**4. Clinical implications of myocardial contractile reserve**

#### **4.1. Exercise capacity and contractile reserve**

The presence of LV inotropic response during dobutamine stress testing is associated with a better performance [14]. Patients with markedly reduced myocardial contractility at rest, but with good residual contractile reserve, have a favorable exercise capacity. On the other hand, patients with mildly abnormal myocardial contractility at rest, but reduced contractile reserve have a poor capacity [34].

Recently, we reported the association between myocardial contractile reserve and exercise capacity in 38 idiopathic DCM patients [23]. Peak VO2 was significantly correlated with ΔLV dP/dtmax, but not with LV dP/dtmax at baseline. In addition, the correlation became more pronounced as the dose of dobutamine was increased (Figure 2). Multivariate regression analysis revealed that ΔLV dP/dtmax was independently correlated with peak VO2 (p=0.011). There was no correlation between minute ventilation/carbon dioxide production (VE/VCO2) slope and ΔLV dP/dtmax.

Initially, routine diagnostic left and right heart catheterization are performed. A 6-F fluid-filled pigtail catheter with a high-fidelity micromanometer (CA-61000-PLB Pressure-tip Catheter, CD Leycom, Zoetermeer, The Netherlands) is placed in the LV cavity for measurement of LV pressure. We evaluate LV dP/dtmax as an index of LV contractility [33]. After collection of baseline hemodynamic data, dobutamine is infused intravenously at incremental doses of 5, 10, and 15 µg/kg/min and hemodynamic measurements are made at the end of each 5-minute infusion period. In addition, we calculate ΔLV dP/dtmax as an index of myocardial contractile reserve [25]. ΔLV dP/dtmax is defined as the percentage increase in LV dP/dtmax induced by

dobutamine, and this index is defined on the basis of the formula.

where x = the dose of dobutamine (µg/kg/min)

50 Cardiomyopathies

**Figure 1.** Protocol for evaluating myocardial contractile reserve in DCM

**4.1. Exercise capacity and contractile reserve**

have a poor capacity [34].

**4. Clinical implications of myocardial contractile reserve**

The presence of LV inotropic response during dobutamine stress testing is associated with a better performance [14]. Patients with markedly reduced myocardial contractility at rest, but with good residual contractile reserve, have a favorable exercise capacity. On the other hand, patients with mildly abnormal myocardial contractility at rest, but reduced contractile reserve

ΔLV dP/dtmax(x) = LV dP/dtmax(x) - LV dP/dtmax(baseline) / LV dP/dtmax(baseline)

ΔLV dP/dtmax was significantly correlated with peak VO2, and the correlation became more pronounced as the dose of dobutamine was increased. In contrast, no significant inverse correlation between ΔLV dP/dtmax and VE/VCO2 slope was apparent, even at the maximum dose of dobutamine. ΔLV dP/dtmax is the percentage increase in LV dP/dtmax in‐ duced by dobutamine. [23]

**Figure 2.** Correlation between myocardial contractile reserve and peak VO2, VE/VCO2 slope.

Paraskevaidis, et al. reported the utility of evaluating the presence of myocardial contractile reserve in patients with intermediate values of peak VO2 (10-14 mL/kg/min) [35]. They conclud‐ ed that contractile reserve may yield the greatest incremental prognostic value in gray zone candidates for cardiac transplantation and provide further information for the risk stratification.

**4.3. Prognosis and contractile reserve**

prognostic predictor [10, 14 - 17].

dictors of cardiac events.

LV contractility has been considered to be the most powerful predictor of prognosis in DCM. Around 2000, an array of studies reported the association between LV contractile reserve and prognosis, and the presence of contractile reserve came to be considered as the most powerful

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We investigated the contractile reserve during dobutamine infusion in relation to the prognosis in 52 patients with mildly symptomatic DCM. In the ΔLV dP/dtmax(10) <60% group, cardiac events were significantly higher than in the ΔLV dP/dtmax(10) ≥60% group. Peak VO2 <18 (mL/ kg/min) (HR:3.18, p=0.029) and ∆LV dP/dtmax(10) <60% (HR:3.25, p=0.026) were comparable predictors of cardiac events (Figure 4). This result indicated that evaluating the myocardial contractile reserve in dobutamine stress testing and peak VO2 in cardiopulmonary exercise testing may be complementary approaches to predict a prognosis of non-ischemic DCM.

In the peak VO2 <18 (mL/kg/min) group, cardiac events were significantly higher than in the peak VO2 ≥18 group. In addition, cardiac events were significantly higher in the ΔLV dP/dtmax(10) <60% group than in the ΔLV dP/dtmax(10) ≥60% group. Peak VO2 <18 (HR:3.18, p=0.029) and ∆LV dP/dtmax(10) <60% (HR:3.25, p=0.026) were comparable pre‐

**Figure 4.** Kaplan-Meier analysis of cardiac event-free survival in 52 DCM patients.

These results suggested that myocardial contractile reserve can be used as an adjunct or an alternative to predict peak VO2 in patients with heart failure, especially when the patients fall into the gray zone of peak VO2 or when the patients have a difficulty in ambulation.

