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Functional tricuspid regurgitation (TR) is a common pathophysiologic condition in adults with ostium secundum atrial septal defect (ASD). The aim of this study was to evaluate long-term outcomes following transcatheter ASD closure, which have not been well studied among patients with significant TR.We reviewed consecutive adult patients who underwent transcatheter ASD closure at Toronto General Hospital, Ontario, Canada, from 1998 to 2016. We linked our hospital registry with Ontario population-based health administrative databases to collect longitudinal data on inpatient and outpatient health care utilisation and vital status.In this cohort study of 949 patients, 199 (22%) had moderate to severe TR before transcatheter ASD closure. A significant proportion of patients (61%) showed improvement in TR severity to at least mild TR after ASD intervention. At a median follow-up of 10.9 years, patients with baseline mild or no TR, compared with those with greater than moderate TR, had significantly lower rates of all-cause mortality (6.8 vs 22.5 per 1000 person-years [PY]; P0.001), composite hospitalisation for atrial fibrillation (AF) or heart failure (HF) (22.3 vs 49.1 per 1000 PY; P0.001), and new onset of AF (10.4 vs 20.2 per 1000 PY; P = 0.002) and HF (5.0 vs 9.2 per 1000 PY; P = 0.039). Preprocedural TR was independently associated with higher all-cause mortality (adjusted hazard ratio 1.69, 95% confidence interval 1.08-2.62).TR severity was independently associated with a higher risk of mortality and morbidity. Further investigation of earlier device closure or concomitant tricuspid valve intervention may be of interest.

Internet search data can accurately assess the intensity of public interest in environmental issues. Although invasive plants are a major environmental problem, public interest in invasive plants is generally considered low compared to climate change and threatened flagship species. To understand what drives public interest in invasive plants in the US, we investigated Google Trends search data from 2010 to 2020 for 210 invasive plant species found in the continental US. We investigated three hypothesized drivers of interest: (1) plant abundance as quantified by national and state-level occurrence records in the Global Biodiversity Information Facility, (2) media coverage, in particular the volume and tone of news articles over the same 10-year period, and (3) five key plant traits that might influence plant conspicuousness to the general public: ornamental use, human health risks, monoculture formation, plants with positive economic value, and time since introduction. Google search interest was positively but indirectly influenced by species’ state and national level abundance patterns. In contrast, public search interest was most strongly and directly determined by species with greater human health risk and enhanced media coverage (through the number and tone of published articles). Ultimately, this suggests that enhanced media coverage of invasive plant species, particularly articles that detail their negative impacts, could generate increased public awareness for biological invasions.

AIM: Climate change is leading to large‐scale shifts in species’ range limits. Mangroves, for example, are encroaching into saltmarshes at numerous tropical–temperate transition zones. However, mangrove expansion varies geographically, in large part because mangroves might not be fully occupying their fundamental niches across their range limits. Here we characterize and compare the fundamental versus realized thermal niches of two mangrove species found near their northern range limits on both coasts of North America. LOCATION: Atlantic and Pacific coasts of North America. TAXA: Red mangrove (Rhizophora mangle), black mangrove (Avicennia germinans). METHODS: Red and black mangrove propagules were collected near range limits on the Atlantic and Pacific coasts and experimentally exposed to simulated overnight freezes ranging from −0.5 to −15°C, and grown in water temperatures ranging from 13 to 25°C. We then modelled range‐specific distributions based on threshold survival responses to cold treatments and compared these predictions to current distributions and climate envelopes. RESULTS: On the Atlantic coast, laboratory physiological thresholds closely matched realized distributions for both black and red mangroves. The Pacific black mangroves were less tolerant to freezes than the Atlantic populations, but laboratory determined thresholds essentially matched their realized distributions. In contrast, Pacific red mangroves were surprisingly freeze tolerant, and our laboratory threshold‐based model predicted suitable habitat far north of their current range limit. Our cold‐water tolerance experiments indicated that mangroves can tolerate chronically colder water temperatures than are currently experienced at either range limit. MAIN CONCLUSIONS: On its own, cold water temperature does not seem to be a limiting factor on either coast of North America. On the Atlantic coast, range limits for both mangrove species are set by extreme cold air temperatures and rapidly shifting in response to climate change. On the warmer but more arid Pacific coast, range limits for black mangroves only appear limited by cold air temperatures, but neither species seems to be undergoing climate change‐related migration. This supports the importance of other range‐restricting factors, such as aridity or dispersal limitation. Thus, distribution models need to incorporate species and range‐specific physiological data to predict the effects of climate change on population‐specific range limits.

