Lerman, Lilach O.

Atherosclerotic renovascular disease (RVD) reduces renal blood flow (RBF) and GFR and accelerates poststenotic kidney (STK) tissue injury. Preclinical studies indicate that mesenchymal stem cells (MSCs) can stimulate angiogenesis and modify immune function in experimental RVD. We assessed the safety and efficacy of adding intra-arterial autologous adipose-derived MSCs into STK to standardized medical treatment in human subjects without revascularization. The intervention group ( n =14) received a single infusion of MSC (1.0 × 10 5 or 2.5 × 10 5 cells/kg; n =7 each) plus standardized medical treatment; the medical treatment only group ( n =14) included subjects matched for age, kidney function, and stenosis severity. We measured cortical and medullary volumes, perfusion, and RBF using multidetector computed tomography. We assessed tissue oxygenation by blood oxygen level–dependent MRI and GFR by iothalamate clearance. MSC infusions were well tolerated. Three months after infusion, cortical perfusion and RBF rose in the STK (151.8–185.5 ml/min, P =0.01); contralateral kidney RBF increased (212.7–271.8 ml/min, P =0.01); and STK renal hypoxia (percentage of the whole kidney with R2*>30/s) decreased (12.1% [interquartile range, 3.3%–17.8%] to 6.8% [interquartile range, 1.8%–12.9%], P =0.04). No changes in RBF occurred in medical treatment only subjects. Single-kidney GFR remained stable after MSC but fell in the medical treatment only group (−3% versus −24%, P =0.04). This first-in-man dose-escalation study provides evidence of safety of intra-arterial infusion of autologous MSCs in patients with RVD. MSC infusion without main renal artery revascularization associated with increased renal tissue oxygenation and cortical blood flow.

Background— People with heart failure and preserved ejection fraction develop increases in left ventricular (LV) end-diastolic pressures during exercise that contribute to dyspnea. In normal open-chest animal preparations, the pericardium restrains LV filling when central blood volume increases. We hypothesized that resection of the pericardium using a minimally invasive epicardial approach would mitigate the increase in LV end-diastolic pressure that develops during volume loading in normal and diseased hearts with the chest intact. Methods and Results— Invasive hemodynamic assessment was performed at baseline and after saline load before and after pericardial resection in normal canines with open (n=3) and closed chest (n=5) and in a pig model with features of human heart failure and preserved ejection fraction with sternum intact (n=4). In closed-chest animals, pericardiotomy was performed using a novel subxiphoid procedure. In both experimental preparations of normal dogs, pericardiotomy blunted the increase in LV end-diastolic pressure with saline infusion, while enhancing the saline-mediated increase in LV end-diastolic volume. With chest intact in the pig model, percutaneous pericardial resection again blunted the increase in LV end-diastolic pressure secondary to volume expansion (+4±3 versus +13±5 mm Hg; P =0.014), while enhancing the saline-mediated increase in LV end-diastolic volume (+17±1 versus +10±2 mL; P =0.016). Conclusions— This proof of concept study demonstrates that pericardial resection through a minimally invasive percutaneous approach mitigates the elevation in LV filling pressures with volume loading in both normal animals and a pig model with diastolic dysfunction. Further study is warranted to determine whether this method is safe and produces similar acute and chronic hemodynamic benefits in people with heart failure and preserved ejection fraction.

Uric acid is a risk factor for coronary artery disease in postmenopausal women, but the association with inflammation and coronary endothelial dysfunction (CED) is not well defined. The aim of this study was to determine the relationship of serum uric acid (SUA), inflammatory markers, and CED. In this prospective cohort study, SUA, high-sensitivity C-reactive protein levels, and neutrophil count were measured in 229 postmenopausal women who underwent diagnostic catheterization, were found to have no obstructive coronary artery disease, and underwent coronary microvascular function testing, to measure coronary blood flow response to intracoronary acetylcholine. The average age was 58 years (interquartile range, 52–66 years). Hypertension was present in 48%, type 2 diabetes mellitus in 5.6%, and hyperlipidemia in 61.8%. CED was diagnosed in 59% of postmenopausal women. Mean uric acid level was 4.7±1.3 mg/dL. Postmenopausal women with CED had significantly higher SUA compared with patients without CED (4.9±1.3 versus 4.4±1.3 mg/dL; P =0.02). There was a significant correlation between SUA and percent change in coronary blood flow to acetylcholine ( P =0.009), and this correlation persisted in multivariable analysis. SUA levels were significantly associated with increased neutrophil count ( P =0.02) and high-sensitivity C-reactive protein levels ( P =0.006) among patients with CED, but not among those without CED. SUA is associated with CED in postmenopausal women and may be related to inflammation. These findings link SUA levels to early coronary atherosclerosis in postmenopausal women.

