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

84 Echocardiography – In Specific Diseases

**A** 

**B** 

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.)

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

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

Pulmonary Venous Flow Pattern and Atrial Fibrillation: Fact and Controversy 87

surrounding the PV-LA junction (**Fig. 4**, **Fig. 5A**). This is considered to be due to the histological, electrical and mechanical abnormalities of the myocardial sleeves. On the other hand, reduced LAFS means the contractile LA remodeling, and increased LADd reflects

**A B**

**C**

Fig. 6. Representative magnetic resonance angiography of patients with paroxysmal (**A**) or permanent (**B**) AF and with sinus rhythm (**C**). Diameters of pulmonary veins in AF patients are greater than those in patients with sinus rhythm. Landmark (\*) showing the center of posterior wall of left atrium was indicated. (From Takase, B.; Nagata, M.; Matsui, T.; Kihara, T.; Kameyama, A.; Hamabe, A.; Noya, K.; Satomura, K.; Ishihara, M.; Kurita, A. & Ohsuzu,

paroxysmal atrial fibrillation using magnetic resonance angiography. *Japanese Heart Journal*

F. Pulmonary vein dimensions and variation of branching pattern in patients with

Vol. 45, No. 1, 2004, pp. 81-92, with permission.)

greater than that of patients without AF (Knackstedt et al, 2003), whereas this ratio was the same among the patient groups of paroxysmal AF, permanent AF and sinus rhythm (Tsao et al, 2001). These discrepant results may be attributed in part to the different imaging modalities and AF patients' enrollment.

In spite of accumulated morphological investigations of PV-LA junction in AF patients, there have been controversies in echocardiographic PVF patterns during sinus rhythm in patients susceptible to AF. Kosmala et al (2006) reported that an abnormal PVF pattern was observed in patients with AF, i.e., abbreviated acceleration time and prolonged deceleration time in **S** wave, indicating impaired LA relaxation and compliance. Similarly, Lindgren et al (2003) reported the reduced **S** wave amplitude as a predictor of AF progression. These are compatible to the findings reported by two-dimensional speckle tracking method (Mori et al, 2011). On the other hand, increased **Ar** wave amplitude in sinus rhythm is reported to be a potential marker of AF progression in hypertensive patients in our laboratory (**Fig. 7**). **Ar** amplitude and velocity-time integral of **Ar** wave are supposed to be linked closely to the sphincter function of myocardial sleeves located in PV (**Fig. 4**, **Fig. 5A**), i.e., impaired sphincter function theoretically allows more PV regurgitation and **Ar** wave augmentation. Surprisingly, increased **Ar** amplitude is associated with reduced, but not increased, LA contractility in our study (Maruyama et al, 2008). These findings imply that PV sphincter dysfunction is linked to the contractile LA remodeling responsible for AF progression. LA contractile performance is usually quantified as LA fractional shortening (LAFS), which is calculated by the following equation (**Fig. 8**),

$$\text{LAFS} = \text{(LADa - Labd)} / \text{LADa} \tag{1}$$

where, LADa is an LA diameter at the beginning of LA contraction, and LADd is a minimum LA diameter during active LA contraction (Barbier et al, 1994). This is a simple measure of LA contractility obtained by M-mode echocardiography, although it is a parameter estimated only in the anteroposterior LA direction. **Ar** wave augmentation is associated with reduced LAFS, and predictive values of PV regurgitation (e.g., peak PV backflow velocity: PVBV), LA contractile function (e.g., LAFS) and LA size (e.g., LADd) for AF progression are assessed. Consequently, receiver-operating curve (ROC) indicated that the amplitude of age-independent **Ar** wave (e.g., PVBV) showed the greatest predictive value for the perpetuation of AF (**Fig. 9**). So far, the reason for discrepant results showing the importance of impaired forward flow (**S** wave) vs. augmented backward flow (**Ar** wave) in AF progression is unknown. PV regurgitation reflected by augmented **Ar** wave amplitude (e.g., PVBV) is determined by LA-PV pressure gradient (e.g., balance between LA contractile function and PV 'sphincter' function). These structures are under the influence of continuous remodeling according to the AF progression, which differs in individual AF patient. There are so many echocardiographic indices with different sensitivities and specificities. Echocardiography recorded during sinus rhythm at different stages of longterm AF progression may have resulted in such discrepant outcomes. Therefore, in personal opinion, it seems uncertain whether or not such comparisons of echocardiographic investigations are meaningful or fruitful.

