Advances in Cardiology最新文献

Arterial stiffness and pulse pressure are important determinants of cardiovascular risk. Patients with hypercholesterolaemia have a higher central pulse pressure and stiffer blood vessels than matched controls, despite similar peripheral blood pressures. These haemodynamic changes may contribute to the increased risk of cardiovascular disease associated with hypercholesterolaemia and their assessment may improve risk stratification. Lipid-lowering therapy, particularly with statins, generally leads to a reduction in arterial stiffness, re-enforcing the concept that stiffness is a modifiable parameter and risk factor. There are a number of potential mechanisms linking arterial stiffness and plasma lipids, including atherosclerosis, changes in the elastic elements of the arterial wall, endothelial dysfunction and inflammation. This review will focus on the current evidence linking cholesterol to larger artery stiffening, potential therapies and mechanisms.

It is well known that dyslipidemia and hypertension frequently coexist. There is increasing recognition of a mutually facilitative interaction between dyslipidemia and renin- angiotensin system (RAS) activation in the development of atherosclerosis. Both of these systems share many of the same properties in terms of activation of pro-inflammatory, pro-oxidant and pro-atherosclerosis pathways. Statins in particular have been shown to influence the biology of endothelial cells, vascular smooth muscle cells and constituents of the interstitial matrix, particularly fibroblasts. It is no wonder that concurrent therapy of dyslipidemia with statins enhances the effects of RAS inhibitors. Although the effects of statins on the regulation of determinants of vascular stiffness are not well defined, it is quite likely that these regulatory pathways will be influenced by dyslipidemia therapy, especially statins.

Large artery stiffening may be both a cause and a consequence of atherosclerosis and is independently related to coronary outcome. This relationship is likely to be causal given the unfavourable effect of large artery stiffening on coronary hemodynamics. There is clear experimental and clinical evidence that large artery stiffening promotes myocardial ischemia secondary to central pulse pressure elevation. Many agents commonly used to treat ischemic heart disease symptoms also reduce large artery stiffness, through both functional and structural mechanisms. Such effects likely contribute to the anti-ischemic actions of these drugs. However, it remains to be elucidated whether agents specifically targeted to reduce large artery stiffness provide ischemic protection in the setting of coronary disease.

It is generally accepted that the increased cardiovascular morbidity and mortality in hypertension are related to target organ damage. Classically, the target organs are heart, brain, and kidneys. This brief report examines whether high arterial pressure may also affect other organs, such as aorta and large arteries. An attempt was also made to elucidate the relationship between disorders of the aorta and large arteries and other cardiovascular risk factors to the pathophysiology and treatment of patients with hypertension and its severe comorbid disease, atherosclerosis.

Gap junction (GJ) channels play an important role in forming a functional network or syncytium of cells by allowing the transfer of small molecules or the conduction of electrical activation. These channels can be regulated at the level of acute opening or closure as well as at the level of expression including synthesis, protein trafficking and degradation. Many of the underlying mechanisms depend on phosphorylation or dephosphorylation of connexins. A number of drugs is available to study GJ function and connexin expression. Some of these drugs have shown therapeutic effects, e.g. the anti-arrhythmic peptides AAP10 and ZP123 in the prevention of certain types of arrhythmia. Moreover, mediators involved in cardiovascular pathophysiology, e.g. angiotensin, endothelin, tumor necrosis factor-alpha, fibroblast growth factor and others, affect connexin expression and can alter the Cx43/Cx40 ratio, which may contribute to the formation of an arrhythmogenic substrate. On the other hand, drugs affecting these mediators may influence GJ networking and may thus open new therapeutic horizons.

Heart rate slowing is generally accepted as effective for angina prevention but this approach has not been rigorously evaluated as no pure heart rate slowing treatment has been available. With the identification of the I(f) current, the primary modulator of heart rate, and use of this as a target for drug development, the role of isolated heart rate slowing can be elucidated. More than 4,000 patients now have been studied in angina prevention trials with ivabradine, a prototype I(f) current inhibitor devoid of other cardiovascular effects. These studies demonstrate the efficacy of isolated heart rate slowing for angina prevention. Indeed, in one direct comparison with atenolol involving 939 patients, ivabradine not only was non inferior to the Beta-blocker but nominally appeared to be more efficient in angina prevention. Moreover, since ivabradine is devoid of most of the adverse effects of beta-blockers (and of calcium channel blockers), it is a suitable alternative when these established drugs are not adequately tolerated. Additional studies now must assess other potential actions in patients with coronary disease.

