**4. Left ventricular twist in cardiac disease**

#### **4.1. Subendocardial dysfunction**

cardial fibres [38]. However, the effective force of contraction of myocardial fibres is expected to be minimal during this part of the cardiac cycle. Nevertheless, dissimilarities of apparent stiffness of the endocardium and epicardium caused by differences in breakdown of actinmyosin cross-bridges may be of influence. The group of Shapiro and Rademakers was one of the first to investigate the physiology of left ventricular untwisting in more detail with MRI [39]. They found, in an open-chest canine model, that left ventricular untwisting and filling are dissociated in time. In the normal resting heart about 40% of left ventricular untwisting occurs during isovolumic relaxation. Dobutamine enhanced the extent of left ventricular untwisting before mitral valve opening and further accentuated the dissociation between left ventricular untwisting and filling. The untwisting rate, the mean left ventricular untwisting velocity during the isovolumic relaxation phase, is proportional to the rate of isovolumic pressure decay [40]. In addition, left ventricular untwisting precedes and is a strong predictor of the intraventricular pressure gradient, a marker of diastolic suction during early left ventricular filling. This may be caused by a temporal dispersion between basal and apical derotation, the diastolic reversal of systolic rotation [41]. At the left ventricular apical level there is faster de-rotation, as compared to the basal level, which may be explained by the relatively increased systolic apical rotation, and thus stored potential energy. Interestingly, at the left ventricular basal level there is still a profound de-rotation from mitral valve opening until the peak of early left ventricular filling velocity. This may be explained by the temporal dispersion in basal and apical repolarization. Since the basal endocardial fibres are the latest to be repolarized (repolarization progresses from the apex to the base of the heart and from the epicardium to the endocardium, and takes approximately 150ms), an extra de-rotating force may still be present during this period at the basal level. Furthermore, there is a brief episode of re-rotation at the basal level from the peak to the end of the early left ventricular filling velocity that may partially be explained by the sudden omission of the de-rotational forces of the endocardial fibres, at the moment of complete cardiac repolarization. In contrast, during this period continuing de-rotation is seen at the left ventricular apical level. Since rotation is related to an increase and de-rotation to a decrease in left ventricular pressure, this phenom‐ enon may facilitate blood flow all the way to the apex. Thus, left ventricular untwisting provides a temporal link between two crucial diastolic phenomena, relaxation and diastolic

In adolescents and young adults, there may be a marked contribution of active left ventricular relaxation to left ventricular filling, resulting in an accentuated early diastolic filling velocity with a short deceleration time, resembling restrictive left ventricular filling at Doppler echocardiography ('pseudo-restrictive' left ventricular filling pattern). Very rapid left ventric‐ ular untwisting plays a pivotal role in this physiological rapid early diastolic filling [42]. In contrast, in dilated cardiomyopathy patients, untwisting is delayed and this impairment to

Marked changes in left ventricular diastolic function are known to occur in healthy elderly [43,44]. As described before, with advancing age left ventricular twist increases, probably due to both a decrease in rotational deformation delay and subendocardial dysfunction leading to loss of the counteraction of the subendocardial fibre helix. The early diastolic release of

utilize suction may impair left ventricular filling [42].

suction.

34 Cardiomyopathies

As mentioned before, left ventricular twist originates from the dynamic interaction between oppositely wound subepicardial and subendocardial myocardial fibres. The direction of left ventricular twist is governed by the subepicardial fibres, mainly owing to their longer arm of movement. Subendocardial ischemia with loss of contraction of the counteracting subendo‐ cardial fibres will lead to increased left ventricular twist. Therefore, left ventricular twist, and in particular changes within one patient, may provide an easily assessable marker of suben‐ docardial ischemia. Increased left ventricular twist has been described in aging healthy subjects (as discussed previously), and in patients with hypertrophic cardiomyopathy (HCM), aortic stenosis (AS), or diabetes.