**Ar** wave augmentation indicating an extent of PV regurgitation is considered to be a PV remodeling based on the impaired 'sphincter' function of the myocardial sleeves

greater than that of patients without AF (Knackstedt et al, 2003), whereas this ratio was the same among the patient groups of paroxysmal AF, permanent AF and sinus rhythm (Tsao et al, 2001). These discrepant results may be attributed in part to the different imaging

In spite of accumulated morphological investigations of PV-LA junction in AF patients, there have been controversies in echocardiographic PVF patterns during sinus rhythm in patients susceptible to AF. Kosmala et al (2006) reported that an abnormal PVF pattern was observed in patients with AF, i.e., abbreviated acceleration time and prolonged deceleration time in **S** wave, indicating impaired LA relaxation and compliance. Similarly, Lindgren et al (2003) reported the reduced **S** wave amplitude as a predictor of AF progression. These are compatible to the findings reported by two-dimensional speckle tracking method (Mori et al, 2011). On the other hand, increased **Ar** wave amplitude in sinus rhythm is reported to be a potential marker of AF progression in hypertensive patients in our laboratory (**Fig. 7**). **Ar** amplitude and velocity-time integral of **Ar** wave are supposed to be linked closely to the sphincter function of myocardial sleeves located in PV (**Fig. 4**, **Fig. 5A**), i.e., impaired sphincter function theoretically allows more PV regurgitation and **Ar** wave augmentation. Surprisingly, increased **Ar** amplitude is associated with reduced, but not increased, LA contractility in our study (Maruyama et al, 2008). These findings imply that PV sphincter dysfunction is linked to the contractile LA remodeling responsible for AF progression. LA contractile performance is usually quantified as LA fractional shortening (LAFS), which is

where, LADa is an LA diameter at the beginning of LA contraction, and LADd is a minimum LA diameter during active LA contraction (Barbier et al, 1994). This is a simple measure of LA contractility obtained by M-mode echocardiography, although it is a parameter estimated only in the anteroposterior LA direction. **Ar** wave augmentation is associated with reduced LAFS, and predictive values of PV regurgitation (e.g., peak PV backflow velocity: PVBV), LA contractile function (e.g., LAFS) and LA size (e.g., LADd) for AF progression are assessed. Consequently, receiver-operating curve (ROC) indicated that the amplitude of age-independent **Ar** wave (e.g., PVBV) showed the greatest predictive value for the perpetuation of AF (**Fig. 9**). So far, the reason for discrepant results showing the importance of impaired forward flow (**S** wave) vs. augmented backward flow (**Ar** wave) in AF progression is unknown. PV regurgitation reflected by augmented **Ar** wave amplitude (e.g., PVBV) is determined by LA-PV pressure gradient (e.g., balance between LA contractile function and PV 'sphincter' function). These structures are under the influence of continuous remodeling according to the AF progression, which differs in individual AF patient. There are so many echocardiographic indices with different sensitivities and specificities. Echocardiography recorded during sinus rhythm at different stages of longterm AF progression may have resulted in such discrepant outcomes. Therefore, in personal opinion, it seems uncertain whether or not such comparisons of echocardiographic

**Ar** wave augmentation indicating an extent of PV regurgitation is considered to be a PV remodeling based on the impaired 'sphincter' function of the myocardial sleeves

LAFS = (LADa – LADd) / LADa (1)

modalities and AF patients' enrollment.

calculated by the following equation (**Fig. 8**),

investigations are meaningful or fruitful.

surrounding the PV-LA junction (**Fig. 4**, **Fig. 5A**). This is considered to be due to the histological, electrical and mechanical abnormalities of the myocardial sleeves. On the other hand, reduced LAFS means the contractile LA remodeling, and increased LADd reflects

Fig. 6. Representative magnetic resonance angiography of patients with paroxysmal (**A**) or permanent (**B**) AF and with sinus rhythm (**C**). Diameters of pulmonary veins in AF patients are greater than those in patients with sinus rhythm. Landmark (\*) showing the center of posterior wall of left atrium was indicated. (From Takase, B.; Nagata, M.; Matsui, T.; Kihara, T.; Kameyama, A.; Hamabe, A.; Noya, K.; Satomura, K.; Ishihara, M.; Kurita, A. & Ohsuzu, F. Pulmonary vein dimensions and variation of branching pattern in patients with paroxysmal atrial fibrillation using magnetic resonance angiography. *Japanese Heart Journal* Vol. 45, No. 1, 2004, pp. 81-92, with permission.)