Ecological release from herbivory due to chemical novelty is commonly predicted to facilitate biological invasions by plants, but has not been tested on a community scale. We used metabolomics based on mass spectrometry molecular networks to assess the novelty of foliar secondary chemistry of 15 invasive plant species compared to 46 native species at a site in eastern North America. Locally, invasive species were more chemically distinctive than natives. Among the 15 invasive species, the more chemically distinct were less preferred by insect herbivores and less browsed by deer. Finally, an assessment of invasion frequency in 2,505 forest plots in the Atlantic coastal plain revealed that, regionally, invasive species that were less preferred by insect herbivores, less browsed by white‐tailed deer, and chemically distinct relative to the native plant community occurred more frequently in survey plots. Our results suggest that chemically mediated release from herbivores contributes to many successful invasions., Ecological release from herbivory due to chemical novelty is predicted to facilitate biological invasions by plants, but has not been tested on a community scale. We used metabolomics to assess the chemical novelty of invasive plant species at a site in eastern North America. Locally, invasive species were more chemically distinctive than natives. Among the invasive species, the more chemically distinct were less preferred by insect herbivores, less browsed by deer, and occurred more frequently in a large, regional network of forest plots. Our results suggest that chemically mediated release from herbivores contributes to many successful invasions.

1. Climate change alters freshwater availability in many ecosystems leading to shifts in distributions for many plants. Despite living exclusively in intertidal, saline environments, mangroves rely on non‐saline water to maintain plant productivity. However, several mangrove species persist in arid environments where non‐saline water from rain and groundwater sources are limited. Under these conditions, foliar water uptake from fog and mist may be an important water acquisition strategy. 2.We conducted a field experiment in arid Baja California Sur, Mexico along with a controlled mist chamber experiment (using seedlings sourced from humid subtropical region, Florida, USA) to show that three co‐occurring, neotropical mangrove species, Avicennia germinans, Laguncularia racemosa and Rhizophora mangle, growing in both arid and humid environments can access water condensed on their leaves. 3. Foliar water uptake was greatest in A. germinans and lowest in R. mangle, possibly reflecting leaf traits associated with species‐specific water balance strategies. In our field misting experiment, the contribution of foliar water uptake was higher in A. germinans (32 ± 2%) than L. racemosa (26 ± 2%) and R. mangle (16 ± 1%). Foliar water uptake also varied across locations for L. racemosa and R. mangle, with declining uptake towards both species’ northern range limits in Baja California 4. Sur, suggesting the distribution patterns of arid‐zone mangroves may be affected by species‐specific spatial variation in foliar water use. Within species, foliar water use was comparable across field and controlled experiments irrespective of source population (Baja California Sur vs. Florida), suggesting foliar water uptake is not an arid‐zone adaptation, and is instead used as a supplemental water balance strategy in arid and humid neotropical mangroves. 5. Synthesis. Our findings indicate mangroves have the potential to access atmospheric water, such as rain, dew and sea fog, through their leaves to offset soil water deficits. Variation in foliar water use across these three neotropical mangrove species may influence mangrove species distributions across arid‐zone and pseudo‐drought (highly saline) environments, with implications for mangrove response to climate change.

Background Evidence of a circadian rhythm in endothelium-dependent vasomotor function, with a nadir in Flow-Mediated Dilation (FMD) in the early morning hours, has been previously reported. These changes have been proposed to be one of the mechanisms explaining the circadian pattern in the incidence of cardiovascular events. We set out to investigate the circadian rhythm of FMD, low-flow mediated dilation (L-FMC) and sympathetic vascular tone. Methods and results 10 young healthy male volunteers (mean age, 28.9±3.7 years) underwent measurements of radial artery endothelium-dependent FMD and L-FMC at 8AM, 2PM and 8PM on the same day. Sympathetic vascular tone was assessed with laser Doppler and Fourier transform analysis. Compared with 2PM and 8PM, FMD decreased markedly in the early morning (2.9±3.4%; 6.2±2.9%; 6.0±4.0%; P = 0.007). In contrast, L-FMC was maximal at 8AM, decreased significantly at 2PM, and returned to higher values at 8PM (-5.1±1.3%; -2.7±2.0%; -4.6±2.2%; P = 0.030), such that the composite endpoint of endothelial function (sum of FMD+L-FMC) was not significantly different among timepoints. Vascular sympathetic tone was maximal early in the morning and lowest in the evening (P = 0.014) without a correlation with the changes in FMD or L-FMC. Conclusions Endothelial responsiveness (FMD) and basal tone (L-FMC) appear to follow different circadian rhythms, with an impaired responsiveness in the early morning and a nadir in baseline tone in the early afternoon.