In HCM patients, left ventricular twist is increased [45,46]. Actually, in particular left ventric‐ ular basal rotation is augmented [46]. The increased basal rotation may be explained by loss of counteraction of the subendocardial fibre helix, caused by endocardial ischemia due to microvascular dysfunction [47,48]. Also, larger radius differences between the subepicardium and subendocardium in hypertrophic muscle may increase the dominant action of the subepicardial fibres and increase basal rotation. Interestingly, left ventricular apical rotation and twist are dependent on the pattern of left ventricular hypertrophy. In patients with a sigmoidal septal curvature, left ventricular apical rotation and twist are increased as compared to patients with a reverse septal curvature. This may be partly explained by the degree of subendocardial ischemia, since patients with a sigmoidal septal curvature more often have left ventricular outflow tract obstruction. The extravascular compressive forces caused by gradients due to the outflow obstruction may lead to more extensive microvascular dysfunc‐ tion and subendocardial ischemia.

ventricular filling. Conversely, in HCM patients systolic twist is only moderately increased, which may thwart this phenomenon. This hypothesis is supported by the fact that increased peak diastolic untwisting velocity hace been found in a subgroup of HCM patients with mild diastolic dysfunction, who had increased systolic twist. It has been suggested that increased untwisting might be a compensatory mechanism, preventing the need to increase left atrial

Left Ventricular Twist in Cardiomyopathy http://dx.doi.org/10.5772/55281 37

Noncompaction cardiomyopathy (NCCM) is a myocardial disorder characterized by excessive and prominent trabeculations associated with deep recesses that communicate with the ventricular cavity but not the coronary circulation [59]. Although NCCM was included in the 2006 World Health Organization classification of cardiomyopathies [60], it remains subject to controversy owing to lack of consensus on its aetiology, pathogenesis, diagnosis, and man‐ agement [61]. The final stage of the development of myocardial architecture is characterized by the formation of compact myocardium and development of oppositely wound epicardial and endocardial myocardial fibre helices [62,63]. Since NCCM is probably caused by intrau‐ terine arrest of this final stage of cardiac embryogenesis [64], it may be anticipated that left ventricular twist characteristics are altered, beyond that seen in patients with impaired left ventricular function and normal compaction. This has been confirmed in a clinical study. NCCM patients were found to show left ventricular rigid body rotation, that is predominantly instantaneous rotation at the basal and apical level in the same direction, with near absent left ventricular twist. In a subsequent, larger study left ventricular rigid body rotation was confirmed to be an objective, quantitative, and reproducible criterion with a good predictive value for the diagnosis of NCCM as established by expert opinion [65]. Interestingly, all familial NCCM patients showed rigid body rotation. Since the diagnosis of NCCM seems most certain in patients with familial NCCM, this finding underscores the excellent sensitivity of solid body rotation for NCCM. Of additional interest was the finding that NCCM patients who were first-degree relatives from one family had identical left ventricular rotation patterns,

Although a significant reduction of left ventricular twist was observed in patients with advanced heart failure, left ventricular twist did not improve after resynchronization therapy, despite significant gains in left ventricular global and short-axis function in responders. In fact, non-responders showed further reduction of left ventricular twist [66]. However, in a more recent study, subendocardial and subepicardial left ventricular twist were investigated separately, which did lead to identification of prognostic value of left ventricular twist in the population undergoing resynchronization [67]. At 6-month follow-up, 53% of the patients showed favorable outcomes after resynchronization therapy. In a multivariate logistic regression analysis, only the immediate improvement of subepicardial left ventricular twist was independently related to favorable outcomes. Furthermore, the immediate improvement of subepicardial left ventricular twist had incremental value over established parameters.

pressure.

**4.3. Noncompaction cardiomyopathy**

suggesting a genetic-functional relationship in NCCM.

**4.4. Cardiac resynchronization therapy**

AS patients are consistently found to have increased left ventricular twist, mainly due to increased left ventricular apical rotation [49-51]. Furthermore, left ventricular apical rotation and twist correlate positively to the severity of AS. This underlines the potential role of subendocardial ischemia as the cause of increased left ventricular apical rotation and twist in AS since the severity of subendocardial ischemia is known to be related to the severity of AS [52]. In addition, left ventricular apical rotation and twist are highest in AS patients with symptoms (angina) or electrocardiographic signs (strain) compatible with subendocardial ischemia [53]. However, deformation of myocardial fibres is known to be inversely related to wall tension. Since increased afterload in AS leads to increased endocardial wall tension, increased left ventricular twist in AS may also be caused by decreased endocardial deformation as a result of increased endocardial wall tension, independently of ischemia.

