**5. PVF during ongoing AF**

82 Echocardiography – In Specific Diseases

In the PVF profile, **Ar** wave reflects physiologic PV regurgitation during LA contraction due to the absence of an anatomic valve at the PV-LA junction. Interestingly, PV wall contains myocardial sleeves instead of anatomic valve. **Fig. 4** is a schematic illustration of human atria and adjacent great veins. Posterior LA wall contains complicated myocardial layers for myocardial sleeves running longitudinally, cross-sectionally and obliquely within the PV walls. Histologically, myocardial sleeves exist in the mid-layer of PV walls (**Fig. 5A**). The myocardial sleeves are, therefore, considered to function as a 'sphincter', which minimizes the PV regurgitation caused by LA contraction. PV contraction is actually confirmed, and this phenomenon is mainly due to the presence of myocardial sleeves contracting synchronously with LA myocardium. This is validated by radiofrequency catheter ablation, i.e., perfect PV isolation (e.g., electrical disconnection of PV-LA junction) is reported to abolish the PV contraction (Atwater et al, 2011). These sleeves also function as 'throttle' valve that regulates cardiac output for systemic circulation (Burch & Romney, 1954). The myocardial sleeves show characteristic electrophysiological properties prone to yield spontaneous repetitive firings which propagate to LA and cause frequent ectopic beats. **Fig. 5B** is the microelectrode recording of the intracellular potentials of guinea-pig LA and myocardial sleeve in PV. Resting membrane potential in myocardial sleeve is less negative relative to that of LA. Moreover, myocardial sleeve in PV show the tendency of spontaneous electrical activity leading to the abnormal automaticity initiating AF. These arrhythmogenic foci act as a 'driver' to trigger and maintain paroxysms of AF. Highly compliant PV wall allows own cyclic stretching due to physiological PV regurgitation. This phenomenon is considered to accentuate intracellular Ca2+ dynamics mediated by stretch-activated ion channels, which is a prerequisite of repetitive electrical firing (de Bakker et al., 2002; Honjo et al., 2003; Chou et al., 2005, Takahara et al, 2011). Moreover, the myocardial sleeves within PV show a complicated anisotropic orientation of myocardial fibers separated by fibrotic tissues causing impaired electrotonic interactions, which accentuates intrinsic spontaneous

Since Haïssaguerre et al (1998) demonstrated the ectopic and spontaneous electrical activities in the myocardial sleeves located in PV responsible for triggering AF, main stream of the AF research has been changed over the past decade, in that recent AF study focused on many areas which had not been given much attention. Importance of the myocardial sleeves as arrhythmogenic foci in AF is confirmed also in the human postmortem studies. Tagawa et al (2001) investigated myocardial sleeve distribution in patients with AF or without AF. They showed that the significantly longer distance of sleeves extending to the peripheral end of PV in AF patients relative to the distance in control patients was confirmed in inferior but not superior PV. In addition, myocytes in PV of AF patients were not uniform and surrounded by fibrous tissues compared with those in controls. Moreover, Steiner et al (2006) reported that amyloid deposition and scarring in myocardial sleeves tended to be observed more frequently in AF patients relative to control patients. Interestingly, the incidence of atrial myocardium extending beyond the PV-LA junction up to the PV periphery in all the examined PV specimens is commonly reported to be 88 to 89%

According with an advance of immunohistochemical techniques, autonomic nervous innervation in PV has been elucidated. Ganglionated plexi are reported to be abundant around the great vessels of the human heart including PV (Armour et al, 1997).

**4. Myocardial sleeves in PV** 

firing and triggered activity (Nathan & Eliakim, 1966).

(Tagawa et al, 2001; Steiner et al, 2006).

PVF is visualized by Doppler echocardiography not only in sinus rhythm but also during AF. AF is characterized by electrophysiological and mechanical properties such as rapid, irregular and fragmented electrical activities and absence of complete LA contraction and relaxation. Therefore, PVF during AF is known as loss of **Ar** wave, blunted **S** wave and relatively dominant **D** wave. Loss of synchronous LA contraction is reflected by disappearance of **Ar** wave. Similarly, loss of complete LA relaxation causes a delayed onset of **S** wave.

Fig. 4. Schematic illustration of human atria and adjacent great veins. Myocardial sleeves run in PV wall longitudinally, obliquely and cross-sectionally. Myocardial sleeve in superior PV is usually longer than that in inferior PV. IVC, inferior vena cava; LAA, left atrial appendage; LIPV, left inferior PV; LSPV, left superior PV; RAA, right atrial appendage; RIPV, right inferior PV; RSPV, right superior PV; SVC, superior vena cava.

