Joao Sergio Neves

Acute Myocardial Response to Stretch: What We (don't) Know

Myocardial stretch, as result of acute hemodynamic overload, is one of the most frequent challenges to the heart and the ability of the heart to intrinsically adapt to it is essential to prevent circulatory congestion. In this review, we highlight the historical background, the currently known mechanisms, as well as the gaps in the understanding of this physiological response. The systolic adaptation to stretch is well-known for over 100 years, being dependent on an immediate increase in contractility—known as the Frank-Starling mechanism—and a further progressive increase—the slow force response. On the other hand, its diastolic counterpart remains largely unstudied. Mechanosensors are structures capable of perceiving mechanical signals and activating pathways that allow their transduction into biochemical responses. Although the connection between these structures and stretch activated pathways remains elusive, we emphasize those most likely responsible for the initiation of the acute response. Calcium-dependent pathways, including angiotensin- and endothelin-related pathways; and cGMP-dependent pathways, comprising the effects of nitric oxide and cardiac natriuretic hormones, embody downstream signaling. The ischemic setting, a paradigmatic situation of acute hemodynamic overload, is also touched upon. Despite the relevant knowledge accumulated, there is much that we still do not know. The quest for further understanding the myocardial response to acute stretch may provide new insights, not only in its physiological importance, but also in the prevention and treatment of cardiovascular diseases.

Chronic alcohol consumption leads to neurochemical changes in the nucleus accumbens that are not fully reversed by withdrawal

Neuropeptide Y (NPY)- and acetylcholine-containing interneurons of the nucleus accumbens (NAc) seem to play a major role in the rewarding effects of alcohol. This study investigated the relationship between chronic alcohol consumption and subsequent withdrawal and the expression of NPY and acetylcholine in the NAc, and the possible involvement of nerve growth factor (NGF) in mediating the effects of ethanol. Rats ingesting an aqueous ethanol solution over 6months and rats subsequently deprived from ethanol during 2months were used to estimate the total number and the somatic volume of NPY and cholinergic interneurons, and the numerical density of cholinergic varicosities in the NAc. The tissue content of choline acetyltransferase (ChAT) and catecholamines were also determined. The number of NPY interneurons increased during alcohol ingestion and returned to control values after withdrawal. Conversely, the number and the size of cholinergic interneurons, and the amount of ChAT were unchanged in ethanol-treated and withdrawn rats, but the density of cholinergic varicosities was reduced by 50% during alcohol consumption and by 64% after withdrawal. The concentrations of dopamine and norepinephrine were unchanged both during alcohol consumption and after withdrawal. The administration of NGF to withdrawn rats significantly increased the number of NPY-immunoreactive neurons, the size of cholinergic neurons and the density of cholinergic varicosities. Present data show that chronic alcohol consumption leads to long-lasting neuroadaptive changes of the cholinergic innervation of the NAc and suggest that the cholinergic system is a potential target for the development of therapeutic strategies in alcoholism and abstinence.

BP Reduction, Kidney Function Decline, and Cardiovascular Events in Patients without CKD

BACKGROUND AND OBJECTIVES In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP treatment (target <120 mm Hg) was associated with fewer cardiovascular events and higher incidence of kidney function decline compared with standard treatment (target <140 mm Hg). We evaluated the association between mean arterial pressure reduction, kidney function decline, and cardiovascular events in patients without CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We categorized patients in the intensive treatment group of the SPRINT according to mean arterial pressure reduction throughout follow-up: <20, 20 to <40, and ≥40 mm Hg. We defined the primary outcome as kidney function decline (≥30% reduction in eGFR to <60 ml/min per 1.73 m2 on two consecutive determinations at 3-month intervals), and we defined the secondary outcome as cardiovascular events. In a propensity score analysis, patients in each mean arterial pressure reduction category from the intensive treatment group were matched with patients from the standard treatment group to calculate the number needed to treat regarding cardiovascular events and the number needed to harm regarding kidney function decline. RESULTS In the intensive treatment group, 1138 (34%) patients attained mean arterial pressure reduction <20 mm Hg, 1857 (56%) attained 20 to <40 mm Hg, and 309 (9%) attained ≥40 mm Hg. Adjusted hazard ratios for kidney function decline were 2.10 (95% confidence interval, 1.22 to 3.59) for mean arterial pressure reduction between 20 and 40 mm Hg and 6.22 (95% confidence interval, 2.75 to 14.08) for mean arterial pressure reduction ≥40 mm Hg. In propensity score analysis, mean arterial pressure reduction <20 mm Hg presented a number needed to treat of 44 and a number needed to harm of 65, reduction between 20 and <40 mm Hg presented a number needed to treat of 42 and a number needed to harm of 35, and reduction ≥40 mm Hg presented a number needed to treat of 95 and a number needed to harm of 16. CONCLUSIONS In the intensive treatment group of SPRINT, larger declines in mean arterial pressure were associated with higher incidence of kidney function decline. Intensive treatment seemed to be less favorable when a larger reduction in mean arterial pressure was needed to attain the BP target.