Author(s): Anand, Inder S; Konstam, Marvin A; Klein, Helmut U; Mann, Douglas L; Ardell, Jeffrey L; Gregory, Douglas D; Massaro, Joseph M; Libbus, Imad; DiCarlo, Lorenzo A; Udelson, John James E; Butler, Javed; Parker, John D; Teerlink, John R | Abstract: AimsClinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation.Methods and resultsDescriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P l 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P l 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P l 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P l 0.04).ConclusionsIn this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

Poorly controlled type 2 diabetes mellitus is associated with the development of cardiovascular and renal complications, resulting in significant morbidity and mortality. Intensive glycemic control has been a major focus for clinical trials and novel drug development. However, narrow treatment strategies developed strictly for glycemic control did not confer a large risk reduction in cardiovascular events. There were also only modest effects in reducing the progression of diabetic kidney disease. Recent cardiovascular safety trials and the dedicated renal protection trial CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) have shown that the sodium-glucose cotransporter-2 (SGLT2) inhibitors, a newer generation of antihyperglycemic agents, improve both cardiovascular and renal outcomes when added to guideline-recommended treatment. This review examines the current evidence on the mechanism underlying the cardiorenal effects of SGLT2 inhibitors and summarizes clinical trial evidence and safety data related to the use of SGLT2 inhibitors for cardiovascular and renal protection.

In contrast to expectations of the enemy release hypothesis, but consistent with the notion of biotic resistance, we found that native generalist crayfishes preferred exotic over native freshwater plants by a 3 : 1 ratio when plants were paired by taxonomic relatedness. Native crayfishes also preferred exotic over native plants when tested across 57 native and 15 exotic plants found growing sympatrically at 11 sites throughout the southeastern USA. Exotic grass carp that share little evolutionary history with most of these plants exhibited no preference for native vs. exotic species. Analyses of three terrestrial data sets showed similar patterns, with native herbivores generally preferring exotic plants, while exotic herbivores rarely exhibited a preference. Thus, exotic plants may escape their coevolved herbivores only to be preferentially consumed by the native generalist herbivores in their new ranges, suggesting that native herbivores may provide biotic resistance to plant invasions.

Objective Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. Methods In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). Results The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P Conclusions A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.

Macroclimatic changes are expected to radically alter coastal wetland ecosystems in the coming century. The trajectory of the response to climate warming may differ based on other concomitantly changing abiotic variables such as soil salinity and relative humidity. Thus, understanding plant responses to multiple interacting stressors is required to accurately predict coastal wetland shifts under climate change. The ongoing poleward shift of mangrove range limits has been linked with a reduction in freeze events, yet interactions between low temperature and other abiotic stressors remain underexplored. We grew two common mangroves (Avicennia germinans and Rhizophora mangle, n = 1222) from propagules for 10 months in environmental growth chambers under experimentally manipulated temperature, salinity, and relative humidity treatments that reflected the range of conditions these species experience in the field. We measured variation in growth and physiological characteristics before, during, and after low temperature exposure. For both species, resistance and resilience to low temperature stress were mediated by salinity and relative humidity conditions. Chronic chilling at 10 °C caused widespread reduction in seedling stem elongation rate, altered leaf gas exchange rates, and increased mortality, particularly under high salinity and low humidity conditions. Additional exposure to an overnight freeze (−4 °C) had relatively minor impacts. Five months after exposure to low temperatures, some R. mangle exhibited the capacity to recover from severe cold damage, but only under optimal humidity and salinity conditions. Although A. germinans were generally more resistant to low temperature stress, severely damaged plants did not recover, even in low salinity and high humidity conditions. We contend that current and future mangrove range limits are the result of interactions between multiple abiotic stressors including temperature, salinity, and relative humidity. Consequently, future modelling approaches to predicting range shifts under climate change need to consider multiple concomitantly changing abiotic variables and their interactions.