Pulmonary Venous Flow Pattern and Atrial Fibrillation: Fact and Controversy 85

This phenomenon is due to loss of **S1** wave that reflects forward PV flow under the active LA relaxation. Moreover, early systolic reversed PVF is sometimes observed (Tabata et al., 2003; Bollmann, 2007). This is reflected by reversed PV-LA pressure gradient at this moment of the early systolic phase. **S2** *per se* is also blunted under the increased LA stiffness during AF. LA functions of 'reservoir' and 'booster pump' are impaired profoundly under the presence of AF. Impaired LA functions result in the reduction of stroke volume by 38% even in AF patients without organic heart diseases (Alboni et al, 1995). Therefore, only the 'conduit' function of LA remains, which leads to the greater **D** wave relative to **S2** wave (Chao et al., 2000). These echocardiographic findings are important predictors of progressive

AF is a progressive disease showing electrical, contractile and structural LA remodeling (Wijffels et al., 1995). It is well known that paroxysms of AF gradually become refractory to pharmacologic treatment and electrical defibrillation. Accordingly, paroxysmal AF becomes persistent AF, and finally converts to permanent AF, although individual difference in such time course exists. For sonographers and cardiologists, one of the greatest echocardiographic interests during sinus rhythm in AF patients is to predict future paroxysms and progression of AF. Conventionally, prediction of AF progression is based mainly on LA size, volume, and functions (Barbier et al, 1994; Verdecchia et al, 2003; Vasan et al, 2003). Such evaluations have been performed historically by various echocardiographic techniques such as M-mode measurement, LV inflow Doppler velocimetry, strain-rate imaging, three-dimensional echocardiography speckle tracking technique and so on. Two-dimensional speckle tracking echocardiography monitors LA volume curve during an entire cardiac cycle, which enables accurate evaluations of aforementioned three kinds of LA functions (e.g., 'reservoir', 'conduit' and 'booster pump' functions). This technique showed reduced 'reservoir' and 'booster pump' functions in

PVF recording in sinus rhythm of AF patients has been receiving increasing attention, because 'focal' AF originates predominantly from PV (Haïssaguerre et al., 1998), and wide spectrum of paroxysmal to persistent AF associated with and without organic heart diseases shows similar characteristics of 'focal' AF. PV orifice morphologies in conjunction with AF progression have been investigated over the years by various modalities such as TEE (Knackstedt et al, 2003), magnetic resonance (MR) imaging (Tsao et al, 2001; Takase et al., 2004) and multislice computed tomography (Scharf et al, 2003). These investigations have been conducted under the uniform hypothesis that largest PV is the main source of ectopic electrical activities triggering and sustaining AF. **Fig. 6** demonstrates the PV images obtained by MR angiography applied to the patients with paroxysmal (**Fig. 6A**) or permanent (**Fig. 6B**) AF and with sinus rhythm (**Fig. 6C**). Four PV diameters are reported to be greater in the order of patients with permanent AF > those with paroxysmal AF > those with sinus rhythm (Takase et al., 2004). Moreover, PV branching pattern observed in AF patients is complicated compared with that of patients with sinus rhythm. These indicate that most permanent and paroxysmal AF stems from 'focal' AF, and that progressive structural remodeling caused by AF affects both LA and PV. With respect to the PV/LA diameter ratio, there has been a controversy, i.e., this ratio in patients with AF tended to be

LA remodeling.

**6. PVF during sinus rhythm in AF patients** 

patients with paroxysmal AF (Mori et al., 2011).

Fig. 5. **A:** Microscopic findings of PV obtained from guinea pig (upper: masson trichrome staining, lower: immunostaining for α-smooth muscle actin). **B:** Electrophysiological characteristics of PV and LA. (From Takahara, A.; Sugimoto, T.; Kitamura, T.; Takeda, K.; Tsuneoka, Y.; Namekata, I. & Tanaka, H. Electrophysiological and pharmacological characteristics of triggered activity elicited in guinea-pig pulmonary vein myocardium. *Journal of Pharmacological Science* Vol. 115, No. 2, 2011, pp. 176-181, with permission.)

This phenomenon is due to loss of **S1** wave that reflects forward PV flow under the active LA relaxation. Moreover, early systolic reversed PVF is sometimes observed (Tabata et al., 2003; Bollmann, 2007). This is reflected by reversed PV-LA pressure gradient at this moment of the early systolic phase. **S2** *per se* is also blunted under the increased LA stiffness during AF. LA functions of 'reservoir' and 'booster pump' are impaired profoundly under the presence of AF. Impaired LA functions result in the reduction of stroke volume by 38% even in AF patients without organic heart diseases (Alboni et al, 1995). Therefore, only the 'conduit' function of LA remains, which leads to the greater **D** wave relative to **S2** wave (Chao et al., 2000). These echocardiographic findings are important predictors of progressive LA remodeling.