Nerve growth factor retrieves neuropeptide Y and cholinergic immunoreactivity in the nucleus accumbens of old rats

The nucleus accumbens (NAc) contains high levels of neuropeptide Y (NPY), which is involved in the regulation of functions and behaviors that deteriorate with aging. We sought to determine if aging alters NPY expression in this nucleus and, in the affirmative, if those changes are attributable to the cholinergic innervation of the NAc. The total number and the somatic volume of NPY- and choline acetyltransferase-immunoreactive neurons, and the density of cholinergic varicosities were estimated in the NAc of adult (6 months old) and aged (24 months old) rats. In aged rats, the number of NPY neurons was reduced by 20% and their size was unaltered. The number of cholinergic neurons and the density of the cholinergic varicosities were unchanged, but their somas were hypertrophied. Nerve growth factor administration to aged rats further increased the volume of cholinergic neurons, augmented the density of the cholinergic varicosities, and reversed the age-related decrease in the number of NPY neurons. Our data show that the age-related changes in NPY levels in the NAc cannot be solely ascribed to the cholinergic innervation of the nucleus.

The effects of angiotensin II signaling pathway in the systolic response to acute stretch in the normal and ischemic myocardium.

Acute myocardial stretch elicits a biphasic increase in contractility: an immediate increase, known as Frank-Starling mechanism (FSM), followed by a progressive increase, regarded as slow force response (SFR). In this study, we characterized the contractile response to acute stretch from 92 to 100% Lmax in rabbit papillary muscles (n=86) under normoxic and ischemic conditions, and its modulation by angiotensin II signaling pathway. Under normoxia, the FSM was independent of Na(+)/H(+)-exchanger, reverse mode of Na(+)/Ca(2+)-exchanger (r-NCX), AT1 receptor, AT2 receptor and PKC. Regarding the SFR, it was mediated by AT1 receptor activation and its downstream effectors PKC, Na(+)/H(+)-exchanger and r-NCX. Ischemia negatively impacted on the FSM and abolished the SFR, with the muscles exhibiting a time-dependent decline in contractility. Under ischemic conditions, FSM was not influenced by AT1 and AT2 receptors or PKC activation. AT1 receptor antagonism rescued the progressive deterioration in contractility, an effect partially dependent on AT2 receptor activation.

Revisiting the slow force response: The role of the PKG signaling pathway in the normal and the ischemic heart☆

INTRODUCTION The myocardial response to acute stretch consists of a two-phase increase in contractility: an acute increase by the Frank-Starling mechanism and a gradual and time-dependent increase in force generated known as the slow force response (SFR). The SFR is actively modulated by different signaling pathways, but the role of protein kinase G (PKG) signaling is unknown. In this study we aim to characterize the role of the PKG signaling pathway in the SFR under normal and ischemic conditions. METHODS Rabbit papillary muscles were stretched from 92 to 100% of maximum length (Lmax) under basal conditions, in the absence (1) or presence of: a PKG agonist (2) and a PKG inhibitor (3); under ischemic conditions in the absence (4) or presence of: a PKG agonist (5); a nitric oxide (NO) donor (6) and a phosphodiesterase 5 (PDE5) inhibitor (7). RESULTS Under normoxia, the SFR was significantly attenuated by inhibition of PKG and remained unaltered with PKG activation. Ischemia induced a progressive decrease in myocardial contractility after stretch. Neither the PKG agonist nor the NO donor altered the myocardial response to stretch under ischemic conditions. However, the use of a PDE5 inhibitor in ischemia partially reversed the progressive deterioration in contractility. CONCLUSIONS PKG activity is essential for the SFR. During ischemia, a progressive decline in the force is observed in response to acute myocardial stretch. This dysfunctional response can be partially reversed by the use of PDE5 inhibitors.

