**3. DCMP in comparison to other clinical treatment options for patients with end-stage heart failure**

#### **3.1. Medical treatment**

The only prospective randomized study comparing DCMP with the medical treatment is C-SMART (Cardiomyoplasty Skeletal Muscle Assist Randomized Trial, [145]). All 103 patients suffered from cardiac failure of NYHA III. C-SMART showed that after 6 months quality of life and sub-maximal physical performance was increased significantly. The main limitation of this study was the short observation time of 6 months. This American study was finished due to the inability to recruit further patients. After these 6 months survival rate did not differ significantly. Due to the knowledge that the DCMP is effective after a longer post-operative period interval we have to rely on retrospective studies only including DCMP patients [20], [118] and medical treated over more than 4 years ([23], [146], [147], [148]). The most favourable medical therapy in NYHA III was comparable to the best results of DCMP patients in the same NYHA class. Summarizing the results of these studies comparing DCMP with medical treatment, following statements can be made:

**1.** As long as medical treatment is effective, it should be continued.


**Figure 13.** Clinical efficacy of the DCMP (NYHA III/IV, 1:2) in comparison to medical treatment options. (a) Rigatelli, 2002, [118] (b) Benicio, 2003, [20] (c) COMET, Poole-Wilson, 2003 [146] (d) CARE-HF, Cleland, 2005 [148] (e) Bocchi, 1996, [23] (f) REMATCH, Rose, 2001, [147]

#### **3.2. Cardiac resynchronization therapy (CRT)**

**Figure 12.** Histology of severe muscle damage is demonstrated using an 1:1 over stimulation. (Gutierrez et al. J Pathol

**3. DCMP in comparison to other clinical treatment options for patients with**

The only prospective randomized study comparing DCMP with the medical treatment is C-SMART (Cardiomyoplasty Skeletal Muscle Assist Randomized Trial, [145]). All 103 patients suffered from cardiac failure of NYHA III. C-SMART showed that after 6 months quality of life and sub-maximal physical performance was increased significantly. The main limitation of this study was the short observation time of 6 months. This American study was finished due to the inability to recruit further patients. After these 6 months survival rate did not differ significantly. Due to the knowledge that the DCMP is effective after a longer post-operative period interval we have to rely on retrospective studies only including DCMP patients [20], [118] and medical treated over more than 4 years ([23], [146], [147], [148]). The most favourable medical therapy in NYHA III was comparable to the best results of DCMP patients in the same NYHA class. Summarizing the results of these studies comparing DCMP with medical

2001; 194: 116-121) [5]

**end-stage heart failure**

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treatment, following statements can be made:

**1.** As long as medical treatment is effective, it should be continued.

**3.1. Medical treatment**

Comparing survival rate of DCMP and cardiac resynchronization therapy (CARE-HF, CRTgroup, [148]), some authors found superior and others equivalent results. The DCMP proce‐ dure is more invasive and expensive than a CRT. But indication for a CRT is a heart failure in combination with a desynchronization of the left and right ventricle (left or right bundle branch

**Figure 14.** Efficacy of the DCMP in comparison to the cardiac resynchronisation therapy (CRT) in patients with bundle branch blocks. (a) Rigatelli, 2002 [118], (b) Chachques 1997, [37], (c) Benicio, 2003 [20], (d) CARE-HF Cleland, 2005 [148]

#### **3.3. Heart transplantation**

Comparing clinical results from the DCMP to those from the heart transplantation (HTX), their survival rates are comparable (figure 15, (a,b,c) vs. (d) [ISHLT, Heart Transplantation, Annual Report 2011 [149])). Objection however is, HTX is mainly suitable to NYHA class IV and DCMP to NYHA III. Taking in account the tremendous lack of donor hearts, it is to consider to apply the DCMP as early as possible in the non-effective medical treatment of NYHA III patients, to avoid a manifest stadium NYHA IV. Furthermore patients with a DCMP have no contraindi‐ cation for HTX procedure. That is why DCMP can be regarded as a bridge to transplant [2] over years. In conclusion DCMP can contribute to a therapy of end-stage heart failure post‐ poning HTX for years.

#### **3.4. Left heart assist devices**

Figure 16 indicates that a therapy by left heart assist devices (LVADs) is inferior to HTX, but due to the lack of donor hearts it is often the only treatment option in severe heart failure. A DCMP in NYHA III however may postpone a LVAD or HTX procedure. A comparison of DCMP and LVADs [150] count similar limitations like mentioned in HTX above, concerning the comparison of groups with different NYHA classes.

