This review defines the role that nitric oxide and β-adrenergic receptors play in mediating the cardioprotective effects of exercise in the setting of ischemia-reperfusion injury.
by
Philippe Genereux;
Philippe Pibarot;
Bjorn Redfors;
Michael J. Mack;
Raj R. Makkar;
Wael A. Jaber;
Lars G. Svensson;
Samir Kapadia;
E. Murat Tuzcu;
Vinod Thourani;
Vasilis Babaliaros;
Howard C. Herrmann;
Wilson Y. Szeto;
David Jay Cohen;
Brian R. Lindman;
Thomas McAndrew;
Maria C. Alu;
Pamela S. Douglas;
Rebecca T. Hahn;
Susheel K. Kodali;
Craig R. Smith;
D. Craig Miller;
John G. Webb;
Martin B. Leon
Aims In patients with aortic stenosis (AS), risk stratification for aortic valve replacement (AVR) relies mainly on valverelated factors, symptoms and co-morbidities. We sought to evaluate the prognostic impact of a newly-defined staging classification characterizing the extent of extravalvular (extra-aortic valve) cardiac damage among patients with severe AS undergoing AVR. Methods and results Patients with severe AS from the PARTNER 2 trials were pooled and classified according to the presence or absence of cardiac damage as detected by echocardiography prior to AVR: no extravalvular cardiac damage (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage (Stage 4). One-year outcomes were compared using Kaplan- Meier techniques and multivariable Cox proportional hazards models were used to identify 1-year predictors of mortality. In 1661 patients with sufficient echocardiographic data to allow staging, 47 (2.8%) patients were classified as Stage 0, 212 (12.8%) as Stage 1, 844 (50.8%) as Stage 2, 413 (24.9%) as Stage 3, and 145 (8.7%) as Stage 4. Oneyear mortality was 4.4% in Stage 0, 9.2% in Stage 1, 14.4% in Stage 2, 21.3% in Stage 3, and 24.5% in Stage 4 (Ptrend < 0.0001). The extent of cardiac damage was independently associated with increased mortality after AVR (HR 1.46 per each increment in stage, 95% confidence interval 1.27-1.67, P < 0.0001). Conclusion This newly described staging classification objectively characterizes the extent of cardiac damage associated with AS and has important prognostic implications for clinical outcomes after AVR.
by
Brian R. Lindman;
Alan Zajarias;
Hersh S. Maniar;
D. Craig Miller;
Rakesh M. Suri;
Suzanne V. Arnold;
John Webb;
Lars G. Svensson;
Susheel Kodali;
Ke Xu;
Girma M. Ayele;
Fay Lin;
Shing-Chiu Wong;
Vasilis Babaliaros;
Vinod Thourani;
Pamela V. Douglas;
Scott Lim;
Martin B. Leon;
Michael J. Mack
Objective: Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS), and when the pulmonary artery pressure is particularly elevated, there may be questions about the clinical benefit of TAVR. We aimed to identify clinical and haemodynamic factors associated with increased mortality after TAVR among those with moderate/severe PH.
Methods: Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the Placement of Aortic Transcatheter Valves (PARTNER) I randomised trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included, and moderate/severe PH was defined as an mPAP ≥35 mm Hg.
Results: Increasing severity of PH was associated with progressively worse 1-year all-cause mortality: none (n=785, 18.6%), mild (n=838, 22.7%) and moderate/severe (n=557, 25.0%) (p=0.01). The increased hazard of mortality associated with moderate/severe PH was observed in females, but not males (interaction p=0.03). In adjusted analyses, females with moderate/severe PH had an increased hazard of death at 1 year compared with females without PH (adjusted HR 2.14, 95% CI 1.44 to 3.18), whereas those with mild PH did not. Among males, there was no increased hazard of death associated with any severity of PH. In a multivariable Cox model of patients with moderate/severe PH, oxygen-dependent lung disease, inability to perform a 6 min walk, impaired renal function and lower aortic valve mean gradient were independently associated with increased 1-year mortality (p<0.05 for all), whereas several haemodynamic indices were not. A risk score, including these factors, was able to identify patients with a 15% vs 59% 1-year mortality.
Conclusions: The relationship between moderate/severe PH and increased mortality after TAVR is altered by sex, and clinical factors appear to be more influential in stratifying risk than haemodynamic indices. These findings may have implications for the evaluation of and treatment decisions for patients referred for TAVR with significant PH.
Accurate identification of in vivo nonlinear, anisotropic mechanical properties of the aortic wall of individual patients remains to be one of the critical challenges in the field of cardiovascular biomechanics. Since only the physiologically loaded states of the aorta are given from in vivo clinical images, inverse approaches, which take into account of the unloaded configuration, are needed for in vivo material parameter identification. Existing inverse methods are computationally expensive, which take days to weeks to complete for a single patient, inhibiting fast feedback for clinicians. Moreover, the current inverse methods have only been evaluated using synthetic data. In this study, we improved our recently developed multi-resolution direct search (MRDS) approach and the computation time cost was reduced to 1~2 hours. Using the improved MRDS approach, we estimated in vivo aortic tissue elastic properties of two ascending thoracic aortic aneurysm (ATAA) patients from pre-operative gated CT scans. For comparison, corresponding surgically-resected aortic wall tissue samples were obtained and subjected to planar biaxial tests. Relatively close matches were achieved for the in vivo-identified and ex vivo-fitted stress-stretch responses. It is hoped that further development of this inverse approach can enable an accurate identification of the in vivo material parameters from in vivo image data.
