Kidney damage represents a frequent event in the course of hypertension, ranging from a benign to a malignant form of nephropathy depending on several factors, that is, individual susceptibility, ...degree of hypertension, type of etiology and underlying kidney disease. Multiple mechanisms are involved in determination of kidney glomerular, tubular and interstitial injuries in hypertension. The present review article discusses relevant contributory molecular mechanisms underpinning the promotion of hypertensive renal damage, such as the renin-angiotensin-aldosterone system (RAAS), oxidative stress, endothelial dysfunction, and genetic and epigenetic determinants. We highlighted major pathways involved in the progression of inflammation and fibrosis leading to glomerular sclerosis, tubular atrophy and interstitial fibrosis, thus providing a state of the art review of the pathogenetic background useful for a better understanding of current and future therapeutic strategies toward hypertensive nephropathy. An adequate control of high blood pressure, obtained through an appropriate therapeutic intervention, still represents the key strategy to achieve a satisfactory control of renal damage in hypertension. In this regard, we reviewed the impact of currently available antihypertensive pharmacological treatment on kidney damage, with particular regard to RAAS inhibitors. Notably, recent findings underscored the ability of the kidneys to regenerate and to repair tissue injuries through the differentiation of resident embryonic stem cells. Pharmacological modulation of the renal endogenous reparative process (that is, with angiotensin-converting enzyme inhibitors and AT1 angiotensin II receptor blockers), as well as future therapeutic strategies targeted to the renopoietic system, offers interesting perspectives for the management of hypertensive nephropathy.
Current guidelines recommend an implantable cardiac defibrillator (ICD) in patients with symptomatic heart failure and reduced ejection fraction (HFrEF; left ventricular ejection fraction LVEF ≤35%) ...despite ≥3 months of optimal medical therapy. Recent observations demonstrated that sacubitril/valsartan induces beneficial reverse cardiac remodeling in eligible HFrEF patients. Given the pivotal role of LVEF in the selection of ICD candidates, we sought to assess the impact of sacubitril/valsartan on ICD eligibility and its predictors in HFrEF patients.
We retrospectively evaluated 48 chronic HFrEF patients receiving sacubitril/valsartan and previously implanted with an ICD in primary prevention. We assumed that ICD was no longer necessary if LVEF improved >35% (or >30% if asymptomatics) at follow-up.
Over a median follow-up of 11 months, sacubitril/valsartan induced a significant drop in LV end-systolic volume (-16.7 ml/m2, p=0.023) and diameter (-6.8 mm, p=0.022), resulting in a significant increase in LVEF (+3.9%, p<0.001). As a consequence, 40% of previously implanted patients resulted no more eligible for ICD at follow-up. NYHA class improved in 50% of the population. A dose-dependent effect was noted, with higher doses associated to more reverse remodeling. Among patients deemed no more eligible for ICD, lower NYHA class (odds ratio (OR) 3.73 95% CI 1.05; 13.24, p=0.041), better LVEF (OR 1.23 95% CI 1.01; 1.48, p=0.032) and the treatment with the intermediate or high dose of sacubitril/valsartan (OR 5.60 1.15; 27.1, p=0.032) were the most important predictors of status change.
In symptomatic HFrEF patients, sacubitril/valsartan induced beneficial cardiac reverse remodeling and improved NYHA class. These effects resulted in a significant reduction of patients deemed eligible for ICD in primary prevention.
Abstract
Background
ICD implantation is recommended for primary prevention in patients with symptomatic NYHA II-III heart failure with reduced ejection fraction (< 35%) (HFrEF) and without left ...ventricle ejection fraction (LVEF) improvement despite at least three months of guideline-directed therapy. The use of angiotensin receptor-neprilysin inhibition with LCZ696 has shown to ameliorate left ventricle function and to reduce the ventricular arrhythmias burden in patients with HFrEF.
Purpose
The profile of patients with HFrEF who may benefit from therapy with LCZ696 without further requiring an ICD in primary prevention is still unknown. We aimed to assess the prevalence of these patients and to find potential clinical predictors of responsiveness to this treatment.
Methods
We enrolled consecutive patients that started LCZ696 treatment for medical therapy optimization in the heart failure clinic of our institution. All of them were previously implanted with an ICD before LCZ696 availability (from 2009 to 2015). A cardiologist evaluated their home medications, clinical, and echocardiographic characteristics both at baseline (before starting LCZ696) and during follow up. The patients were grouped also according to the etiology of HF (ischemic/non-ischemic) and by gender. Patients were excluded if candidates to cardiac resynchronization therapy. Responsiveness to LCZ696 treatment was defined as an increase of LVEF to values > 35% at follow up (FU).
Results
A total of 49 patients (67.1 ± 9.8 years of age) were enrolled in this study and followed in the heart failure clinic of our institution (mean follow up 11.5 ± 4.9 months). Among them, 19 patients (38%) showed an increase in LVEF to values > 35% at follow up and a significant improvement in LVEF was appreciated (baseline LVEF: 31.2 ± 4.5 vs. follow up LVEF: 35.4 ± 8.0; p 0.003). No significant differences were recorded at baseline in LVEF within HF etiology and gender groups. At follow up, we found a significant increase in post-therapy LVEF only in the non-ischemic etiology group (from 31.5 ± 4.4 to 37.1 ± 8.1, p = 0.001) and in the male group (from 31.4 ± 4.5 to 34.9 ± 7.9, p = 0.005) in comparison with the ischemic etiology and the female group, respectively. No significant statistical differences were appreciated between responders and non-responders neither in terms of home medications nor in the LCZ696 doses, both at baseline and follow up.
Conclusion
This study suggests a potential impact of angiotensin receptor-neprilysin inhibition therapy in the selection of patients with HFrEF candidates to ICD in primary prevention. In this real-world experience from our HF clinic, we found a significant LVEF improvement in approximately 40% of patients treated with LCZ696. These patients, in FU evaluation, would not have needed for an ICD implantation. This benefit appears related to the non-ischemic etiology of HF and the male gender.
Abstract Figure. LVEF VARIATIONS
Abstract
This paper develops a model where money is demanded in excess of spending needs. As a result, money coexists with large availabilities of credit and the model explains the levels of monetary ...aggregates held in modern economies via the endogenous creation of inside money. At the heart of the model, there is a search friction in the goods market, which generates spare production and spending capacity. As a consequence, there is an endogenous productivity wedge, due to spare production capacity, and an endogenous money velocity, due to spare spending capacity.
Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for ...oxidative phosphorylation (OXPHOS). In mammals, a gene‐dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.
Labour composition by gender, age, and education has undergone dramatic changes over the last half century in the United States. Furthermore, the volatility of total market hours differs ...systematically between genders, age, and education groups. I develop a large scale business cycle model where these demographic patterns and their transitional dynamics are taken into account and find that demographic change accounts for 30% of the observed changes in aggregate volatility over this period of time. Additionally, these demographic changes are responsible for a significant fraction of the GDP growth observed in the considered period of time.
We investigate the interaction between the product of invariant types and domination–equivalence. We present a theory where the latter is not a congruence with respect to the former, provide ...sufficient conditions for it to be, and study the resulting quotient when it is.
We compute the domination monoid in the theory DMT$\mathsf {DMT}$ of dense meet‐trees. In order to show that this monoid is well‐defined, we prove weak binarity of DMT$\mathsf {DMT}$ and, more ...generally, of certain expansions of it by binary relations on sets of open cones, a special case being the theory DTR$\mathsf {DTR}$ from 7. We then describe the domination monoids of such expansions in terms of those of the expanding relations.
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