Screening for hypertension in adults: protocol for evidence reviews to inform a Canadian Task Force on Preventive Health Care guideline update.

PURPOSE: To inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening in a primary care setting for hypertension in adults aged 18 years and older. This protocol outlines the scope and methods for a series of systematic reviews and one overview of reviews. METHODS: To evaluate the benefits and harms of screening for hypertension, the Task Force will rely on the relevant key questions from the 2021 United States Preventive Services Task Force systematic review. In addition, a series of reviews will be conducted to identify, appraise, and synthesize the evidence on (1) the association of blood pressure measurement methods and future cardiovascular (CVD)-related outcomes, (2) thresholds for discussions of treatment initiation, and (3) patient acceptability of hypertension screening methods. For the review of blood pressure measurement methods and future CVD-related outcomes, we will perform a de novo review and search MEDLINE, Embase, CENTRAL, and APA PsycInfo for randomized controlled trials, prospective or retrospective cohort studies, nested case-control studies, and within-arm analyses of intervention studies. For the thresholds for discussions of treatment initiation review, we will perform an overview of reviews and update results from a relevant 2019 UK NICE review. We will search MEDLINE, Embase, APA PsycInfo, and Epistemonikos for systematic reviews. For the acceptability review, we will perform a de novo systematic review and search MEDLINE, Embase, and APA PsycInfo for randomized controlled trials, controlled clinical trials, and observational studies with comparison groups. Websites of relevant organizations, gray literature sources, and the reference lists of included studies and reviews will be hand-searched. Title and abstract screening will be completed by two independent reviewers. Full-text screening, data extraction, risk-of-bias assessment, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers. Results from included studies will be synthesized narratively and pooled via meta-analysis when appropriate. The GRADE approach will be used to assess the certainty of evidence for outcomes. DISCUSSION: The results of the evidence reviews will be used to inform Canadian recommendations on screening for hypertension in adults aged 18 years and older. SYSTEMATIC REVIEW REGISTRATION: This protocol is registered on PROSPERO and is available on the Open Science Framework (osf.io/8w4tz).

Whither digitalis? What we can still learn from cardiotonic steroids about heart failure and hypertension.

Cloning of the "Na+ pump" (Na+,K+-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.

Effects of CPAP on Blood Pressure and Sympathetic Activity in Patients With Diabetes Mellitus, Chronic Kidney Disease, and Resistant Hypertension.

BACKGROUND: Patients with obstructive sleep apnea (OSA) have increased sympathetic activity and frequently also have resistant hypertension (HTN). Treatment of OSA with continuous positive airway pressure (CPAP) decreases awake and sleep blood pressure (BP) and sympathetic activity. This study was designed to assess the effect of treatment of OSA with CPAP on sympathetic activity and BP in patients with diabetes mellitus (DM), chronic kidney disease (CKD), and resistant HTN. METHODS: This was a randomized, double-blind, sham-controlled trial. Patients with DM, CKD, and resistant HTN were randomized to treatment with a therapeutic or subtherapeutic CPAP for 6 weeks. They underwent 24-hour ambulatory BP monitoring and assessment of muscle sympathetic nerve activity before and after 6 weeks on treatment. RESULTS: Treatment with therapeutic CPAP caused significant decreases in awake systolic and diastolic BP from 144 to 136 mm Hg (P = 0.004) and from 79 to 74 mm Hg (P = 0.004) and in sleep BP from 135 to 119 mm Hg (P = 0.045) and from 75 to 65 mm Hg (P = 0.015) compared with treatment with subtherapeutic CPAP. In contrast, treatment with therapeutic CPAP did not decrease sympathetic activity as assessed from muscle sympathetic nerve activity. CONCLUSIONS: Decrease in BP by treatment with CPAP in patients with DM, CKD, and OSA indicates the contribution of OSA to severity of HTN in this clinical scenario. Decrease in BP in the absence of changes in sympathetic activity is suggestive that other mechanisms induced by OSA play a larger role in the maintenance of HTN in these patients.

