Journal of Cardiovascular Pharmacology and Therapeutics

Several studies have shown that angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are useful in the treatment of hypertension, cardiovascular disease, chronic heart failure, and some types of nephropathy. In this context, dual renin-angiotensin system blockade with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may be more effective than treatment with each agent alone. Many clinical trials have demonstrated the beneficial effect of this combined treatment on proteinuria, hypertension, heart failure, and cardiovascular events. Moreover, these studies demonstrated that dual renin-angiotensin system blockade is generally safe and well tolerated. Long-term studies are under way to confirm these effects and also investigate the effectiveness of dual reninangiotensin system blockade on cerebrovascular disease and prevention of type 2 diabetes mellitus. These studies are expected to define the optimal use of combination treatment in everyday clinical practice. This review considers the most important clinical trials that evaluated the effect of dual renin-angiotensin system blockade on blood pressure, heart failure, and renal function.

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor super family that modulate gene expression upon ligand activation. They are 3 major subtypes of PPARs: alpha, delta (also called beta), and gamma. PPAR-γ is widely expressed in the cardiovascular system and is involved in the regulation of tissue inflammation and smooth muscle cell growth pathways as well as in lipoprotein metabolism and coagulation cascades. PPAR-γ ligands of (e.g., rosigitazone and pioglitazone) have been shown to exert antiatherogenic effects both in vitro and in vivo. PPAR-α ligands (e.g., clofibrate and benzofibrate) modulate lipoprotein metabolism, and affect inflammation and coagulation cascade. These effects may be helpful in resolving the dilemma arising from studies that showed significant mortality and morbidity benefits of fibrates in the face of minimal changes in HDL-cholesterol levels. The role of PPAR-δ in atherogenesis remains largely unknown, although it appears that PPAR-δ activation affects lipoprotein metabolism. PPAR ligands appear to be promising agents in limiting atherosclerosis; however, large-scale clinical trials are required to assess their safety and efficacy before they can be added to the clinicians' arsenal of antiatherosclerotic agents.

Pulmonary hypertension is an uncommon, yet devastating, syndrome with a complex underlying pathobiology. Hypoxia, inflammation, and increased shear stress appear to be the primary pathogenic events; however, mechanisms by which these processes lead to pulmonary hypertension remain incompletely understood. The ultimate increase in pulmonary vascular resistance is attributed to remodelling of the walls of resistance vessels, which can lead to encroachment on and reduction of the vascular lumen. The number of blood vessels per unit of cross-sectional area in the hypertensive lung is also reduced, which can contribute to increased vascular resistance. Regardless of its etiology, endothelial dysfunction underlies pulmonary hypertension, one manifestation of which is the attenuated production of bioactive nitric oxide. Nitric oxide administration can exert beneficial effects at various stages of the disease. Here we review the known pathobiology of pulmonary hypertension, with a principal focus on endothelial nitric oxide, and also summarize the data on nitric oxide replacement therapy and other novel therapies that relate to nitric oxide as one approach to treatment.

Accumulation of oxidized-matrix (fibrosis) between the endothelium (the endothelial cells embedded among the myocytes) and cardiomyocytes is a hallmark of diabetes mellitus and causes diastolic impairment. In diabetes mellitus, elevated levels of homocysteine activate matrix metalloproteinase and disconnect the endothelium from myocytes. Extracellular matrix functionally links the endothelium to the cardiomyocyte and is important for their synchronization. However, in diabetes mellitus, a disconnection is caused by activated metalloproteinase, with subsequent accumulation of oxidized matrix between the endothelium and myocyte. This contributes to endothelial-myocyte uncoupling and leads to impaired diastolic relaxation of the heart in diabetes mellitus. Elevated levels of homocysteine in diabetes are attributed to impaired homocysteine metabolism by glucose and insulin and decreased renal clearance. Homocysteine induces oxidative stress and is inversely related to the expression of peroxisome proliferators activated receptor (PPAR). Several lines of evidence suggest that ablation of the matrix metalloproteinase (MMP-9) gene ameliorates the endothelial-myocyte uncoupling in diabetes mellitus. Homocysteine competes for, and decreases the PPARγ activity. In diabetes mellitus, endothelial-myocyte uncoupling is associated with matrix metalloproteinase activation and decreased PPARγ activity. The purpose of this review is to discuss the role of endothelial-myocyte uncoupling in diabetes mellitus and increased levels of homocysteine, causing activation of latent metalloproteinases, decreased levels of thioredoxin and peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase (CIMP) in response to antagonizing PPARγ.