IMPORTANCE: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. OBJECTIVE: To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. DESIGN, SETTING, AND PARTICIPANTS: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o(2)), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. INTERVENTIONS: Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the change from baseline in peak V̇o(2) in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). RESULTS: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o(2) were 0.04 mL/kg/min (95% CI, –0.49 to 0.56) and −0.26 mL/kg/min (95% CI, −0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was −0.30 mL/kg/min ([95% CI, −0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was –16.7 m (95% CI, −47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was −0.3 (95% CI, −1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group). CONCLUSIONS AND RELEVANCE: Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o(2) from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03254485

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide1,2. Regrowing natural forests is a prominent strategy for capturing additional carbon3, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates2,3. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)4,5 may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported3 owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy. A one-kilometre-resolution map of aboveground carbon accumulation rates of forest regrowth shows 100-fold variation across the globe, with rates 32% higher on average than IPCC estimates.

The role of tree diversity in restored forests and its impact on key ecological processes like growth and resistance to herbivory has become increasingly important. We analyzed height growth and white-tailed deer Odocoileus virginianus browsing damage to saplings of 16 broadleaved tree species in a large-scale (13 ha) reforestation experiment in Maryland, USA, where we manipulated tree diversity in 70 1,225-m2 plots. After four growing seasons, higher plot-level tree richness led to increased deer browsing damage (i.e., associational susceptibility). Despite increased deer damage to saplings in mixed plots, tree richness had no overall effect on sapling height growth. However, diversity–height relationships were related to species functional traits. Light demanding species with large leaves and faster growth rates had reduced heights in mixtures, whereas shade-tolerant, slower-growing species generally had either increased or unchanged height growth in diverse tree communities, likely related to increased canopy closure in mixtures relative to monocultures. We show that tree diversity can improve growth of late successional species despite exacerbated mammalian herbivore damage. By facilitating the establishment of species with a range of life-history strategies, increased tree diversity may enhance ecosystem multi-functionality in the early stages of forest restoration.

Background The phosphodiesterase-5 (PDE5) inhibitors that have been available for nearly 20 years are highly effective in treating erectile dysfunction and have been consistently shown to be safe when used according to package insert instructions. Aim To review the cardiovascular (CV) safety of PDE5 inhibitors used to treat erectile dysfunction. Methods PubMed, the Derwent Drug File, and Embase were searched to identify papers published from 1990–2016 presenting CV safety data for PDE5 inhibitors. Outcomes This narrative review focuses mainly on papers published in the last 10 years with CV safety data for sildenafil, tadalafil, or vardenafil. Results Similar to earlier studies, newer studies demonstrate that PDE5 inhibitors do not show an increased incidence of serious CV adverse events such as cardiac death or myocardial infarction. There are drug–drug interactions with PDE5 inhibitors that for the most part are now commonly known, and PDE5 inhibitors are generally safe to use with other commonly used drugs including antihypertensive agents. Conclusion PDE5 inhibitors are a class of drugs that when used appropriately demonstrate a favorable CV safety profile and present some encouraging signals for new CV indications, which will require additional study. Kloner RA, Goldstein I, Kirby MG, et al. Cardiovascular Safety of Phosphodiesterase Type 5 Inhibitors After Nearly 2 Decades on the Market. Sex Med Rev 2018;6:583–594.

Low molecular weight heparin has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women; however, the results from these trials have been conflicting. This review discusses the potential mechanisms of action of low molecular weight heparin for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials, and the importance of trial standardization.

Non-invasive hemodynamic monitoring has the potential to be a valuable clinical tool for the screening and management of hypertensive disorders of pregnancy. The objective of this study was to validate the clinical utility of the non-invasive cardiac output monitoring (NICOM) system in pregnant women.Twenty healthy pregnant women with a singleton pregnancy at 22 to 26 weeks' gestation were enrolled in this study. Measures of heart rate, stroke volume, and cardiac output were obtained through NICOM and compared with Doppler echocardiography.NICOM significantly overestimated measures of both stroke volume and cardiac output compared with Doppler echocardiography (95 ± 4 vs. 73 ± 4 mL, P0.0001; and 7.4 ± 0.2 vs. 5.6 ± 0.2 L/min, P0.0001; respectively).There is no gold standard for the measurement of cardiac output in the setting of pregnancy. However, once normal values have been established, NICOM has the potential to be a useful clinical tool for monitoring maternal hemodynamics in pregnant women. Further investigation regarding the validity of NICOM is required in larger populations of healthy and hypertensive pregnant women to determine whether this device is appropriate for maternal hemodynamic assessment during pregnancy.