**Figure 15.** Clinical efficacy of a DCMP treatment in comparison to heart transplantation (HTX). (a) Rigatelli,2002, [118] (b) Chachques, 1997, [37] (c) Benicio, 2003 [20] (d) ISHLT, 2011, [149]

**Figure 16.** Efficacy of DCMP in comparison to mechanical assist devices (HeartMate II) and heart transplantation (HTX). (a) Rigatelli, 2002, [118], (b) Chachques, 1997 [37], (c) Benicio, 2003 [20], (d) ISHLT, 2011, [149] (e) Park, 2012, [150]

#### **3.5. Stem cell therapy**

block). Additionally CRT is not effective in one third of these patients. Those are candidates

**Figure 14.** Efficacy of the DCMP in comparison to the cardiac resynchronisation therapy (CRT) in patients with bundle branch blocks. (a) Rigatelli, 2002 [118], (b) Chachques 1997, [37], (c) Benicio, 2003 [20], (d) CARE-HF Cleland, 2005

Comparing clinical results from the DCMP to those from the heart transplantation (HTX), their survival rates are comparable (figure 15, (a,b,c) vs. (d) [ISHLT, Heart Transplantation, Annual Report 2011 [149])). Objection however is, HTX is mainly suitable to NYHA class IV and DCMP to NYHA III. Taking in account the tremendous lack of donor hearts, it is to consider to apply the DCMP as early as possible in the non-effective medical treatment of NYHA III patients, to avoid a manifest stadium NYHA IV. Furthermore patients with a DCMP have no contraindi‐ cation for HTX procedure. That is why DCMP can be regarded as a bridge to transplant [2] over years. In conclusion DCMP can contribute to a therapy of end-stage heart failure post‐

Figure 16 indicates that a therapy by left heart assist devices (LVADs) is inferior to HTX, but due to the lack of donor hearts it is often the only treatment option in severe heart failure. A DCMP in NYHA III however may postpone a LVAD or HTX procedure. A comparison of DCMP and LVADs [150] count similar limitations like mentioned in HTX above, concerning

for a DCMP.

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[148]

**3.3. Heart transplantation**

poning HTX for years.

**3.4. Left heart assist devices**

the comparison of groups with different NYHA classes.

The stem cell therapy of the human myocardium with mesenchymal stem cells (MSCs) has been evaluated in several clinical studies [151], [152]. The MSCs were applied intracoronar‐ illy after myocardial infarction, and intra-myocardially solely and in combination with aorto- coronary bypass-surgery [153]. Thereby the ejection fraction (EF) of the left heart ventricle was seldom enhanced by more than 5% in the long time. The therapeutic effect never lasted longer than 6 to 9 months which was due to the disappearance of the MSCs from the myocardium within several months. Thereafter MSC's were found predominant‐ ly in liver and spleen. Thus DCMP treatment might be superior to a MSC' s therapy, however there are not enough comparative clinical data yet. A combination of both seems favourable. An additive therapeutic effect specially with a stem cell transforming into cardiomyocytes and a permanent homing within the myocardium might enhance this therapy (Guldner et al. 2006, [154], 2009, [155]).

### **4. Summarizing appraisal of the clinical efficacy from DCMP**

Evaluating 139 papers from literature about clinical dynamic cardiomyoplasty, DCMP showed to be effective accordingly to survival rate, NYHA class, hospitalization rate and ejection fraction of the hemodynamic from the left heart ventricle. Survival rate was clinically relevant higher in NYHA class III than in NYHA IV (Figure 4, [37]) and additionally more patients survived synchronized in 1:2 mode than in 1:1 pacing (Fig.5, [20]). Quality of life showed to be enhanced by a decreased NYHA of 1.57 (pre-operatively NYHA 3.26 ± 0.63 to postoperatively NYHA 1.69 ± 0.34 [p<0.05]). The ejection fraction of the left heart ventricle was increased from 21.9 ± 4.5 % to 28.9 ± 5.9% (p<0.05). A better clinical outcome is documented in cases with a reduced electrical stimulation [4], [33], [34], [117–125] accompanied with a day and night regime. A higher stimulation frequency might result in a muscle damage [5]. Dynamic cardiomyoplasty in comparison to other treatment options for end-stage heart failure like heart transplantation, resynchronization therapy, mechanical left ventricular assist devices and stem cell therapy has a clearly defined therapeutic indication. These are patients with a non-pharmacologically treatable heart failure of the NYHA class III and the nonresponders of the resynchronization therapy (CRT). Due to poor therapeutic results, NYHA IV class patients are not to be considered for a DCMP.