Increased left ventricular twist was also described in diabetics with a normal left ventricular ejection fraction [54-56]. Several potential mechanisms for the supposed loss of counteraction of the subendocardial fibres have been mentioned, including metabolic disturbances triggered by hyperglycemia, increased free fatty acid oxidation, altered calcium homeostasis, myocyte death, fibrosis, small-vessel diseases, and cardiac autonomic neuropathy.

In all the above mentioned examples, increased left ventricular twist may serve as a compen‐ satory mechanism to balance loss of left ventricular myocardial contraction in other directions, which with subendocardial dysfunction is usually a loss of contraction in the longitudinal direction, and thereby preserve left ventricular ejection fraction.

#### **4.2. Diastolic dysfunction**

The need for objective evidence of left ventricular diastolic dysfunction has led to an extensive search for accurate, noninvasive, load-independent methods to quantify its severity. Takeuchi et al. [57] examined whether left ventricular hypertrophy adversely affects left ventricular untwisting in hypertension patients. Patients with moderate to severe left ventricular hyper‐ trophy had reduced and delayed left ventricular untwisting as compared to patients without left ventricular hypertrophy, which may contribute to the left ventricular relaxation abnor‐ mality seen in these patients.

In both HCM [58] and AS [51], the untwisting rate, the mean untwisting velocity during the isovolumic relaxation phase, is decreased and untwisting is delayed. Subendocardial ischemia may lead to loss of active untwisting normally caused by the subendocardial fibres during early diastole. In addition, the impaired compliance of the left ventricles of these patients will prevent optimal transformation of the potential energy stored in systolic left ventricular twisting into kinetic energy. However, *peak* diastolic untwisting velocity is decreased in HCM patients, whereas it is increased in AS patients. In AS patients, systolic left ventricular twist is clearly increased as compared to controls. The increased potential energy stored in this more twisted left ventricular will be released after all, which may lead to increased, but delayed, peak diastolic untwisting velocity, that may serve as a compensatory mechanism to help left ventricular filling. Conversely, in HCM patients systolic twist is only moderately increased, which may thwart this phenomenon. This hypothesis is supported by the fact that increased peak diastolic untwisting velocity hace been found in a subgroup of HCM patients with mild diastolic dysfunction, who had increased systolic twist. It has been suggested that increased untwisting might be a compensatory mechanism, preventing the need to increase left atrial pressure.

#### **4.3. Noncompaction cardiomyopathy**

gradients due to the outflow obstruction may lead to more extensive microvascular dysfunc‐

AS patients are consistently found to have increased left ventricular twist, mainly due to increased left ventricular apical rotation [49-51]. Furthermore, left ventricular apical rotation and twist correlate positively to the severity of AS. This underlines the potential role of subendocardial ischemia as the cause of increased left ventricular apical rotation and twist in AS since the severity of subendocardial ischemia is known to be related to the severity of AS [52]. In addition, left ventricular apical rotation and twist are highest in AS patients with symptoms (angina) or electrocardiographic signs (strain) compatible with subendocardial ischemia [53]. However, deformation of myocardial fibres is known to be inversely related to wall tension. Since increased afterload in AS leads to increased endocardial wall tension, increased left ventricular twist in AS may also be caused by decreased endocardial deformation

Increased left ventricular twist was also described in diabetics with a normal left ventricular ejection fraction [54-56]. Several potential mechanisms for the supposed loss of counteraction of the subendocardial fibres have been mentioned, including metabolic disturbances triggered by hyperglycemia, increased free fatty acid oxidation, altered calcium homeostasis, myocyte

In all the above mentioned examples, increased left ventricular twist may serve as a compen‐ satory mechanism to balance loss of left ventricular myocardial contraction in other directions, which with subendocardial dysfunction is usually a loss of contraction in the longitudinal

The need for objective evidence of left ventricular diastolic dysfunction has led to an extensive search for accurate, noninvasive, load-independent methods to quantify its severity. Takeuchi et al. [57] examined whether left ventricular hypertrophy adversely affects left ventricular untwisting in hypertension patients. Patients with moderate to severe left ventricular hyper‐ trophy had reduced and delayed left ventricular untwisting as compared to patients without left ventricular hypertrophy, which may contribute to the left ventricular relaxation abnor‐