Pulmonary Venous Flow Pattern and Atrial Fibrillation: Fact and Controversy 89

stunning depends on the duration of AF, mode of defibrillation, and LA size, i.e., AF lasting 10 to 20 minutes does not cause observable stunning (Sparks et al, 1999) and recovery of LA contractile function is early in the order of spontaneous conversion to sinus rhythm > pharmacological defibrillation > electrical defibrillation. AF patients with normal LA size are

Thromboembolic event is a major complication of AF. This complication after defibrillation has been attributed to the dislodgement of LA thrombi during the recovery from LA stunning. Therefore, serial echocardiographic investigation and optimal anticoagulation treatment are necessary during this period. LA stunning is observed also in the case of AF treated with radiofrequency catheter ablation. Stavrakis et al (2011) investigated the acute changes of LA function and PVF pattern following PV isolation associated with ganglionated plexi ablation by TEE. They reported augmentation of both **D** and **S** waves, decrease of **S**/**D** ratio, and trend toward an increase in LA appendage emptying velocities after the ablation. LA appendage emptying velocity closely relates to LA stunning, and reduced **S**/**D** ratio reflects impaired LA relaxation in the postablative period. These TEE findings are consistent with those reported by

also apt to show earlier LA functional recovery (Mattioli et al, 1998; Khan, 2003).

Lindgren et al (2003) in the paroxysmal interval of AF patients.

**P**

**Q**

**R**

**S**

**LADa LADd LADs**

Fig. 8. Schematic illustration of the M-mode estimation of left atrial (LA) contractile function. LA dimension is variable depending on cardiac cycle. LADa, LA dimension immediately prior to the onset of LA contraction; LADd, minimal LA dimension at the end of the active LA contraction; LADs, maximal LA dimension at the end-systole. LA fractional

shortening (LAFS) is calculated by equation (1) in the text. LA plays three kinds of hemodynamic function during an entire cardiac cycle (text). Aortic valve opening time corresponds to the left ventricular ejection period. Ao, aortic root; ECG, electrocardiogram;

RVOT, right ventricular outflow tract; UCG, ultrasound cardiogram.

**T**

**ECG**

**UCG**

**RVOT**

**Ao**

**LA**

in part the structural LA remodeling. It is, therefore, of interest which part of remodeling shows the greatest influence on the AF progression and perpetuation. In our study, PV remodeling demonstrated the greatest influence on the perpetuation of AF by the ROC analysis (**Fig. 9**). Knackstedt et al (2003) reported no correlation between PV diameter and LA size in patients with or without AF. Considering their TEE study, PV remodeling (e.g., dilation and regurgitation) plays a key role in AF progression (Scharf et al, 2003), although it is uncertain whether PV remodeling is a cause or a consequence of AF progression. PV wall is relatively more compliant and hence more susceptible to hemodynamics altered by paroxysms of AF than LA wall. Therefore, in personal opinion, these vessel properties of PV relates to susceptibility to AF-induced remodeling.

Fig. 7. Representative pulsed-wave Doppler findings of time-matched LV inflow (upper) and right superior pulmonary vein (PV) flow patterns (lower) during sinus rhythm in patients with AF which became permanent (**A**) or remained paroxysmal (**B**). Peak velocity of PV backflow (**Ar** wave) during left atrial (LA) contraction in **A** (left white arrow) was obviously greater than that in **B** (right white arrow). Time-integral of PV backflow in **A** is also greater than that in **B**. Note that scale in LV inflow is different from that in PV flow. (From Maruyama, T.; Kishikawa, T.; Ito, H.; Kaji, Y.; Sasaki, Y. & Ishihara, Y. Augmentation of pulmonary vein backflow velocity during left atrial contraction: a novel phenomenon responsible for progression of atrial fibrillation in hypertensive patients. *Cardiology* Vol. 109, No. 1, 2008, pp. 33-40, with permission.)