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures ( P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan ( P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan ( P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF.

Aims Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. Methods and results We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00–1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00–1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. Conclusions In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients.

We investigated the impact of short-acting and extended release nifedipine on sympathetic activity using radiotracer methodology in patients with stable coronary artery disease in order to more accurately document the response of the sympathetic nervous system to different formulations of this dihydropyridine calcium channel antagonist. Participants were randomized to placebo, short-acting or extended release nifedipine for 7–10 days. On the final day, systemic blood pressure, cardiac filling pressures, cardiac output, plasma norepinephrine (NE) and total body NE spillover were measured at baseline (time 0) and repeated at intervals for 6 hours. There were no differences in baseline measures between groups. Following the morning dose of study medication there were no changes in hemodynamics or sympathetic activity in the placebo group. However, there was a significant fall in blood pressure and a significant increase in total body NE spillover in both nifedipine groups. Importantly, the increase in sympathetic activity in response to short-acting nifedipine began earlier (30 minutes) and was much greater than that observed in the extended release group, which occurred later (270 minutes). These findings confirm that sustained therapy with nifedipine is associated with activation of the sympathetic nervous system which is dependent on the pharmacokinetics of the formulation.

Biotic resistance to plant invasions takes many forms: consumption by native herbivores, competition with native plants and infection by native pathogens. But how often does biotic resistance prevent the damaging monocultures that typify the most problematic plant invaders, and how often is biotic resistance overwhelmed by the direct and indirect impacts of human activities? This chapter attempts to answer these questions, drawing on the long history of research into biotic resistance. We first briefly describe the major forms of biotic resistance to exotic plant invasions as an antecedent to other, more detailed chapters on competition, herbivory and pathogens. We then describe a new neutral model where variance in disturbance promotes invasions over the short term, but over longer timescales only propagule pressure drives invasions. These findings are a cautionary tale; pending increases in global trade and travel, particularly to the tropics, may provide the prerequisite disturbance and propagule pressure needed to ultimately stoke further invasions. Finally, we highlight case studies where invasions have been mitigated by restoration of biotic resistance from native herbivores and competitors. These studies provide strong empirical support that conservation of native biodiversity can be a nature-based solution to some invasions, although it remains to be seen if climate change will alter these effects over longer timescales.

Although decades of research have typically demonstrated a positive correlation between biodiversity of primary producers and associated trophic levels, the ecological drivers of this association are poorly understood. Recent evidence suggests that the plant microbiome, or the fungi and bacteria found on and inside plant hosts, may be cryptic yet important drivers of important processes, including primary production and trophic interactions. Here, using high-throughput sequencing, we characterized foliar fungal community diversity, composition, and function from 15 broadleaved tree species (N = 545) in a recently established, large-scale temperate tree diversity experiment using over 17,000 seedlings. Specifically, we tested whether increases in tree richness and phylogenetic diversity would increase fungal endophyte diversity (the “Diversity Begets Diversity” hypothesis), as well as alter community composition (the “Tree Diversity–Endophyte Community” hypothesis) and function (the “Tree Diversity–Endophyte Function” hypothesis) at different spatial scales. We demonstrated that increasing tree richness and phylogenetic diversity decreased fungal species and functional guild richness and diversity, including pathogens, saprotrophs, and parasites, within the first three years of a forest diversity experiment. These patterns were consistent at the neighborhood and tree plot scale. Our results suggest that fungal endophytes, unlike other trophic levels (e.g., herbivores as well as epiphytic bacteria), respond negatively to increasing plant diversity.