CONTEXTE: Les patients atteints d'apnée obstructive du sommeil (AOS) présentent une activité sympathique accrue qui est souvent accompagnée d'hypertension artérielle (HTA) réfractaire. Le traitement de l'AOS par ventilation en pression positive continue (CPAP, pour Continuous Positive Airway Pressure) diminue la pression artérielle (PA) à l'état de veille et durant le sommeil ainsi que l'activité sympathique. Cette étude était conçue pour évaluer l'effet du traitement de l'AOS par CPAP sur l'activité sympathique et la PA chez des patients atteints de diabète sucré (DS), d'insuffisance rénale chronique (IRC) et d'HTA réfractaire. MÉTHODOLOGIE: Il s'agissait d'une étude à double insu et à répartition aléatoire contrôlée par simulation. Les patients atteints de DS, d'IRC et d'HTA réfractaire ont été répartis de façon aléatoire pour recevoir un traitement par CPAP thérapeutique ou subthérapeutique pendant 6 semaines. Une surveillance ambulatoire de la PA et une évaluation de l'activité nerveuse sympathique musculaire sur 24 h ont été effectuées chez les patients avant et après 6 semaines de traitement. RÉSULTATS: Comparativement à la CPAP subthérapeutique, la CPAP thérapeutique a entraîné une diminution significative de la PA systolique et de la PA diastolique à l'état de veille, qui sont passées respectivement de 144 à 136 mmHg (p = 0,004) et de 79 à 74 mmHg (p = 0,004). La même observation a été faite à l'égard de la PA systolique et de la PA diastolique durant le sommeil, qui sont passées respectivement de 135 à 119 mmHg (p = 0,045) et de 75 à 65 mmHg (p = 0,015). En revanche, l'évaluation de l'activité nerveuse sympathique musculaire n'a révélé aucune diminution de l'activité sympathique associée au traitement par CPAP thérapeutique. CONCLUSIONS: La diminution de la PA associée au traitement par CPAP chez les patients atteints de DS, d'IRC et d'AOS indique que l'AOS contribue à l'intensité de l'HTA dans ce scénario clinique. La diminution de la PA en l'absence de modification de l'activité sympathique laisse supposer que d'autres mécanismes induits par l'AOS jouent un rôle plus important dans le maintien de l'HTA chez ces patients.

Effects of exercise on BDNF-TrkB signaling in the paraventricular nucleus and rostral ventrolateral medulla in rats post myocardial infarction.

Brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) is associated with cardiovascular regulation. Exercise increases plasma BDNF and attenuates activation of central pathways in the PVN and RVLM post myocardial infarction (MI). The present study assessed whether MI alters BDNF-TrkB signaling and intracellular factors Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Akt in the PVN and RVLM of male Wistar rats with or without exercise or treatment with the TrkB blocker ANA-12. A 4-week period of treadmill exercise training was performed in MI rats. A separate experiment was conducted with 2.5 mg/kg ANA-12 in sedentary MI rats. At 5 weeks post MI, in both the PVN and RVLM, the ratio of full-length TrkB (TrkB.FL) and truncated TrkB (TrkB.T1) was decreased. 0.5 mg/kg ANA-12 did not affect BDNF-TrkB signaling and cardiac function post MI, but 2.5 mg/kg ANA-12 further decreased ejection fraction (EF). Exercise increased mature BDNF (mBDNF) and decreased Akt activity in the PVN, whereas in the RVLM, exercise did not affect mBDNF but lowered p-CaMKIIß. ANA-12 prevented the exercise-induced increase in mBDNF in the PVN and decrease in p-CaMKIIß in the RVLM. In conclusion, exercise decreases Akt activity in the PVN and decreases p-CaMKIIß in the RVLM post MI. BDNF-TrkB signaling only mediates the decrease in p-CaMKIIß in the RVLM. The exercise-induced decreases in Akt activity in the PVN and p-CaMKIIß in the RVLM may contribute to the attenuation of the decrease in EF and sympathetic hyperactivity post MI.

Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure.

Accumulating evidence obtained over the last three decades has revealed a neuroendocrine system in the brain that mediates long term increases in blood pressure. The system involves distinct ion transport pathways including the alpha-2 isoform of the Na,K pump and epithelial sodium channels, as well as critical hormone elements such as angiotensin II, aldosterone, mineralocorticoid receptors and endogenous ouabain. Activation of this system either by circulating or central sodium ions and/or angiotensin II leads to a cascading sequence of events that begins in the hypothalamus and involves the participation of several brain nuclei including the subfornical organ, supraoptic and paraventricular nuclei and the rostral ventral medulla. Key events include heightened aldosterone synthesis and mineralocorticoid receptor activation, upregulation of epithelial sodium channels, augmented synthesis and secretion of endogenous ouabain from hypothalamic magnocellular neurons, and sustained increases in sympathetic outflow. The latter step depends upon increased production of angiotensin II and the primary amplification of angiotensin II type I receptor signaling from the paraventricular nucleus to the rostral ventral lateral medulla. The transmission of sympathetic traffic is secondarily amplified in the periphery by increased short- and long-term potentiation in sympathetic ganglia and by sustained actions of endogenous ouabain in the vascular wall that augment expression of sodium calcium exchange, increase cytosolic Ca2+ and heighten myogenic tone and contractility. Upregulation of this multi-amplifier system participates in forms of hypertension where salt, angiotensin and/or aldosterone are elevated and contributes to adverse outcomes in heart failure.

Effect of exercise training on the FNDC5/BDNF pathway in spontaneously hypertensive rats.

Increased sympathetic activity contributes to the development of cardiovascular diseases such as hypertension. Exercise training lowers sympathetic activity and is beneficial for the prevention and treatment of hypertension and associated cognitive impairment. Increased BDNF expression in skeletal muscle, heart, and brain may contribute to these actions of exercise, but the mechanisms by which this occurs are unknown. We postulated that hypertension is associated with decreased hippocampal BDNF, which can be restored by exercise-mediated upregulation of fibronectin type-II domain-containing 5 (FNDC5). Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 5 weeks of motorized treadmill training. BDNF and FNDC5 expressions were measured in the left ventricle (LV), quadriceps, soleus muscle, and brain areas. Exercise training reduced blood pressure (BP) in both strains. BDNF and FNDC5 protein in the LV were increased in SHR, but exercise increased only BDNF protein in both strains. BDNF mRNA, but not protein, was increased in the quadriceps of SHR, and BDNF mRNA and protein were decreased by exercise in both groups. FNDC5 protein was higher in SHR in both the quadriceps and soleus muscle, whereas exercise increased FNDC5 protein only in the quadriceps in both strains. BDNF mRNA was lower in the dentate gyrus (DG) of SHR, which was normalized by exercise. BDNF mRNA expression in the DG negatively correlated with BP. No differences in FNDC5 expression were observed in the brain, suggesting that enhanced BDNF signaling may contribute to the cardiovascular and neurological benefits of exercise training, and these processes involve peripheral, but not central, FNDC5.

Role of Myocardial Infarction-Induced Neuroinflammation for Depression-Like Behavior and Heart Failure in Ovariectomized Female Rats.

After myocardial infarction (MI), ovariectomized (OVX) female rats develop depression-like behaviors and an increase of pro-inflammatory cytokine (PIC) levels in the prefrontal cortex (PFC). We hypothesized that inhibition of neuroinflammation by the PIC synthesis inhibitor, pentoxifylline (PTX) would prevent depression-like behaviors induced by heart failure (HF) post-MI in OVX female rats. PTX treatment was initiated in female Wistar rats, 1 week after ovariectomy, and 1 week before MI by occlusion of the left anterior descending artery. Eight weeks post-MI, OVX female rats treated with vehicle or PTX exhibited a similar MI size and degree of cardiac dysfunction. OVX female rats post-MI developed depression-like behaviors consisting of anhedonia, despair behavior and enhanced freezing behavior in the cued conditioning test. PTX prevented the depression-like behavior symptoms and enhanced freezing. Cytokine levels were elevated in plasma and both paraventricular nucleus (PVN) and PFC, and the mature brain-derived neurotrophic factor (mBDNF) was decreased in the PFC of OVX female rats post-MI. PTX treatment limited the decrease of mBDNF, and decreased cytokine levels in plasma, PVN and PFC to (below) sham levels. These findings show that OVX female rats post-MI exhibit an increase in both peripheral and central inflammation. PTX treatment prevents increases in PIC levels in plasma and PVN but does not attenuate the progression of cardiac dysfunction. In contrast, PTX prevents enhanced PIC production in the PFC, as well as limits depression-like behaviors induced by MI in OVX female rats.