Objectives: The purpose of this study was to characterize operative outcomes for ascending aorta and arch replacement on a national scale and to develop risk models for mortality and major morbidity. Background: Contemporary outcomes for ascending aorta and arch replacement in North America are unknown. Methods: We queried the Society of Thoracic Surgeons Database for patients undergoing ascending aorta (with or without root) with or without arch replacement from 2004 to 2009. The database captured 45,894 cases, including 12,702 root, 22,048 supracoronary ascending alone, 6,786 ascending plus arch, and 4,358 root plus arch. Baseline characteristics and clinical outcomes were analyzed. A parsimonious multivariable logistic regression model was constructed to predict risks of mortality and major morbidity. Results: Operative mortality was 3.4% for elective cases and 15.4% for nonelective cases. A risk model for operative mortality (c-index 0.81) revealed a risk-adjusted odds ratio for death after emergent versus elective operation of 5.9 (95% confidence interval: 5.3 to 6.6). Among elective patients, end-stage renal disease and reoperative status were the strongest predictors of mortality (adjusted odds ratios: 4.0 [95% confidence interval: 2.6 to 6.4] and 2.3 (95% confidence interval: 1.9 to 2.7], respectively; p < 0.0001). Conclusions: Current outcomes for ascending aorta and arch replacement in North America are excellent for elective repair; however, results deteriorate for nonelective status, suggesting that increased screening and/or lowering thresholds for elective intervention could potentially improve outcomes. The predictive models presented may serve clinicians in counseling patients.
by
Hemal Gada;
Ajay J Kirtane;
Kaijun Wang;
Yang Lei;
Elizabeth Magnuson;
Matthew R Reynolds;
Mathew R Williams;
Susheel Kodali;
Torsten P Vahl;
Suzanne V Arnold;
Martin B Leon;
Vinod Thourani;
Wilson Y Szeto;
David J Cohen
Background - In the Placement of AoRTic TraNscathetER Valve (PARTNER) randomized controlled trial (RCT), which represented the first exposure to transapical transcatheter aortic valve replacement (TA-TAVR) for many clinical sites, high-risk patients undergoing TA-TAVR derived similar health-related quality of life (HRQoL) outcomes when compared with surgical aortic valve replacement (SAVR). With increasing experience, it is possible that HRQoL outcomes of TA-TAVR may have improved.
Methods and Results - We evaluated HRQoL outcomes at 1-, 6-, and 12-month follow-ups among 875 patients undergoing TA-TAVR in the PARTNER nonrandomized continued access (NRCA) registry and compared these outcomes with those of the TA-TAVR and SAVR patients in the PARTNER RCT. HRQoL was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Medical Outcomes Study Short-Form 12, and the EuroQoL-5D, with the KCCQ overall summary score serving as the primary end point. The NRCA TA-TAVR and RCT TA-TAVR and SAVR groups were generally similar. The primary outcome, the KCCQ summary score, did not differ between the NRCA TA-TAVR and the RCT TA-TAVR group at any follow-up timepoints, although there were small differences in favor of the NRCA cohort on several KCCQ subscales at 1 month. There were no significant differences in follow-up HRQOL between the NRCA-TAVR and the RCT SAVR cohorts on the KCCQ overall summary scale or any of the disease-specific or generic subscales.
Conclusions - Despite greater experience with TA-TAVR in the NRCA registry, HRQoL outcomes remained similar to those of TA-TAVR in the original RCT cohort and no better than those with SAVR. These findings have important implications for patient selection for TAVR when transfemoral access is not an option.
Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation. Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure. Methods and Results Mice (C57BL/6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days. Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days. Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure. Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ‐51 and blocking endogenous vascular endothelial growth factor C with a neutralizing antibody blunted the increase in lymphatic vessel density, blunted lymphatic transport, increased inflammation, increased edema, and increased cardiac dysfunction. Subsequent studies revealed that augmentation of the endogenous lymphangiogenesis response with vascular endothelial growth factor C treatment reduced inflammation, reduced edema, and improved cardiac dysfunction. Conclusions These results suggest that the endogenous lymphangiogenesis response plays an adaptive role in the development of ischemic‐induced heart failure and supports the emerging concept that therapeutic lymphangiogenesis is a promising new approach for the treatment of cardiovascular disease.
Exercise training confers sustainable protection against ischemia/reperfusion injury. However, the mechanism by which this process occurs is not fully understood. Previously, it was shown that β3-adrenergic receptors (β3-ARs) play a critical role in regulating the activation of endothelial nitric oxide synthase (eNOS) in response to exercise and play a critical role in exercise-mediated cardioprotection. Intriguingly, a deficiency in β3-ARs led to increased myocardial injury following exercise training. The purpose of the current study was to determine mechanisms by which β3-ARs are linked to eNOS activation and to determine the mechanism responsible for the exacerbated ischemia/reperfusion injury displayed by β3-AR deficient (β3-AR KO) mice after exercise training. Wild-type (n = 37) and β3-AR KO ( n = 40) mice were subjected to voluntary wheel running for 4 weeks. Western blot analysis revealed that neither protein kinase B nor protein kinase A linked β3-ARs to eNOS following exercise training. However, analysis revealed a role for AMP-activated protein kinase (AMPK). Specifically, exercise training increased the phosphorylation of AMPK in the hearts of wild-type mice, but failed to do so in the hearts of β3-AR KO mice. Additional studies revealed that exercise training rendered eNOS less coupled and increased NOS-dependent superoxide levels in β3-AR KO mice. Finally, supplementing β3-AR KO mice with the eNOS coupler, tetrahydrobiopterin, during the final week of exercise training reduced myocardial infarction. These findings provide important information that exercise training protects the heart in the setting of myocardial ischemia/reperfusion injury by activating and coupling eNOS via the stimulation of a β3-AR-AMPK signaling pathway.