angiographic restenosis occurred in 46% of the patients (95% confidence interval [CI], 35%-57%). The pattern of restenosis was focal, proliferative, and total occlusion in 19 lesions (46%), 14 lesions (34%), and 8 lesions (20%), respectively. At 12 months, the incidences of death, myocardial infarction, target-lesion revascularization, and target-vessel revascularization were 2%, 2%, 37%, and 39%, respectively. At 12 months, symptoms were improved, unchanged, or worse compared with baseline in 89 patients, 8 patients, and 1 patient, respectively (2 patients died before the 12-month follow-up). On multivariable analysis, smaller stent diameter was associated with higher risk for binary angiographic restenosis. CONCLUSION: High rates of angiographic restenosis and repeat revascularization were observed among patients receiving EES in coronary CTOs, but most had significant symptom improvement.

Heart rate recovery after maximal exercise is blunted in hypertensive seniors.

Abnormal heart rate recovery (HRR) after maximal exercise may indicate autonomic dysfunction and is a predictor for cardiovascular mortality. HRR is attenuated with aging and in middle-age hypertensive patients, but it is unknown whether HRR is attenuated in older-age adults with hypertension. This study compared HRR among 16 unmedicated stage 1 hypertensive (HTN) participants [nine men/seven women; 68 ± 5 (SD) yr; awake ambulatory blood pressure (BP) 149 ± 10/87 ± 7 mmHg] and 16 normotensive [control (CON)] participants (nine men/seven women; 67 ± 5 yr; 122 ± 4/72 ± 5 mmHg). HR, BP, oxygen uptake (V̇o2), cardiac output (Qc), and stroke volume (SV) were measured at rest, at two steady-state work rates, and graded exercise to peak during maximal treadmill exercise. During 6 min of seated recovery, the change in HR (ΔHR) was obtained every minute and BP every 2 min. In addition, HRR and R-R interval (RRI) recovery kinetics were analyzed using a monoexponential function, and the indexes (HRRI and RRII) were calculated. Maximum V̇o2, HR, Qc, and SV responses during exercise were not different between groups. ΔHR was significantly different (P < 0.001) between the HTN group (26 ± 8) and the CON group (36 ± 12 beats/min) after 1 min of recovery but less convincing at 2 min (P = 0.055). BP recovery was similar between groups. HRRI was significantly lower (P = 0.016), and there was a trend of lower RRII (P = 0.066) in the HTN group compared with the CON group. These results show that in older-age adults, HRR is attenuated further with the presence of hypertension, which may be attributable to an impairment of autonomic function.

Effect of pulsatile and nonpulsatile flow on cerebral perfusion in patients with left ventricular assist devices.

BACKGROUND: Insertion of a left ventricular assist device (LVAD) is an accepted therapy for advanced heart failure patients. However, the effects on end-organ perfusion, including cerebral autoregulation, are unclear in the presence of reduced pulsatility. Therefore, the objective of this study was to determine whether cerebral autoregulation is impaired in patients with continuous-flow (CF) LVADs. METHODS: Dynamic cerebral autoregulation was assessed in both time-domain (autoregulatory index) and frequency-domain (transfer function analysis) analyses in 9 CF-LVAD subjects, 5 pulsatile LVAD subjects and 10 healthy controls, by evaluating mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) during a sit-stand maneuver at 0.05 Hz (10-second sit, 10-second stand). The autoregulatory index was calculated as the percent change in mean CBFV per mm Hg change in MAP. RESULTS: The magnitude of oscillation in MAP and CBFV was greater in subjects with pulsatile LVADs than either CF-LVADs or healthy controls (p = 0.065 for MAP, p = 0.004 for CBFV). The autoregulatory index and transfer function gain were similar among groups, indicating that dynamic cerebral autoregulation is preserved among patients with CF-LVADs. CONCLUSIONS: Cerebral blood flow in patients with CF-LVADs is comparable to that of healthy controls across a range of blood pressures. Patients with pulsatile devices have greater oscillations in MAP and CBFV. However, dynamic cerebral autoregulation is preserved among subjects with either type of device. Thus, the reduction in pulsatility afforded by CF-LVADs does not impair normal autoregulatory processes.

Impact of lifelong exercise "dose" on left ventricular compliance and distensibility.

BACKGROUND: Sedentary aging has deleterious effects on the cardiovascular system, including decreased left ventricular compliance and distensibility (LVCD). Conversely, Masters level athletes, who train intensively throughout adulthood, retain youthful LVCD. OBJECTIVES: The purpose of this study was to test the hypothesis that preservation of LVCD may be possible with moderate lifelong exercise training. METHODS: Healthy seniors (n = 102) were recruited from predefined populations, screened for lifelong patterns of exercise training, and stratified into 4 groups: "sedentary" (<2 sessions/week); "casual" (2 to 3 sessions/week); "committed" (4 to 5 sessions/week); and "competitive" Masters level athletes (6 to 7 sessions/week). Right heart catheterization and echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion to define LV pressure-volume relationships and Frank-Starling curves. RESULTS: Peak oxygen uptake and LV mass increased with escalating doses of lifelong exercise, with little change in systolic function. At baseline, LV distensibility was greater in committed (21%) and competitive (36%) exercisers than in sedentary subjects. Group LV stiffness constants (sedentary: 0.062 ± 0.039; casual: 0.079 ± 0.052; committed: 0.055 ± 0.033; and competitive: 0.035 ± 0.033) revealed: 1) increased stiffness in sedentary subjects compared to competitive athletes, whereas lifelong casual exercise had no effect; and 2) greater compliance in committed exercisers than in sedentary or casual exercisers. CONCLUSIONS: Low doses of casual, lifelong exercise do not prevent the decreased compliance and distensibility observed with healthy, sedentary aging. In contrast, 4 to 5 exercise sessions/week throughout adulthood prevent most of these age-related changes. As LV stiffening has been implicated in the pathophysiology of many cardiovascular conditions affecting the elderly, this "dose" of exercise training may have important implications for prevention of cardiovascular disease.