Inhibition of inflammation by minocycline improves heart failure and depression-like behaviour in rats after myocardial infarction.

RATIONALE: Patients with heart failure have an increased incidence of depression. Central and peripheral inflammation play a major role in the pathophysiology of both heart failure and depression. AIM: Minocycline is an antibiotic that inhibits microglia activation and release of pro-inflammatory cytokines. We assessed effects of minocycline on extent of heart failure and depression at 2 and 8 weeks post myocardial infarction. METHODS/RESULTS: Male Wistar rats were randomly divided into 3 groups: (i) sham + vehicle; (ii) MI + vehicle; and (iii) MI + minocycline with n/group of 8, 9 and 9 at 2 weeks, and 10, 16, 8 at weeks, respectively. Oral minocycline (50 mg/kg/day) or vehicle started 2 days before surgery. Depression-like behaviour was assessed with sucrose preference and forced swim tests, and cardiac function with echo and hemodynamics. After myocardial infarction, microglia activation and plasma/brain pro-inflammatory cytokines increased, which were mostly prevented by minocycline. At 8 weeks, cardiac dysfunction was attenuated by minocycline: infarct size (MI + Vehicle 29±1, MI + Min 23±1%), ejection fraction (Sham 80±1, MI + Vehicle 48±2, MI + Min 58±2%) and end diastolic pressure (Sham 3.2±0.3, MI + Vehicle 18.2±1.1, MI + Min 8.5±0.9 mm Hg). Depression-like behaviour was significantly improved by minocycline in sucrose preference test (% Sucrose Intake: Sham 96±1, MI + Vehicle 78±2, MI + Min 87±2) and forced swim test (% Immobile: Sham 40±4, MI + Vehicle 61±3, MI + Min 37±6). CONCLUSION: Rats post myocardial infarction develop systemic inflammation, heart failure and depression-like behaviour that are all attenuated by minocycline. Targeting (neuro) inflammation may represent new therapeutic strategy for patients with heart failure and depression.

Specific Inhibition of Brain Angiotensin III Formation as a New Strategy for Prevention of Heart Failure After Myocardial Infarction.

AIMS: Inhibition of brain angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure in rats after myocardial infarction (MI). This study evaluated effectiveness of systemic treatment with firibastat compared with AT1R blocker, losartan. METHODS AND RESULTS: MI was induced by ligation of left coronary artery in male Wistar rats. Rats were treated from 1 to 5 weeks after MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/d subcutaneously (s.c.) or 150 mg/kg/d oral, once daily, and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, left ventricle function was evaluated by echocardiography and Millar catheter. After MI, rats developed moderate severe heart failure. Both s.c. and oral firibastat inhibited brain APA and attenuated left ventricle dysfunction. Oral firibastat and losartan similarly improved left ventricular end diastolic pressure. However, whereas firibastat improved dP/dtmax, losartan lowered dP/dtmax and left ventricular peak systolic pressure, and increased plasma creatinine by ~50%. On the other hand, losartan more effectively inhibited cardiac fibrosis. CONCLUSION: Inhibition of the brain renin-angiotensin system by oral APA inhibitor is at least as effective as oral AT1R blocker to inhibit cardiac dysfunction after MI but without hypotension or renal dysfunction.