In both HCM [58] and AS [51], the untwisting rate, the mean untwisting velocity during the isovolumic relaxation phase, is decreased and untwisting is delayed. Subendocardial ischemia may lead to loss of active untwisting normally caused by the subendocardial fibres during early diastole. In addition, the impaired compliance of the left ventricles of these patients will prevent optimal transformation of the potential energy stored in systolic left ventricular twisting into kinetic energy. However, *peak* diastolic untwisting velocity is decreased in HCM patients, whereas it is increased in AS patients. In AS patients, systolic left ventricular twist is clearly increased as compared to controls. The increased potential energy stored in this more twisted left ventricular will be released after all, which may lead to increased, but delayed, peak diastolic untwisting velocity, that may serve as a compensatory mechanism to help left

as a result of increased endocardial wall tension, independently of ischemia.

death, fibrosis, small-vessel diseases, and cardiac autonomic neuropathy.

direction, and thereby preserve left ventricular ejection fraction.

tion and subendocardial ischemia.

36 Cardiomyopathies

**4.2. Diastolic dysfunction**

mality seen in these patients.

Noncompaction cardiomyopathy (NCCM) is a myocardial disorder characterized by excessive and prominent trabeculations associated with deep recesses that communicate with the ventricular cavity but not the coronary circulation [59]. Although NCCM was included in the 2006 World Health Organization classification of cardiomyopathies [60], it remains subject to controversy owing to lack of consensus on its aetiology, pathogenesis, diagnosis, and man‐ agement [61]. The final stage of the development of myocardial architecture is characterized by the formation of compact myocardium and development of oppositely wound epicardial and endocardial myocardial fibre helices [62,63]. Since NCCM is probably caused by intrau‐ terine arrest of this final stage of cardiac embryogenesis [64], it may be anticipated that left ventricular twist characteristics are altered, beyond that seen in patients with impaired left ventricular function and normal compaction. This has been confirmed in a clinical study. NCCM patients were found to show left ventricular rigid body rotation, that is predominantly instantaneous rotation at the basal and apical level in the same direction, with near absent left ventricular twist. In a subsequent, larger study left ventricular rigid body rotation was confirmed to be an objective, quantitative, and reproducible criterion with a good predictive value for the diagnosis of NCCM as established by expert opinion [65]. Interestingly, all familial NCCM patients showed rigid body rotation. Since the diagnosis of NCCM seems most certain in patients with familial NCCM, this finding underscores the excellent sensitivity of solid body rotation for NCCM. Of additional interest was the finding that NCCM patients who were first-degree relatives from one family had identical left ventricular rotation patterns, suggesting a genetic-functional relationship in NCCM.

#### **4.4. Cardiac resynchronization therapy**

Although a significant reduction of left ventricular twist was observed in patients with advanced heart failure, left ventricular twist did not improve after resynchronization therapy, despite significant gains in left ventricular global and short-axis function in responders. In fact, non-responders showed further reduction of left ventricular twist [66]. However, in a more recent study, subendocardial and subepicardial left ventricular twist were investigated separately, which did lead to identification of prognostic value of left ventricular twist in the population undergoing resynchronization [67]. At 6-month follow-up, 53% of the patients showed favorable outcomes after resynchronization therapy. In a multivariate logistic regression analysis, only the immediate improvement of subepicardial left ventricular twist was independently related to favorable outcomes. Furthermore, the immediate improvement of subepicardial left ventricular twist had incremental value over established parameters. Several reasons may explain this finding. First, subepicardial left ventricular twist may reflect the positive effects of cardiac resynchronization therapy better than subendocardial left ventricular twist, because the subepicardial layer is the major determinant of left ventricular twist. Second, left ventricular pacing in cardiac resynchronization therapy is applied from the epicardial surface, which may be more closely related to mechanical changes in the subepi‐ cardial than the subendocardial left ventricular layer.

**5. Conclusion**

future.

**Author details**

**References**

1141-7.

B.M. van Dalen and M.L. Geleijnse

Erasmus University Medical Center Rotterdam, The Netherlands

ing 2006;Hasselt, Belgium: BSWK, bvba:1-4.

tion has been rapidly increasing.