Can Adiponectin Help us to Target Diastolic Dysfunction

Adiponectin is the most abundant adipokine and exhibits anti-inflammatory, antiatherogenic and antidiabetic properties. Unlike other adipokines, it inversely correlates with body weight and obesity-linked cardiovascular complications. Diastolic dysfunction is the main mechanism responsible for approximately half of all heart failure cases, the so-called heart failure with preserved ejection fraction (HFpEF), but therapeutic strategies specifically directed towards these patients are still lacking. In the last years, a link between adiponectin and diastolic dysfunction has been suggested. There are several mechanisms through which adiponectin may prevent most of the pathophysiologic mechanisms underlying diastolic dysfunction and HFpEF, including the prevention of myocardial hypertrophy, cardiac fibrosis, nitrative and oxidative stress, atherosclerosis and inflammation, while promoting angiogenesis. Thus, understanding the mechanisms underlying adiponectin-mediated improvement of diastolic function has become an exciting field of research, making adiponectin a promising therapeutic target. In this review, we explore the relevance of adiponectin signaling for the prevention of diastolic dysfunction and identify prospective therapeutic targets aiming at the treatment of this clinical condition.

Pregnancy after bariatric surgery: Maternal and fetal outcomes of 39 pregnancies and a literature review

We aimed to evaluate the impact of bariatric surgery (BS) on maternal and fetal outcomes.

Lesions of the laterodorsal tegmental nucleus alter the cholinergic innervation and neuropeptide Y expression in the medial prefrontal cortex and nucleus accumbens

The effects of the ibotenic acid infused into the area of the laterodorsal tegmental nucleus (LDT) of rats on the expression of cortical and accumbal neuropeptides were assessed. The effects of this manipulation were determined in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) by estimating the numerical density of varicosities immunoreactive for vesicular acetylcholine transporter and the total number of NAc neurons immunoreactive for choline acetyltransferase (ChAT) and neuropeptide Y (NPY) as well as the total number of mPFC neurons immunoreactive for NPY and vasoactive intestinal polypeptide (VIP). In LDT-lesioned rats, the density of the cholinergic varicosities was reduced in the ventral divisions of the mPFC and in all divisions of the NAc. In addition, in these rats, the total number of NPY-immunoreactive neurons was reduced in all subregions of the mPFC and in the NAc. Conversely, the total number of VIP-immunoreactive neurons in the mPFC and of ChAT-immunoreactive neurons in the NAc did not differ between LDT- and sham-lesioned rats. These data provide the first direct evidence for a relationship between selective damage of LDT cholinergic neurons and decreased expression of NPY in the mPFC and NAc. They also reveal that different types of cortical and accumbal interneurons respond differently to the cholinergic denervation induced by LDT lesions.

Comment on Bress et al. Effect of Intensive Versus Standard Blood Pressure Treatment According to Baseline Prediabetes Status: A Post Hoc Analysis of a Randomized Trial. Diabetes Care 2017;40:1401–1408

We read with interest the article by Bress et al. (1) reporting on the effect of intensive versus standard blood pressure treatment according to baseline prediabetes status in a post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). The authors concluded that the beneficial effects of intensive blood pressure treatment were similar among patients with prediabetes and patients with normoglycemia. We have participated in the SPRINT Data Analysis Challenge (2), and we also analyzed the effects of glycemia status in this population. Whereas we agree with the conclusions presented by the authors, we believe it is also important to assess the effect …