Effects of exercise training and TrkB blockade on cardiac function and BDNF-TrkB signaling postmyocardial infarction in rats.

Exercise training is beneficial for preserving cardiac function postmyocardial infarction (post-MI), but the underlying mechanisms are not well understood. We investigated one possible mechanism, brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling, with the TrkB blocker ANA-12 (0.5 mg·kg-1·day-1). Male Wistar rats underwent sham surgery or ligation of the left descending coronary artery. The surviving MI rats were allocated as follows: sedentary MI rats treated with vehicle, exercise-trained MI rats treated with vehicle, and exercise-trained MI rats treated with ANA-12. Exercise training was done 5 days/wk for 4 wk on a motor-driven treadmill. At the end, left ventricular (LV) function was evaluated by echocardiography and a Millar catheter. Mature BDNF and downstream effectors of BDNF-TrkB signaling, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Akt, and AMP-activated protein kinase (AMPK), were assessed in the noninfarct area of the LV by Western blot analysis. Exercise training increased stroke volume and cardiac index and attenuated the decrease in ejection fraction (EF) and increase in LV end-diastolic pressure post-MI. ANA-12 blocked the improvement of EF and attenuated the increases in stroke volume and cardiac index but did not affect LV end-diastolic pressure. Exercise training post-MI prevented decreases in mature BDNF, phosphorylated (p-)CaMKII, p-Akt, and p-AMPKα expression. These effects were all blocked by ANA-12 except for p-AMPKα. In conclusion, the exercise-induced improvement of EF is mediated by the BDNF-TrkB axis and the downstream effectors CaMKII and Akt. BDNF-TrkB signaling appears to contribute to the improvement in systolic function by exercise training. NEW & NOTEWORTHY Exercise training improves ejection fraction and left ventricular end-diastolic pressure (LVEDP) and increases stroke volume and cardiac index in rats postmyocardial infarction (post-MI). The improvement of EF but not LVEDP is mediated by activation of the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) axis and downstream effectors Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Akt. This suggests that activation of BDNF-TrkB signaling and CaMKII and Akt is a promising target to attenuate progressive cardiac dysfunction post-MI.

Sex differences in depression-like behavior and neuroinflammation in rats post-MI: role of estrogens.

Patients with heart failure (HF) have a high prevalence of depression associated with a worse prognosis, particularly in older women. The present study evaluated whether sex and estrogens affect depression-like behavior and associated neuroinflammation induced by myocardial infarction (MI) in rats. MI was induced by occlusion of the left anterior descending artery in young adult male and female Wistar rats or in ovariectomized (OVX) female rats without and with estrogen [17ß-estradiol (E2)] replacement. MI groups showed a comparable degree of cardiac dysfunction. Eight weeks post-MI, male rats with HF exhibited depression-like behaviors, including anhedonia and higher immobility in the sucrose preference and forced swim tests, which were not observed in female rats with HF. In the cued fear conditioning test, male but not female rats with HF froze more than sham rats. After OVX, female sham rats developed mild depression-like behaviors that were pronounced in OVX female rats post-MI and were largely prevented by E2 replacement. Cytokine levels in the plasma and paraventricular nucleus increased in both sexes with HF, but only male rats with HF showed an increase in cytokine levels in the prefrontal cortex. OVX alone did not affect cytokine levels, but OVX-MI caused significant increases in the prefrontal cortex, which were shifted to an anti-inflammatory pattern by E2 replacement. These results suggest that estrogens prevent depression-like behavior induced by HF post-MI in young adult female rats by inhibiting proinflammatory cytokine production and actions in the prefrontal cortex. NEW & NOTEWORTHY In contrast to male rats, female rats with heart failure after myocardial infarction do not develop depression-like behavior or increases in prefrontal cortex cytokines. However, after ovariectomy, female rats exhibit similar changes, which are prevented by 17ß-estradiol replacement. Neuroinflammation in the prefrontal cortex in male subjects may contribute to depression-like behavior, whereas its estrogen-dependent absence in female subjects may protect against depression.

Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats.