Background: Previous studies have shown that angiotensin II (Ang II) receptors are preset in a wide variety of target tissues and that Ang II regulates the target tissue functions through Ang II receptors. However, the action of Ang II receptors on transsarcolemmal currents in ventricular myocytes has not been elucidated.

Methods and Results: We performed whole-cell voltage clamp and patch clamp experi ments to determine the effects of Ang II-receptor agonists and antagonists on ionic currents in single isolated guinea pig ventricular myocytes. We found that extracellular perfusion of Ang II (30 nM) increased the L-type Ca²⁺ current from 581 ± 27 to 837 ± 42 pA (n = 5, P < .01). Ang II also prolonged the Ca²⁺ current activation and inactivation time constants. These were reversible by losartan (100 nM), a type 1 Ang II receptor (AT,) blockade. On the other hand, perfusion of 30 nM Ang II decreased K⁺ current (I_K) from 1543 ± 28 to 1194 ± 50 pA (n = 5, P < .05) and K+ tail current (I_K-tail ) from 275 ± 24 to 206 ± 29 pA (n = 5, P < .05). These effects were also abolished by perfusion of losartan. However, perfusion of Ang II resulted in an increase of inward rectified K⁺ current (I_K1) in whole-cell recordings. Single- channel recordings showed that the increase in I_K1 was attributed to a burst opening current with a larger unit of amplitude. These effects were reversed by saralasin but not losartan, indicating possible type 2 Ang II receptor (AT₂) involvement.

Conclusions : Our results provide evidence that Ang II receptors regulate the transsar colemmal currents in single guinea pig ventricular myocytes. Therefore, Ang II regulation of ionic currents is mediated through the different subtypes of Ang II receptors.

Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, but other lipid variables such as triglycerides (TRGs), high-density lipoprotein cholesterol (HDL-C) and lipoprotein a [Lp(a)] also affect cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-C concentration but also modestly improve the concentrations of TRGs and HDL-C and more robustly decrease Lp(a) levels. The review presents the associated mechanisms of the beneficial effects of PCSK9 inhibitors on the other than LDL-C lipid variables, including the effects on lipid/apolipoprotein secretion and clearance and the heteroexchange between lipoproteins, as well as the possible effects on other variables involved in lipid metabolism such as sortilin. Proprotein convertase subtilisin/kexin type 9 inhibitors improve the overall lipid profile, and these beneficial effects may play a role in the reduction of cardiovascular risk.

Background: The VA Stroke Prevention in Nonrheumatic Atrial Fibrillation study was a prospective, randomized, double-blind study comparing low-dose warfarin with placebo in patients with nonrheumatic atrial fibrillation. The trial showed a 79% reduction in stroke rate in warfarin randomized patients without an increase in bleeding complications. We examined the need for frequent prothrombin time monitoring (international normalized ratios [INR] were not measured directly) in patients receiving warfarin.

Methods and Results: Patients were initiated on 4.0 mg/d warfarin with a goal of main taining the prothrombin time ratio (PTR) within the range of 1.2-1.5 (estimated INR: 1.4-2.8). PTR monitoring was performed weekly during a 12-week induction period and monthly thereafter for a total follow-up of 3 years. Two hundred sixty patients were ran domized to receive warfarin. During the induction period, the proportion of patients whose PTRs were in the desired range increased from 28% at 1 week postrandomization to 65% at 12 weeks postrandomization; the proportion of patients requiring a dose adjustment decreased from 52% to 16% during the same period. During the maintenance period, the mean proportion of patients whose PTRs were within 1.2-1.5 was 60.5% ± 6.2%.