Even though left ventricular twist is indispensable for proper left ventricular function, little is known about it in "the cardiology community". Mainly due to the development of speckle tracking echocardiography, allowing accurate, reproducible and rapid bedside assessment of left ventricular twist, interest in this important mechanical aspect of left ventricular deforma‐

Left Ventricular Twist in Cardiomyopathy http://dx.doi.org/10.5772/55281 39

Although the vital physiological role of left ventricular twist is indisputable, the clinical relevance of assessment of left ventricular twist in cardiomyopathies still needs to be con‐ firmed. Nonetheless, left ventricular twist evaluation has already provided significant pathophysiological insight in a broad variety of cardiomyopathies. It has become clear that increased left ventricular twist in for example HCM, AS, and diabetics, but also in a healthy ageing population, may serve as a compensatory mechanism to preserve ejection fraction. Furthermore, demonstration of left ventricular rigid body rotation in NCCM may provide a unique way to objectively confirm this difficult diagnosis. Diastolic left ventricular untwisting represents the elastic recoil caused by the release of restoring forces that have been generated during the preceding systolic left ventricular twist and has an important contribution in left ventricular filling through suction generation. Measurement of left ventricular untwisting may become an important element of diastolic function evaluation in cardiomyopathies in the

[1] Sutherland GR, Hatle L, Claus P, D'hooge J, Bijnens BH. Doppler Myocardial Imag‐

[2] Heimdal A, Stoylen A, Torp H, Skjaerpe T. Real-time strain rate imaging of the left

[3] Notomi Y, Setser RM, Shiota T, Martin-Miklovic MG, Weaver JA, Popovic ZB, et al. Assessment of left ventricular torsional deformation by Doppler tissue imaging: vali‐ dation study with tagged magnetic resonance imaging. Circulation 2005;111(9):

ventricle by ultrasound. J Am Soc Echocardiogr 1998;11(11):1013-9.

#### **4.5. Ischemic heart disease**

Sun et al. [68] subjected 7 pigs to myocardial infarction by occlusion of the left anterior descending coronary artery. After 8 weeks, left ventricular twist was decreased significantly in the left anterior descending coronary artery territory areas, whereas there was no change in twist in adjacent and remote left ventricular areas. Therefore, the authors proposed that left ventricular twist may be suitable for noninvasive quantification of left ventricular regional function in ischemic heart disease. Kroeker et al. [69], using an optical device coupled to the left ventricular apex in 16 open-chest dogs, also found a decrease of left ventricular apical rotation with ischemia caused by occlusion of the left anterior descending coronary artery. Interestingly, in the first 10 seconds of occlusion, there was a paradoxical increase in left ventricular apical rotation, which was attributed to isolated subendocardial ischemia leading to loss of the counteractive action of the subendocardial helix of myofibres.

In clinical studies in patients with a prior anterior myocardial infarction it was found that, although left ventricular basal rotation was preserved, left ventricular apical rotation was decreased, leading to decreased left ventricular twist [70]. In patients with a left ventricular aneurysm, left ventricular apical rotation was nonexistent or even inverted, leading to severely decreased left ventricular twist.

#### **4.6. Congenital heart disease**

In the majority of left ventricular twist studies in congenital heart disease, investigators focused on patients with a congenital transposition of the great arteries. In patients operated with atrial switch, the systemic right ventricle shows absence of twist, whereas the subpulmonary left ventricle shows reduced twist [71,72]. Furthermore, there are regional differences of apical rotation of the subpulmonary left ventricular, whereas apical rotation is homogeneous in a normal left ventricle [73,74]. In a theoretical model of situs inversus totalis, and in 8 patients with this condition [75,76] it was shown that, although gross anatomy is mirror imaged, this is not the case for left ventricular systolic deformation. Both the left ventricular base and apex rotated in a counterclockwise direction, whereas the midventricular section exhibited hardly any rotation. These findings may be explained by the arrangement of myofibres in these patients. Anatomical studies have revealed that in situs inversus totalis arrangement of myofibres is normal in the apical regions leading to normal counterclockwise rotation, whereas at the basal level a partly mirror-imaged pattern of the normal transmural change in fibre angle is seen.