#### **5. Rational of pre-stimulation**

Enhanced capillary density in skeletal muscle, induced by different stimulation patterns, has been well investigated in small animals [156], [157] and only a few investigations are in big animals [11]. But these experiments seldomly correlate capillary density with blood flow. Thus, an evaluation of blood flow, and capillary density of a clinically feasible two weeks electrically in-situ-conditioning in latissimus dorsi muscle (LDM) was investigated at rest and exercise in human sized animals. In five adult female Boer goats (52±9 kg), the left LDM (group I) was stimulated in-situ electrically over 14 days (10 Hz, 2-5V, 12h/day, 1h on-1h off). The right LDM served as control (group II). After conditioning, the LDMs blood flow was measured at rest and exercise ( electric muscle stimulation over 10 minutes) by an ultrasonic flow probe around the A. thoracodorsalis. Muscle samples of different regions of LDM were harvested to evaluate the capillary to fiber ratio, mean diameter of the muscle fibers and their myosin heavy chain composition (type I /II).

from the myocardium within several months. Thereafter MSC's were found predominant‐ ly in liver and spleen. Thus DCMP treatment might be superior to a MSC' s therapy, however there are not enough comparative clinical data yet. A combination of both seems favourable. An additive therapeutic effect specially with a stem cell transforming into cardiomyocytes and a permanent homing within the myocardium might enhance this

Evaluating 139 papers from literature about clinical dynamic cardiomyoplasty, DCMP showed to be effective accordingly to survival rate, NYHA class, hospitalization rate and ejection fraction of the hemodynamic from the left heart ventricle. Survival rate was clinically relevant higher in NYHA class III than in NYHA IV (Figure 4, [37]) and additionally more patients survived synchronized in 1:2 mode than in 1:1 pacing (Fig.5, [20]). Quality of life showed to be enhanced by a decreased NYHA of 1.57 (pre-operatively NYHA 3.26 ± 0.63 to postoperatively NYHA 1.69 ± 0.34 [p<0.05]). The ejection fraction of the left heart ventricle was increased from 21.9 ± 4.5 % to 28.9 ± 5.9% (p<0.05). A better clinical outcome is documented in cases with a reduced electrical stimulation [4], [33], [34], [117–125] accompanied with a day and night regime. A higher stimulation frequency might result in a muscle damage [5]. Dynamic cardiomyoplasty in comparison to other treatment options for end-stage heart failure like heart transplantation, resynchronization therapy, mechanical left ventricular assist devices and stem cell therapy has a clearly defined therapeutic indication. These are patients with a non-pharmacologically treatable heart failure of the NYHA class III and the nonresponders of the resynchronization therapy (CRT). Due to poor therapeutic results, NYHA

Enhanced capillary density in skeletal muscle, induced by different stimulation patterns, has been well investigated in small animals [156], [157] and only a few investigations are in big animals [11]. But these experiments seldomly correlate capillary density with blood flow. Thus, an evaluation of blood flow, and capillary density of a clinically feasible two weeks electrically in-situ-conditioning in latissimus dorsi muscle (LDM) was investigated at rest and exercise in human sized animals. In five adult female Boer goats (52±9 kg), the left LDM (group I) was stimulated in-situ electrically over 14 days (10 Hz, 2-5V, 12h/day, 1h on-1h off). The right LDM served as control (group II). After conditioning, the LDMs blood flow was measured at rest and exercise ( electric muscle stimulation over 10 minutes) by an ultrasonic flow probe around the A. thoracodorsalis. Muscle samples of different regions of LDM were harvested to evaluate the capillary to fiber ratio, mean diameter of the muscle fibers and their myosin heavy chain

**4. Summarizing appraisal of the clinical efficacy from DCMP**

therapy (Guldner et al. 2006, [154], 2009, [155]).

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IV class patients are not to be considered for a DCMP.

**5. Rational of pre-stimulation**

composition (type I /II).

**Figure 17.** Operative situs in a goat during flow evaluation.The neuro-vascular bundle including the arteria thoracodorsalis leading to the latissimus dorsi muscle is demonstrated (arrow). The flow probe (\*) is situated around the arte‐ ria thoraco-dorsalis.