Percutaneous Pericardiotomy ToolIntroductionEpicardial procedures frequently require pericardial manipulation. We aimed to develop a nonsurgical percutaneous pericardial modification tool that may (1) facilitate epicardial‐based procedures by enabling adhesiolysis or (2) attenuate the myocardial constraining effect of the pericardium.MethodsThree novel devices were developed to enable pericardiotomy, all of which can be deployed in over‐the‐wire fashion following percutaneous epicardial access. The grasper permits us to seize the pericardial membrane providing leverage for incision. The scissors enables anterograde cutting maneuvers. The reverse‐slitter allows retrograde incisions; in addition, this device has a deflectable tip that increases the potential cutting area. We optimized these tools for safety by including electrodes to test for phrenic nerve stimulation as well as myocardial stimulation to determine directionality of the cutting devices. The base of the scissors and reverse‐slitter are also blunt ensuring that the cutting element is always away from the myocardium.ResultsFollowing 5 nonbeating heart bench test experiments for prototype development, 11 animal (9 canine, 2 swine) studies were performed. Of these 2 were proof‐of‐concept open chest studies; the remaining 9 were entirely closed‐chest, percutaneous procedures allowing for remodification of the prototypes. The tools successfully permitted incision of the pericardium in all studies. Hemodynamic measurements were assessed postincision and showed no compromise of systolic function. No coronary artery or phrenic nerve damage was seen in any study.ConclusionPercutaneous pericardiotomy is feasible and appears to be safe. It may provide leverage in epicardial‐based procedures and offer treatment options in disease processes characterized by pericardial restraint.

Background The study compared downstream coronary and conduit disease progression in the left anterior descending coronary artery treated with coronary artery bypass grafting using the left internal mammary artery ( LIMA ) versus percutaneous coronary intervention with bare metal stent ( BMS ) or drug eluting stent ( DES ). Methods and Results A total of 12 301 consecutive patients underwent isolated primary coronary revascularization, of which 2386 met our inclusion criteria (Percutaneous coronary intervention, n=1450; coronary artery bypass grafting, n=936). Propensity score analysis matched 628 patients, of which 468 were treated to the left anterior descending with coronary artery bypass grafting with LIMA (n=314), percutaneous coronary intervention with BMS (n=94), and DES (n=60). Coronary angiograms were analyzed by quantitative coronary angiography ( QCA ; n=433). Cumulative downstream coronary and conduit disease progression were estimated by Kaplan–Meier method and effect of treatment type by Cox proportional hazard models. Patients treated with LIMA had significantly lower risk of downstream coronary disease progression at follow‐up angiogram compared with BMS and DES (hazard ratio [ HR ] [95% CI ], 0.34; [0.20–0.59]; P =0.0002; and HR [95% CI ], 0.39; [0.20–0.79]; P =0.01, respectively). LIMA was associated with a lower risk of conduit disease progression compared to BMS and DES ( HR [95% CI ], 0.18; [0.12–0.28]; P <0.001; and HR [95% CI ], 0.27; [0.16–0.46]; P <0.001, respectively). BMS was associated with higher HR for downstream coronary and conduit disease progression compared with DES , but the difference did not reach statistical significance ( HR [95% CI], 1.13; [0.57–2.36]; P =0.73; and HR [95% CI ], 1.46; [0.88–2.50]; P =0.14, respectively). Conclusions LIMA grafting to left anterior descending is associated with significantly lower risk of downstream coronary and conduit disease progression compared to percutaneous coronary intervention with BMS and DES .

Background The mechanisms of atrial fibrillation (AF) are highly divergent. The prevalence of AF increases significantly with age, and underling mechanisms might vary with age. Endothelial dysfunction may be associated with AF and atrial arrhythmia recurrence after catheter ablation. We tested the hypothesis that the impact of endothelial dysfunction on arrhythmia recurrence following catheter ablation is age dependent. Methods and Results This study enrolled 92 participants with AF undergoing catheter ablation. Endothelial function was assessed by peripheral arterial tonometry before ablation, and the natural logarithmic transformation of reactive hyperemia index was calculated. Endothelial dysfunction was defined as a natural logarithmic transformation of reactive hyperemia index <0.618 (median). Participants were followed for atrial tachycardia, flutter, and fibrillation recurrence for a median of 14 months. The mean age was 57±10 years. There was significant interaction between age and endothelial dysfunction in association with recurrence of AF ( P =0.029) and any atrial arrhythmia ( P =0.015), and the risk associated with endothelial dysfunction for arrhythmia recurrence was higher in younger versus older participants. Participants were divided into 2 age groups at a threshold of 60 years. Among participants aged ≤60 years, multivariate Cox proportional hazards analysis revealed the independent association between endothelial dysfunction and increased risk of arrhythmia recurrence (hazard ratio for AF 4.18 [95% CI 1.33–15.82], P =0.014, and for any atrial arrhythmia 3.62 [95% CI 1.29–11.81], P =0.014). Kaplan–Meier analysis showed that participants with endothelial dysfunction had significantly higher rates of recurrence of AF ( P =0.01) and any atrial arrhythmia ( P =0.002). Conclusions The risk associated with endothelial dysfunction for arrhythmia recurrence following catheter ablation was age dependent and was higher in younger participants.

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/heart-rate-modeling/ .