**2. Clinical efficacy of DCMP**

#### **2.1. Survival**

to other treatment options for end-stage heart failure is performed in this report. And last but not least new experimental insights concerning the DCMP procedure should be demonstrated. This experience from clinical application over more than 20 years and new experimental data about dynamic cardiomyoplasty procedures should become compared and discussed. From these insights, conclusions should be drawn to improve clinically results from DCMP which are needed urgently for a more effective treatment of pharmacologically non-treatable heart

electrodes are placed wavelike around the branches of nervus thoracodorsalis at a distance of 6 cm.

**Figure 1.** Latissimus dorsi muscle (LDM) is dissected free from the left thoracic wall before placing it into the thoracic cavity via a window of the thoracic wall after a partial resection of the second rib. Artery, vein and nervus thoracodorsalis remain untouched. LDM's tendon is cut (arrow) before it's re-fixation to the thoracic wall. Two stimulation

**Figure 2.** When latissimus dorsi muscle (LDM) has been transferred intra-thoracally it is wrapped around the heart and stimulated electrically by a myostimulator via two muscular electrodes near the branches of the thoraco-dorsal nerve. Stimulation bursts are synchronized with the heart action via additional epicardial sensing electrodes.

failure.

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An analysis of survival curves of different investigators for DCMP-procedures shown in figure 3 may give insights in factors determining the best survival rate.

#### *2.1.1. Survival rate and NYHA — Class*

Observing and comparing the survival curves in figure 3 demonstrates, that a pre-operative NYHA class III has a better long term survival than NYHA class IV. In the upper half of the diagram with the higher survival, NYHA III is predominantly present while in the lower half mostly appears NYHA IV.

**Figure 3.** Survival rates of patients with a DCMP published by different authors (a) Rigatelle et al, 2002 (ITDDC = Ita‐ lien Demand Dynamic Cardiomyoplasty) *[118]* (b) Chachques et al. 1997 [37] (c) Benicio et al. 2003, [20] (d) Bocchi et al. 1994, [25] (e) Bocchi et al. 1996 [23]

To demonstrate the influence of the pre-operative NYHA class, results of the "French DCMP Experience" from the year 1997 are selected from figure 3 and documented in figure 4 separately. The survival rate of class NYHA III patients at 5 years after DCMP was 68% compared to NYHA IV with 23 % (Chachques JC, 1997) [37]. Another group reports (figure 3 (d)) about no survivor of pre-operative NYHA IV patients 3 years after the DCMP procedure [25].

#### *2.1.2. Survival rate and stimulation pattern*

A re-evaluation of long-term outcomes of dynamic cardiomyoplasties from the Sao Paulo Group Brazil [20] in 43 patients with dilated cardiomyopathies showed impressive results

**Figure 4.** Kaplan-Meier statistics of the event-free survival after dynamic cardiomyoplasty according to pre-operative New York Heart Association functional class (upper curve NYHA III, lower curve NYHA IV) (a) Chachques, 1997, [37]

using different stimulation modes by synchronizing the electrical stimulation of the muscle wrap to the heart in 1:1 and 1:2 mode (stimulations bursts per heart beat). In 1:2 mode after 10 years of DCMP, there is a survival of about 40 % while in 1:1 there is no survivor. A muscle damage as shown in the histology (figure 11, chapter 2.5, [5]) using also a 1:1 stimulation pattern may be the reason of this insufficient result.

**Figure 5.** Survival rate of DCMP procedures 10 years after different synchronization modes with the heart contractions. 1:2 synchronization results in a 40 % survival, while in a 1:1 mode there was no survivor. (a) Benicio et al. 2003, [20]

The highest survival rate, upper curve in figure 3 (a), has been reported by Rigatelli et. al 2003 [118]. They applied the lowest mean pulse frequency of all investigators and used a day and night regime with a myostimulator on at day and off at night.

