Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease

PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

Abbreviations

6MWD

6‐min walking distance

ACEI

ACE inhibitor

ARB

angiotensin receptor blocker

BPS

British Pharmacological Society

CCB

calcium channel blocker

CKD

chronic kidney disease

C_max

maximum plasma/serum concentration

CTEPH

chronic thromboembolic pulmonary hypertension

CVD

cardiovascular disease

CYP2C19

cytochrome P450, family 2, subfamily C, polypeptide 19

CYP2C9

cytochrome P450, family 2, subfamily C, polypeptide 9

CYP2D6

cytochrome P450, family 2, subfamily D, polypeptide 6

CYP3A

cytochrome P450, family 3, subfamily A

CYP3A4

cytochrome P450, family 3, subfamily A, polypeptide 4

CYP450

cytochrome P450 enzyme family

DN

diabetic nephropathy

ED

erectile dysfunction

eGFR

estimated GFR

ERA

endothelin receptor antagonist

ET

endothelin

ET‐1

endothelin‐1

FGR

fetal growth restriction

GSK3B

glycogen synthase kinase 3 β

HbA1c

glycated Hb

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

IC₅₀

half maximal inhibitory concentration

IUPHAR

International Union of Basic and Clinical Pharmacology

MI

myocardial infarction

mitoK_ATP

mitochondrial ATP‐sensitive potassium channels

NAION

nonarteritic anterior ischaemic optic neuropathy

Na⁺/K⁺‐ATPase

sodium–potassium pump

NOS1

neuronal NOS

NOS2

inducible NOS

NOS3

endothelial NOS

PAH

pulmonary arterial hypertension

PDE5I

PDE type 5 inhibitor

PH

pulmonary hypertension

PPHN

persistent pulmonary hypertension of the newborn

RCT

randomised controlled trial

RHTN

treatment‐resistant hypertension

RP

Raynaud''s phenomenon

sGC

soluble GC

SGLT2

sodium–glucose cotransporter 2

T_max

time taken to reach the maximum plasma concentration

T2DM

type 2 diabetes mellitus

UACR

urinary albumin/creatinine ratio

V/Q

ventilation/perfusion

     

Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma

Among the numerous signaling pathways involved in tumorigenesis, PI3K‐AKT‐mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p‐) AKT, mTOR, p70S6K and 4E‐BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p‐mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal–Wallis ANOVA, I/II vs III/IV, p = 0.0500). Μoreover, maximum p‐mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann–Whitney U test, I/II vs III, p = 0.0565). Interestingly, p‐4E‐BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann–Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p‐mTOR and p‐4E‐BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings.     

Clinical outcomes of bypass-first versus endovascular-first strategy in patients with chronic limb-threatening ischemia due to infrageniculate arterial disease

Background

Chronic limb-threatening ischemia (CLTI), defined as ischemic rest pain or tissue loss secondary to arterial insufficiency, is caused by multilevel arterial disease with frequent, severe infrageniculate disease. The rise in CLTI is in part the result of increasing worldwide prevalence of diabetes, renal insufficiency, and advanced aging of the population. The aim of this study was to compare a bypass-first with an endovascular-first revascularization strategy in patients with CLTI due to infrageniculate arterial disease.

Periodization in Anterior Cruciate Ligament Rehabilitation: A Novel Framework

More than 250,000 anterior cruciate ligament (ACL) injuries occur each year in the USA, and approximately 65% of these injuries undergo reconstructive surgery. Appropriate rehabilitation after ACL reconstruction can yield predictably good outcomes, with return to previous levels of activity and high knee function. At present, periodization is used at all levels of sports training. Whether conceptualized and directed by coaches, or by athletes themselves, competitors structure their training in a cyclic fashion, enabling athletes to best realize their performance goals. In practical application, sport physical therapists use periodization: postoperative “protocols” serve as rudimentary forms of periodization, albeit implemented over shorter time frames than that typically employed in preparation for competition. An ACL injury should not be considered a “simple” musculoskeletal pathology with only local mechanical or motor dysfunctions. Together with the psychological trauma and reduction in physical capacity, there is a cascade of events, including neurological insult to the central nervous system and reduction in afferences to the sensorimotor system. Rehabilitation should consider all these issues, and periodization would allow to better define and to plan aims and objectives to return athletes to their sport. Technological resources including advanced neuroimaging methods, virtual reality for injury risk screening and return to sport assessment, and interactive artificial reality-based neuromuscular training methods offer new approaches and tools to address this important biomedical problem. The cost and availability of many of these technologies will continue to decrease, providing greater availability, scientific rigor, and ultimately, utility for cost-effective and data-driven assessments.