After the termination of AF episode, LA contractile function is briefly impaired. This impairment is gradually restored, and this reversible phenomenon is well known as LA stunning. One of the main causes of this stunning is considered to be based on the intracellular handling of cytosolic Ca2+, which is important in cardiac performance but disturbed during AF. The aspects of atrial cardiomyopathy induced by tachycardia and atrial hibernation or fibrosis are also involved in the genesis of LA stunning (Khan, 2003). Recovery from LA

in part the structural LA remodeling. It is, therefore, of interest which part of remodeling shows the greatest influence on the AF progression and perpetuation. In our study, PV remodeling demonstrated the greatest influence on the perpetuation of AF by the ROC analysis (**Fig. 9**). Knackstedt et al (2003) reported no correlation between PV diameter and LA size in patients with or without AF. Considering their TEE study, PV remodeling (e.g., dilation and regurgitation) plays a key role in AF progression (Scharf et al, 2003), although it is uncertain whether PV remodeling is a cause or a consequence of AF progression. PV wall is relatively more compliant and hence more susceptible to hemodynamics altered by paroxysms of AF than LA wall. Therefore, in personal opinion, these vessel properties of PV

Fig. 7. Representative pulsed-wave Doppler findings of time-matched LV inflow (upper) and right superior pulmonary vein (PV) flow patterns (lower) during sinus rhythm in patients with AF which became permanent (**A**) or remained paroxysmal (**B**). Peak velocity of PV backflow (**Ar** wave) during left atrial (LA) contraction in **A** (left white arrow) was obviously greater than that in **B** (right white arrow). Time-integral of PV backflow in **A** is also greater than that in **B**. Note that scale in LV inflow is different from that in PV flow. (From Maruyama, T.; Kishikawa, T.; Ito, H.; Kaji, Y.; Sasaki, Y. & Ishihara, Y. Augmentation of pulmonary vein backflow velocity during left atrial contraction: a novel phenomenon responsible for progression of atrial fibrillation in hypertensive patients. *Cardiology* Vol. 109,

After the termination of AF episode, LA contractile function is briefly impaired. This impairment is gradually restored, and this reversible phenomenon is well known as LA stunning. One of the main causes of this stunning is considered to be based on the intracellular handling of cytosolic Ca2+, which is important in cardiac performance but disturbed during AF. The aspects of atrial cardiomyopathy induced by tachycardia and atrial hibernation or fibrosis are also involved in the genesis of LA stunning (Khan, 2003). Recovery from LA

relates to susceptibility to AF-induced remodeling.

**A B**

No. 1, 2008, pp. 33-40, with permission.)

stunning depends on the duration of AF, mode of defibrillation, and LA size, i.e., AF lasting 10 to 20 minutes does not cause observable stunning (Sparks et al, 1999) and recovery of LA contractile function is early in the order of spontaneous conversion to sinus rhythm > pharmacological defibrillation > electrical defibrillation. AF patients with normal LA size are also apt to show earlier LA functional recovery (Mattioli et al, 1998; Khan, 2003).

Thromboembolic event is a major complication of AF. This complication after defibrillation has been attributed to the dislodgement of LA thrombi during the recovery from LA stunning. Therefore, serial echocardiographic investigation and optimal anticoagulation treatment are necessary during this period. LA stunning is observed also in the case of AF treated with radiofrequency catheter ablation. Stavrakis et al (2011) investigated the acute changes of LA function and PVF pattern following PV isolation associated with ganglionated plexi ablation by TEE. They reported augmentation of both **D** and **S** waves, decrease of **S**/**D** ratio, and trend toward an increase in LA appendage emptying velocities after the ablation. LA appendage emptying velocity closely relates to LA stunning, and reduced **S**/**D** ratio reflects impaired LA relaxation in the postablative period. These TEE findings are consistent with those reported by Lindgren et al (2003) in the paroxysmal interval of AF patients.

Fig. 8. Schematic illustration of the M-mode estimation of left atrial (LA) contractile function. LA dimension is variable depending on cardiac cycle. LADa, LA dimension immediately prior to the onset of LA contraction; LADd, minimal LA dimension at the end of the active LA contraction; LADs, maximal LA dimension at the end-systole. LA fractional shortening (LAFS) is calculated by equation (1) in the text. LA plays three kinds of hemodynamic function during an entire cardiac cycle (text). Aortic valve opening time corresponds to the left ventricular ejection period. Ao, aortic root; ECG, electrocardiogram; RVOT, right ventricular outflow tract; UCG, ultrasound cardiogram.