#### **2.2. NYHA — Class**

using different stimulation modes by synchronizing the electrical stimulation of the muscle wrap to the heart in 1:1 and 1:2 mode (stimulations bursts per heart beat). In 1:2 mode after 10 years of DCMP, there is a survival of about 40 % while in 1:1 there is no survivor. A muscle damage as shown in the histology (figure 11, chapter 2.5, [5]) using also a 1:1 stimulation

**Figure 4.** Kaplan-Meier statistics of the event-free survival after dynamic cardiomyoplasty according to pre-operative New York Heart Association functional class (upper curve NYHA III, lower curve NYHA IV) (a) Chachques, 1997, [37]

**Figure 5.** Survival rate of DCMP procedures 10 years after different synchronization modes with the heart contractions. 1:2 synchronization results in a 40 % survival, while in a 1:1 mode there was no survivor. (a) Benicio et al. 2003, [20]

pattern may be the reason of this insufficient result.

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In order to determine the best course of therapy, physicians often assess the stage of heart failure according to the New York Heart Association (NYHA) functional classification system. This system relates symptoms to everyday activities and the patient's quality of life.


In 101 from 139 publications about clinical DCMP authors report about the efficacy of DCMP on the clinical severity in heart failure using the classification of the New York Heart Associ‐ ation (NYHA). The DCMP outcome is reported between 1989 and 2009.

In figure 6 the higher bars in all cases represent the pre-operative NYHA-class and the lower bars show the post-operative results. In summary there is a significant improvement from NYHA 3.26 ± 0.63 to 1.69 ± 0.34 (p<0.05, figure 7).

#### **2.3. Hospitalization rate**

Evaluating data from 264 patients of 7 publications [31], [35], [40], [96], [118], [136], [138], the pre-operative hospitalization rate was 2.79 ± 0.83 days/year. The post-operative hospitaliza‐ tionrate of DCMP patients was significantly decreased with 0.48 ± 0.23 days/year (Figure 8).

**Figure 8.** Mean values of the pre-operative (left) and post-operative (right) hospitalization (p< 0.05).

#### **2.4. Ejection Fraction (EF)**

p < 0.05

**Figure 7.** Mean values of the pre-operative (left) and post-operative (right) NYHA-classes (p< 0.05).

2.79 ± 0.83 d/y.

**Figure 8.** Mean values of the pre-operative (left) and post-operative (right) hospitalization (p< 0.05).

Evaluating data from 264 patients of 7 publications [31], [35], [40], [96], [118], [136], [138], the pre-operative hospitalization rate was 2.79 ± 0.83 days/year. The post-operative hospitaliza‐ tionrate of DCMP patients was significantly decreased with 0.48 ± 0.23 days/year (Figure 8).

p < 0.05

0.48 ± 0.23 d/y.

**2.3. Hospitalization rate**

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According to the clinical improvement documented by the NYHA-decline in figure 6, there is an increase of the ejection fraction (EF) of the left heart ventricle from 21.8 ± 4.5 to 28.9 ± 5.9 (p< 0.05). Figure 9 demonstrates an overview of the ejection fraction (EF) of 89 DCMP relevant reports.

**Figure 9.** Ejection fraction (EF) after DCMP improved from 21.9 to 28.9%

#### **2.5. PV-loop evaluation**

The conductance catheter method visualizes an impressive documentation of DCMP' s clinical efficacy. It is performed by heart catheterization where a conductance catheter is placed along the longitudinal axis of the left heart ventricle (LV). It enables a real time volumetry of the stroke volume of the LV by recording the changes of intra-ventricular blood conductivity caused by a volume reduction (stroke volume). A simultaneous measurement of the LV's pressure allows generating pressure-volume loops in real time. The area surrounded by the loop represents the stroke work of the left heart ventricle. Thus the influence of an activated DCMP on the hemodynamic of the LV can be demonstrated as shown in figure 10(n=9 patients). A stimulated DCMP enhances the stroke work of the left ventricle.