Background Vagus Nerve Stimulation (VNS) is meant to deliver Autonomic Regulation Therapy (ART) to neurological targets with sufficient neuromodulation (NM) to ameliorate chronic heart failure (CHF). VNS delivery consists of its intensity (a combination of pulse amplitude, pulse frequency, and pulse duration), polarity, duty cycle (DC; stimulation “on” time and “off” time), and mode (continuous, or intermittent and periodic). In the ANTHEM-HF Pilot Study patients with CHF and reduced ejection fraction (HFrEF), VNS intensity was up-titrated until a change in heart rate (HR) dynamics was objectively confirmed. This did not require any change in GDMT and was associated with significant improvements in LVEF, 6-minute walk distance (6MWD), Minnesota Living with HF (MLWHF) score, and HR variability. Methods Qualitative and quantitative analyses used data from peer-reviewed publications and other sources in the public domain to compare VNS delivery in ANTHEM-HF, INOVATE-HF, and NECTAR-HF. Results (Table): Up-titration of VNS intensity was attempted in all 3 studies. In contrast to ANTHEM-HF, INOVATE-HF aimed only at peripheral neural targets. VNS intensity was delivered at a lower pulse frequency, and had a variable DC as a consequence of R-wave synchronization and only intermittent, periodic stimulation. In NECTAR-HF VNS intensity was delivered at a higher pulse frequency, and this was associated with intolerable adverse off-target effects which restricted VNS up-titration. Significant improvements in EF, 6MWD, MLWHF, and SDNN occurred in ANTHEM-HF relative to the other studies. ANTHEM-HF (n=60) INOVATE-HF (n=436) NECTAR-HF (n=63) Neural Target Central/Peripheral Peripheral Central/Peripheral Delivery Site Left or right CVN Right CVN Right CVN Delivery Intensity: Amplitude (milliamperes) 2.0±0.6 3.9±1.0 1.4±0.8 Frequency (Hertz) 10 1–2 20 Duration (microseconds) 250 500 300 Electrode Polarity (Cathode) Caudal Cephalad Caudal Duty Cycle 23% 25% 17% On Time/Off Time (seconds) 18/62 Variable 10/50 Mode of Delivery Cyclic/Continuous Intermittent/Periodic Cyclic/Continuous Clinical Efficacy at 6 Months: EF 32.4±7.2 to 37.2±10.4 Not available 30.5±6.0 to 32.7±6.4 6MWD 287±66 to 346±78 317±109 to 347±123 Not available MLWHFS 40±14 to 21±10 Not available 44.2±22.2 to 35.8±20.8 SDNN 94±26 to 111±50 Not available 146±48 to 130±52 Values reported as mean ± standard deviation; CVN = Cervical vagus nerve. *p Conclusion VNS differed in ANTHEM-HF when compared to INOVATE-HF and NECTAR-HF. The neural targets, pulse frequencies for titration, and the DC for NM were different. VNS in ANTHEM-HF was clinically efficacious. The ongoing ANTHEM-HFrEF Pivotal Study uses a similar paradigm. Acknowledgement/Funding LivaNova PLC

HF is associated with decreased renal blood flow and RAAS activation, which may be aggravated in the presence of T2D. The renal arterial-venous gradient for RAAS markers has not been previously reported in HF patients. Our aim was to characterize renal hemodynamic function and renal arterial-venous gradient for RAAS markers in patients with: (1) HF with T2D, (2) HF without T2D, and (3) controls without HF or T2D. In this post hoc analysis, GFRinulin, ERPFPAH, plasma angiotensin converting enzyme (ACE), ACE2, aldosterone, angiotensinogen, plasma renin activity (PRA) and ACE activity were measured in renal artery and vein samples from 20 HF with T2D, 28 HF without T2D and 24 controls. RAAS inhibitors were used in 90% of HF and 63% of controls. GFR and ERPF were higher in controls vs. HF with and without T2D (p HF patients exhibited lower renal perfusion vs. non-HF patients regardless of T2D status. A larger renal arterial-venous gradient for the RAAS markers suggests a renal origin for neurohormonal activation in HF patients. T2D status did not impact renal hemodynamics or RAAS markers in patients with HF, highlighting the need to broadly target neurohormonal abnormalities in these patients. Disclosure Y. Lytvyn: None. K.D. Burns: None. A. Lytvyn: None. J.P. Ambinathan: None. O. Osuntokun: None. L.C. Godoy: None. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. J.D. Parker: Research Support; Self; Ironwood Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Theracos, Inc. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Servier, Theracos, Inc.