Aims: High salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt. Methods and results: In protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150 ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14 days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) blockers (eplerenone, spironolactone), epithelial sodium channel (ENaC) blocker (benzamil), angiotensin II type 1 receptor (AT1R) blocker (losartan) or vehicles. Ang II alone raised mean arterial pressure (MAP) ∼10 mmHg, but Ang II-high salt increased MAP ∼50 mmHg. Ang II-high salt elevated plasma corticosterone, aldosterone and endogenous ouabain but not Ang II alone. Both Ang II alone and Ang II-high salt increased mRNA and protein expression of CYP11B2 (aldosterone synthase gene) in the adrenal cortex but not of CYP11B1 (11-ß-hydroxylase gene). In the aorta, Ang II-high salt increased sodium-calcium exchanger-1 (NCX1) protein. The Ang II-high salt induced increase in MAP was largely prevented by central infusion of MR blockers, benzamil or losartan. Central blockades significantly lowered plasma aldosterone and endogenous ouabain and markedly decreased Ang II-high salt induced CYP11B2 mRNA expression in the adrenal cortex and NCX1 protein in the aorta. Conclusion: These results suggest that in Ang II-high salt hypertension, MR-ENaC-AT1R signalling in the brain increases circulating aldosterone and endogenous ouabain, and arterial NCX1. These factors can amplify blood pressure responses to centrally-induced sympatho-excitation and thereby contribute to severe hypertension.

Update on angiotensin II: new endocrine connections between the brain, adrenal glands and the cardiovascular system.

In the brain, angiotensinergic pathways play a major role in chronic regulation of cardiovascular and electrolyte homeostasis. Increases in plasma angiotensin II (Ang II), aldosterone, [Na+] and cytokines can directly activate these pathways. Chronically, these stimuli also activate a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels and endogenous ouabain (EO). This pathway increases AT1R and NADPH oxidase subunits and maintains/further increases the activity of angiotensinergic pathways. These brain pathways not only increase the setpoint of sympathetic activity per se, but also enhance its effectiveness by increasing plasma EO and EO-dependent reprogramming of arterial and cardiac function. Blockade of any step in this slow pathway or of AT1R prevents Ang II-, aldosterone- or salt and renal injury-induced forms of hypertension. MR/AT1R activation in the CNS also contributes to the activation of sympathetic activity, the circulatory and cardiac RAAS and increase in circulating cytokines in HF post MI. Chronic central infusion of an aldosterone synthase inhibitor, MR blocker or AT1R blocker prevents a major part of the structural remodeling of the heart and the decrease in LV function post MI, indicating that MR activation in the CNS post MI depends on aldosterone, locally produced in the CNS. Thus, Ang II, aldosterone and EO are not simply circulating hormones that act on the CNS but rather they are also paracrine neurohormones, locally produced in the CNS, that exert powerful effects in key CNS pathways involved in the long-term control of sympathetic and neuro-endocrine function and cardiovascular homeostasis.

Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart.

The post-natal heart adapts to stress and overload through hypertrophic growth, a process that may be pathologic or beneficial (physiologic hypertrophy). Physiologic hypertrophy improves cardiac performance in both healthy and diseased individuals, yet the mechanisms that propagate this favorable adaptation remain poorly defined. We identify the cytokine cardiotrophin 1 (CT1) as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity. The capacity of CT1 to induce physiologic hypertrophy originates from a CK2-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth. Exogenous CT1 protein delivery attenuated pathology and restored contractile function in a severe model of right heart failure, suggesting a novel treatment option for this intractable cardiac disease.

Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction.