Unlabelled: Previous studies have shown that two linked polymorphisms within regulatory regions of the gene for connexin40 (Cx40), at nucleotides -44 (G --> A) and +71 (A --> G) occur in about 7% of the general population. Cx40 is abundant in the atrium, and homozygosity for the linked polymorphisms combined with an SCN5A mutation appeared to be responsible for familial atrial standstill. We hypothesized that these polymorphisms are associated with the atrial electrophysiologic substrate favoring reentrant mechanisms for initiation of atrial fibrillation (AF). Reentry is promoted by spatial dispersion of refractoriness that can be expressed as a coefficient of dispersion (CD).

Methods: CD was calculated from the standard deviation of 12 local mean fibrillatory intervals recorded at right atrial sites during induced AF in 30 patients without structural heart disease (14 sporadic AF episodes, 16 no AF history). CD

Results: Mean CD in AF patients was 5.96 +/- 0.70 and without AF 1.59 +/- 0.18 (p < 0.001). Thirteen of fourteen patients with AF had enhanced CD. Carriers of -44 AA genotype had higher CD compared with those with -44 GG genotype (6.37 +/- 1.21 vs. 2.38 +/- 0.39, p = 0.018), whereas heterozygotes showed intermediate values (3.95 +/- 1.38, NS).

Conclusion: The rare linked Cx40 polymorphisms are associated with enhanced CD and thus with the substrate for reentry in AF.

Cardiac gap junction channels are crucial for conduction of the electric impulse. Between cardiomyocytes there exist gap junctions constructed from connexin40 (Cx40), Cx43 and Cx45. A fourth isoform, Cx37, is expressed in the endothelial lining. Each of these channel types possesses specific properties and their functioning is regulated by various mechanisms. In this chapter we compare the physiological differences between these channels and discuss the factors involved in modulation of channel properties. Next, we evaluate how alterations in expression and differential regulation of channel properties affect cardiac impulse propagation.

Ivabradine is a novel heart-rate-lowering agent that acts specifically on the sinoatrial node by selectively inhibiting the I(f) current, which is the current predominantly responsible for the slow diastolic depolarization of pacemaker cells. Unlike many rate-lowering agents, ivabradine reduces heart rate in a dose-dependent manner both at rest and during exercise without producing any negative inotropic or vasoconstrictor effect. The bradycardic effect of ivabradine is proportional to the resting heart rate, such that the effect tends to plateau. Thus, extreme sinus bradycardia is uncommon. Less than 1% of patients withdrew from therapy because of untoward sinus bradycardia. The QT interval is expectedly prolonged with the reduction in heart rate, but after appropriate correction for heart rate and in direct comparisons of the QT interval when the influence of the heart rate was controlled by atrial pacing, no significant effect of ivabradine on ventricular repolarization duration was demonstrated. Consequently, ivabradine has no direct torsadogenic potential, although, for obvious reasons, the specific bradycardic drug should not be administered with agents which have known rate-lowering and/or QTprolonging effects. Ivabradine has little effect on the atrioventricular node and ventricular refractoriness, but because of its effect on the sinus node, it should be avoided in patients with sick sinus syndrome. The physiological significance of upregulation of the I(f) current in the His-Purkinje system and ventricular myocardium due to ionic remodeling in pathophysiological conditions, such as end-stage heart failure, and the effects of ivabradine have yet to be explored. Because ivabradine also binds to hyperpolarization voltage-gated channels which carry the I(h) current in the eye, transient, dose-dependent changes of the electroretinogram resulting in mild to moderate visual side effects (phenomes) may occur in approximately 15% of patients exposed to ivabradine. Ivabradine does not cross the blood-brain barrier and therefore, has no effect on the I(h) current in central nervous system neurons. The safety of ivabradine has been assessed in a development program that enrolled over 3,500 patients and 800 healthy volunteers in 36 countries from Europe, North and South America, Africa, Asia and Australia, 1,200 of whom were exposed to ivabradine for over 1 year. Ivabradine has been associated with a good safety profile during its clinical development and its safety will be further assessed by postmarketing surveillance and during on-going clinical trials.

Heart failure is a major health problem, and is one of the few cardiovascular diseases that increased its prevalence over the last decade. Increased heart rate, generally observed in patients with heart failure, is involved in the deterioration of cardiac pump function. However, the effects of 'pure' heart rate reduction on the progression of heart failure are unknown. In a rat model of heart failure, ivabradine, a blocker of I(f) channels reduces dose-dependently heart rate without modification of blood pressure. This heart rate reduction is associated with an improvement in cardiac function. After chronic administration, this improvement of cardiac function persists after ivabradine withdrawal, revealing an improvement in intrinsic myocardial function. This beneficial effect could be explained by direct effects of heart rate reduction induced by ivabradine, i.e. improved myocardial oxygen supply to demand ratio, and/or myocardial tissular effects induced by chronic decrease in heart rate such, i.e. decreased extracellular collagen accumulation, increased myocardial microcirculation. In conclusion, 'pure' chronic heart rate reduction can be beneficial in heart failure.