In three patients A, B and C (Figure 11, [74]), left ventricular pressure-volume loops and relations performed by the conductance method are recorded before the cardiomyoplasty procedure and 1 year after surgery. As demonstrated by example in the baseline panel for patient A, multiple pressure- volume loops are used to measure end-systolic pressure-volume

**Figure 10.** Pressure-volume-loops of 9 patients. The dotted lines represent non-supported and the solid lines show DCMP-supported heart cycles. Vlv expresses the volume of the left ventricle and Plv represents left ventricular pres‐ sure. (Schreuder et al.1995 [130])

relation (ESPVR) and diastolic pressure-volume relation (DPVR), defining the active and passive limits of cardiac performance, respectively.

Summarizing the results of Kass et al., the most important finding is a leftward shift of the PVloop, indicating a volume reduction of the dilated, failing heart. This reverse remodelling improves left ventricular performance.

#### **2.6. Histology**

Dynamic cardiomyoplasty patients had an initial clinical improvement followed by a decrease in cardiac failure indices mostly in a 1:1 stimulation mode [20]. A histopathological study of the skeletal muscle was undertaken by Gutierrezz et al. 2001 [5] to explain this. Latissimus dorsi fragments from 15 patients submitted to dynamic cardiomyoplasty in a 1:1 conditioning were analysed by light microscopy. The interval between surgery and obtaining the specimens (13 from necropsies, two from heart transplants) ranged from 37 days to 6 years. Nuclear

relation (ESPVR) and diastolic pressure-volume relation (DPVR), defining the active and

**Figure 10.** Pressure-volume-loops of 9 patients. The dotted lines represent non-supported and the solid lines show DCMP-supported heart cycles. Vlv expresses the volume of the left ventricle and Plv represents left ventricular pres‐

Summarizing the results of Kass et al., the most important finding is a leftward shift of the PVloop, indicating a volume reduction of the dilated, failing heart. This reverse remodelling

Dynamic cardiomyoplasty patients had an initial clinical improvement followed by a decrease in cardiac failure indices mostly in a 1:1 stimulation mode [20]. A histopathological study of the skeletal muscle was undertaken by Gutierrezz et al. 2001 [5] to explain this. Latissimus dorsi fragments from 15 patients submitted to dynamic cardiomyoplasty in a 1:1 conditioning were analysed by light microscopy. The interval between surgery and obtaining the specimens (13 from necropsies, two from heart transplants) ranged from 37 days to 6 years. Nuclear

passive limits of cardiac performance, respectively.

improves left ventricular performance.

sure. (Schreuder et al.1995 [130])

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**2.6. Histology**

**Figure 11.** Effect of cardiomyoplasty on cardiac function by pressure volume relations one year after the operative DCMP procedure [74].

clumps and internalization, the presence of round fibres, inflammation, and fibrosis were analysed semi-quantitatively; the thickness of muscle fibres and the percentage of tissue fat were measured by image analysis. The quantitative data were also compared, in 12 cases, with gender- and age-matched necropsy controls. The mean thickness of muscle fibres in cases and controls was 27.21 ± 5.33 and 40.84 ± 9.42 μ, respectively (p=0.001). The percentage of tissue fat in cases and controls was 12.04 ± 12.66% and 0.93 ± 0.91%, respectively (p=0.008). Accordingly, a negative correlation was found between the duration of graft usage and the mean diameter of fibers, characterizing muscle atrophy (R=-0.66, p=0.01). The longer the post-surgical period, the more intense the degenerative lesions. This study shows that skeletal muscle used in human dynamic cardiomyoplasty may atrophy and be replaced by fat when stimulation is synchronized to every cardiac beat [20]. These findings could play a role in explaining the longterm results in DCMP procedures as shown in Fig.5 chapter 1.2.1 with no survivors after 10 years of an electrical stimulation in a 1:1 mode.

**Figure 12.** Histology of severe muscle damage is demonstrated using an 1:1 over stimulation. (Gutierrez et al. J Pathol 2001; 194: 116-121) [5]