NEW FINDINGS: What is the central question of this study? Exercise training increases brain-derived neurotrophic factor (BDNF) in the hippocampus, which depends on a myokine, fibronectin type III domain-containing protein 5 (FNDC5). Whether exercise training after myocardial infarction induces parallel increases in FNDC5 and BDNF expression in skeletal muscle and the heart has not yet been studied. What is the main finding and its importance? Exercise training after myocardial infarction increases BDNF protein in skeletal muscle and the non-infarct area of the LV without changes in FNDC5 protein, suggesting that BDNF is not regulated by FNDC5 in skeletal muscle and heart. An increase in cardiac BDNF may contribute to the improvement of cardiac function by exercise training. Exercise training after myocardial infarction (MI) attenuates progressive left ventricular (LV) remodelling and dysfunction, but the peripheral stimuli induced by exercise that trigger these beneficial effects are still unclear. We investigated as possible mediators fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the skeletal muscle and heart. Male Wistar rats underwent either sham surgery or ligation of the left descending coronary artery, and surviving MI rats were allocated to either a sedentary (Sed-MI) or an exercise group (ExT-MI). Exercise training was done for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated, and FNDC5 and BDNF mRNA and protein were assessed in soleus muscle, quadriceps and non-, peri- and infarct areas of the LV. At 5 weeks post MI, FNDC5 mRNA was decreased in soleus muscle and all areas of the LV, but FNDC5 protein was increased in the soleus muscle and the infarct area. Mature BDNF (mBDNF) protein was decreased in the infarct area without a change in mRNA. Exercise training attenuated the decrease in ejection fraction and the increase in LV end-diastolic pressure post MI. Exercise training had no effect on FNDC5 mRNA and protein, but increased mBDNF protein in soleus muscle, quadriceps and the non-infarct area of the LV. The mBDNF protein in the non-infarct area correlated positively with ejection fraction and inversely with LV end-diastolic pressure. In conclusion, mBDNF is induced by exercise training in skeletal muscle and the non-infarct area of the LV, which may contribute to improvement of muscle dysfunction and cardiac function post MI.

On-treatment blood pressures of older hypertensive patients in Canada: implications for Systolic blood PRessure INtervention Trial.

OBJECTIVE: The therapeutic target level for the blood pressure (BP) on antihypertensive drug treatment in older hypertensive patients is still extensively debated. We assessed the achieved BP levels in older treated hypertensive patients in a representative sample of the population. DESIGN: During the 2006 Ontario Survey on the Prevalence and Control of Hypertension, BP (using the SPRINT protocol) and treatment data were collected in 2551 respondents from a random and representative sample of the adult (20-79 years) population. Responses are weighted to the Ontario hypertensive population of 1367 384, of which 684 928 were in the 60-79-year age range. RESULTS: Among 60-79-year-old individuals, using traditional definitions the prevalence of hypertension was 49%. Hypertension treatment rates were high (85%) as were control rates among treated hypertensive patients (85% for 60-69-year-old and 70% for 70-79-year-old patients). A total of 38% of older hypertensive patients were treated with a single antihypertensive drug. A total of 54% of these had a SBP less than 130 mmHg and 23% less than 120 mmHg. Of those treated with combination therapy, 75% had a SBP less than 130 mmHg, and 44% had a SBP less than 120 mmHg. For treated and controlled hypertensive patients, average SBP was 120 mmHg for the 60-69-year age groups, and 119 mmHg in the 70-79-year age groups. CONCLUSION: These findings suggest that intensive BP control, now being considered for high-risk hypertensive patients based on results from SPRINT, was actually already being achieved ∼10 years ago in a large section of the general hypertensive population of Ontario, Canada.

Pivotal role of α2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease.

Reduced smooth muscle (SM)-specific α2 Na+ pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensin II (Ang II) and dietary NaCl, whilst SM-α2 overexpression lowers basal BP and decreases Ang II/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain-resistant mutation of the α2 ouabain binding site (α2R/R mice) confers resistance to several forms of hypertension. Pressure overload-induced heart hypertrophy and failure are attenuated in cardio-specific α2 knockout, cardio-specific α2 overexpression and α2R/R mice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by Ang II and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain-sensitive α2 Na+ pump activity and Ca2+ transporter expression and, via Na+ /Ca2+ exchange, Ca2+ homeostasis. This regulates sensitivity to sympathetic activity, Ca2+ signalling and arterial and cardiac contraction.