Conclusions: Low-dose anticoagulation with warfarin in outpatients should be initiated at the anticipated maintenance dose. This approach reduces the chance of being out of range on the high side. Weekly INR estimation during this phase seems optimal. Considerable dose adjusting was required during the maintenance phase to keep patients within range; monthly INRs are required. Because of the need for dose adjustments, fixed-dose warfarin regimens are unlikely to keep patients in the desired narrow therapeutic range.

Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of α-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and affects over 33 million people worldwide. AF is associated with stroke and systemic thromboembolism, unpleasant symptoms and reduced quality of life, heart failure, and increased mortality, and treatment of AF and its complications are associated with significant cost. Antiarrhythmic drugs (AADs) can suppress AF, allowing long-term maintenance of sinus rhythm, and have the potential to relieve symptoms and reverse or prevent adverse effects associated with AF. However, large randomized controlled studies evaluating use of AADs have not demonstrated a clear benefit to maintaining sinus rhythm, and AADs often have significant limitations, including a modest rate of overall success at maintaining sinus rhythm, frequent side effects, and potentially life-threatening toxicities. Although some of the currently available AADs have been available for almost 100 years, better tolerated and more efficacious AADs have recently been developed both for long-term maintenance of sinus rhythm and for chemical cardioversion of AF to sinus rhythm. Advances in automated AF detection with cardiac implantable electronic devices have suggested that AADs might be useful for suppressing AF to allow safe discontinuation of anticoagulation in select patients who are in sinus rhythm for prolonged periods of time. AADs may also have synergistic effects with catheter ablation of AF. This review summarizes the pharmacology and clinical use of currently available AADs for treatment of AF and discusses novel AADs and future directions for rhythm control in AF.

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process by which endothelial cells lose their endothelial cell characteristics and acquire mesenchymal cell properties under certain physiological or pathological conditions. Recently, it has been found that EndMT plays an important role in the occurrence and development of fibrotic cardiovascular diseases. In this review, we first summarize the main induction pathways involved in EndMT process. In addition, we discuss the role of EndMT in fibrotic cardiovascular diseases and its potential implication in new therapeutic interventions.

Dofetilide is a class III antiarrhythmic agent approved by the Food and Drug Administration for the conversion of atrial fibrillation and atrial flutter and maintenance of sinus rhythm in symptomatic patients with persistent arrhythmia. Drug trials showed neutral mortality in post–myocardial infarction patients and those with heart failure. This is a review of postmarket data, including real-world efficacy and safety in a variety of populations. Dofetilide has been used off-label with success in patients with paroxysmal atrial fibrillation and atrial flutter, as well as atrial tachycardia and ventricular tachycardia. The real-world acute conversion rate of atrial fibrillation and atrial flutter is higher than that reported in clinical trials. Dofetilide has an acceptable safety profile when initiated (or reloaded) under hospital monitoring and dosed according to creatinine clearance. Dofetilide is well tolerated and a good choice for patients with acceptable renal function and a normal QT interval, especially if atrioventricular nodal blockade needs to be avoided.

Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an update of clinical trials for diuretics during the past 5 years. Compared to other classes of medications, thiazide diuretics are at least as effective in reducing cardiovascular events (CVEs) in patients with hypertension and are more effective than β-blockers and angiotensin-converting enzyme inhibitors in reducing stroke. Observational cohort data and a network analysis have shown that CVEs are lowered by one-fifth from chlorthalidone when compared to the commonly used thiazide, hydrochlorothiazide. Relative to placebo, chlorthalidone increases life expectancy. In those aged 80 years and older, the diuretic, indapamide, lowers CVEs relative to placebo. The aldosterone antagonist, eplerenone, lowers total mortality in early congestive heart failure. The benefit of eplerenone following acute myocardial infarction (MI) is limited to administration within 3 to 6 days post-MI. Aldosterone antagonists have been shown to lower the incidence of sudden cardiac death and to reduce proteinuria. In the setting of heart failure, long acting loop diuretics azosemide and torasemide are more effective in improving heart failure outcomes than the far more commonly used short acting furosemide. Evening dosing of diuretics appears to lower CVEs relative to morning dosing. In conclusion, diuretics are a diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.