Pulmonary Venous Flow Pattern and Atrial Fibrillation: Fact and Controversy 91

procedure for ablation is electrical isolation of PV-LA junctions, i.e., disconnection of arrhythmogenic PV and adjacent antrum. Although recent advance in navigation system and new catheter device have enabled safe and effective PV isolation, PV stenosis remains a major complication especially of circumferential PV isolation. Pulmonary veno-occlusive syndrome associated with secondary pulmonary hypertension is a serious late-onset complication. During this procedure, mild-to-moderate forward PVF (e.g., **S** and **D** waves) acceleration is recorded, but this acceleration is transient and well tolerated (Ren et al., 2002). PVF monitoring is a practical and cost-effective method for early detection of this serious complication (Tabata et al., 2003; Bollmann 2007). When considering PVF is influenced by heart rate and autonomic tone (Ren et al., 2004), computed tomography or MR imaging is

required to determine the therapeutic indication for balloon dilatation of PV stenosis.

All the components of PVF have the potential role to evaluate AF progression, i.e., **S** wave attenuation and consequent relative **D** wave augmentation indicate impaired LA relaxation and compliance. Considering increased **D** and **Ar** wave amplitudes during sinus rhythm in AF patients, PVF increases exclusively during LV diastole, whichever PVF direction is forward (e.g., **D** wave) or backward (e.g., **Ar** wave). If ectopic beats originating from PV are mechanically triggered, these echocardiographic findings indicate that ectopic beats are prone to occur during diastole. Therefore, repetitive PV ectopic beats easily capture ventricles that are out of refractory period, and induce rapid ventricular response during 'focal' AF. This is important because rapid AF is easy to promote electrical remodeling

> PV backflow during LA contraction

repetitive or fibrillatory electrical firing

**Vicious Cycle**

progression of AF

Fig. 10. Possible mechanisms of reversed PV flow (**Ar** wave) augmentation contributing to

cyclic stretch of PV musculature

**8. PVF and AF progression** 

(Wijffels et al., 1995).

the AF progression.

loss of regular 'sphincter' function

### **7. PVF in AF management**

Pharmacological AF management is mainly divided into rhythm control and rate control strategies, both of which show equivalent outcomes in long-term prognosis of AF patients provided that appropriate anticoagulation therapy is conducted (Wyse, 2005). However, choice of better strategy based only on electrophysiologic or electrocardiographic perspectives seems insufficient. PVF evaluation has the potential to play a role in this decision-making process, i.e., PVF recording enables evaluation of contractile LA and PV functions, which vary during the long period of AF remodeling affecting both LA and PV. For AF management, it is important to assess the stage of AF progression in individual AF patient with different clinical background. For this purpose, assessment of LA stiffness or contractility and severity of PV regurgitation by PVF profile is important for AF management in individual patient.

Radiofrequency catheter ablation is widely conducted in many electrophysiologic laboratories. It is a first line therapy for 'focal' AF originating from PV, and is currently applied not only to paroxysmal AF but also to persistent AF. Remodeling makes AF drugrefractory. Moreover, antiarrhythmic drugs often suppress cardiac performance (negative inotropism) and are sometimes arrhythmogenic (proarrhythmic effects). The main

Fig. 9. Receiver-operating curve (ROC) discriminated PV backflow velocity (PVBV) as the best predictor of the progression of AF. Areas under the ROC for PVBV, left atrial fractional shortening (LAFS) and left atrial diameter at end-diastole (LADd) are 0.873, 0.740 and 0.623, respectively. Cut-off PVBV for predicting future AF perpetuation is 21.8 cm/sec (sensitivity 84.6%, specificity 78.3%). LAFS is calculated by equation (1) in the text. (From Maruyama, T.; Kishikawa, T.; Ito, H.; Kaji, Y.; Sasaki, Y. & Ishihara, Y. Augmentation of pulmonary vein backflow velocity during left atrial contraction: a novel phenomenon responsible for progression of atrial fibrillation in hypertensive patients. *Cardiology* Vol. 109, No. 1, 2008, pp. 33-40, with permission.)

procedure for ablation is electrical isolation of PV-LA junctions, i.e., disconnection of arrhythmogenic PV and adjacent antrum. Although recent advance in navigation system and new catheter device have enabled safe and effective PV isolation, PV stenosis remains a major complication especially of circumferential PV isolation. Pulmonary veno-occlusive syndrome associated with secondary pulmonary hypertension is a serious late-onset complication. During this procedure, mild-to-moderate forward PVF (e.g., **S** and **D** waves) acceleration is recorded, but this acceleration is transient and well tolerated (Ren et al., 2002). PVF monitoring is a practical and cost-effective method for early detection of this serious complication (Tabata et al., 2003; Bollmann 2007). When considering PVF is influenced by heart rate and autonomic tone (Ren et al., 2004), computed tomography or MR imaging is required to determine the therapeutic indication for balloon dilatation of PV stenosis.