#### **4.2. Cardiac sympathetic function and contractile reserve**

In 2005, we reported the correlation of impaired contractile reserve with cardiac sympathetic dysfunction in 24 DCM patients [24]. A significant correlation was observed between the delayed 123I-MIBG heart-mediastinum ratio (HMR) and the percentage change in LV dP/ dtmax from the baseline to the peak heart rate (Figure 3). The delayed 123I-MIBG HMR was significantly lower in patients with a worsening change in LV dP/dtmax (p=0.004). As for the expression of mRNA, there is no significant difference in abundance for sarcoplasmic reticu‐ lum Ca2+-ATPase (SERCA2). However, SERCA2/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratio was significantly lower in low HMR group, indicating that reduced expression of SERCA2 is associated with impaired cardiac sympathetic activity.

**Figure 3.** Relationship between the delayed 123I-MIBG HMR and the percentage change in LV dP/dtmax from the base‐ line to the peak or critical heart rate. (modified from [24])

This result indicated that the myocardial 123I-MIBG scintigraphy may reflect myocardial con‐ tractile reserve, and may be useful in non-invasively predicting residual contractile reserve.

#### **4.3. Prognosis and contractile reserve**

Paraskevaidis, et al. reported the utility of evaluating the presence of myocardial contractile reserve in patients with intermediate values of peak VO2 (10-14 mL/kg/min) [35]. They conclud‐ ed that contractile reserve may yield the greatest incremental prognostic value in gray zone candidates for cardiac transplantation and provide further information for the risk stratification.

These results suggested that myocardial contractile reserve can be used as an adjunct or an alternative to predict peak VO2 in patients with heart failure, especially when the patients fall

In 2005, we reported the correlation of impaired contractile reserve with cardiac sympathetic dysfunction in 24 DCM patients [24]. A significant correlation was observed between the delayed 123I-MIBG heart-mediastinum ratio (HMR) and the percentage change in LV dP/ dtmax from the baseline to the peak heart rate (Figure 3). The delayed 123I-MIBG HMR was significantly lower in patients with a worsening change in LV dP/dtmax (p=0.004). As for the expression of mRNA, there is no significant difference in abundance for sarcoplasmic reticu‐ lum Ca2+-ATPase (SERCA2). However, SERCA2/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratio was significantly lower in low HMR group, indicating that reduced expression

**Figure 3.** Relationship between the delayed 123I-MIBG HMR and the percentage change in LV dP/dtmax from the base‐

This result indicated that the myocardial 123I-MIBG scintigraphy may reflect myocardial con‐ tractile reserve, and may be useful in non-invasively predicting residual contractile reserve.

into the gray zone of peak VO2 or when the patients have a difficulty in ambulation.

**4.2. Cardiac sympathetic function and contractile reserve**

52 Cardiomyopathies

of SERCA2 is associated with impaired cardiac sympathetic activity.

line to the peak or critical heart rate. (modified from [24])

LV contractility has been considered to be the most powerful predictor of prognosis in DCM. Around 2000, an array of studies reported the association between LV contractile reserve and prognosis, and the presence of contractile reserve came to be considered as the most powerful prognostic predictor [10, 14 - 17].

We investigated the contractile reserve during dobutamine infusion in relation to the prognosis in 52 patients with mildly symptomatic DCM. In the ΔLV dP/dtmax(10) <60% group, cardiac events were significantly higher than in the ΔLV dP/dtmax(10) ≥60% group. Peak VO2 <18 (mL/ kg/min) (HR:3.18, p=0.029) and ∆LV dP/dtmax(10) <60% (HR:3.25, p=0.026) were comparable predictors of cardiac events (Figure 4). This result indicated that evaluating the myocardial contractile reserve in dobutamine stress testing and peak VO2 in cardiopulmonary exercise testing may be complementary approaches to predict a prognosis of non-ischemic DCM.

In the peak VO2 <18 (mL/kg/min) group, cardiac events were significantly higher than in the peak VO2 ≥18 group. In addition, cardiac events were significantly higher in the ΔLV dP/dtmax(10) <60% group than in the ΔLV dP/dtmax(10) ≥60% group. Peak VO2 <18 (HR:3.18, p=0.029) and ∆LV dP/dtmax(10) <60% (HR:3.25, p=0.026) were comparable pre‐ dictors of cardiac events.

**Figure 4.** Kaplan-Meier analysis of cardiac event-free survival in 52 DCM patients.

Kasama S, et al. evaluated the LV response using dobutamine gated blood pool scintigraphy in 22 DCM patients [20]. In the good response group to 15 µg/kg/min dobutamine (the presence of contractile reserve; echocardiographic LV ejection fraction >5% improvement), LV systolic function was significantly improved after 1 year of ß-blocker therapy. Cardiac sympathetic nerve activity and New York Heart Association functional class also improved with cardiac reverse remodeling. In addition, they investigated contractile reserve using 99mTc-tetrofosmin quantitative gated single photon emission computed tomography (SPECT) and the similar findings were shown [21].

mRNA Group I Group IIa Group IIb

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Beta1-AR 1.39 ± 0.68 0.71 ± 0.19\* 0.66 ± 0.29\* Beta2-AR 1.29 ± 0.92 0.95 ± 0.18 0.91 ± 0.40 GRK2 1.54 ± 0.63 1.53 ± 0.26 1.59 ± 0.58 G5 alpha 1.18 ± 0.40 0.94 ± 0.17 1.04 ± 0.34 Gi2 alpha 0.78 ± 0.35 0.77 ± 0.15 0.85 ± 0.25 SERCA2a 0.60 ± 0.29 0.36 ± 0.08\* 0.37 ± 0.12\* Phospholamban 0.82 ± 0.28 0.56 ± 0.12\* 0.36 ± 0.16\* Ryanodine receptor-2 0.74 ± 0.42 0.56 ± 0.17 0.69 ± 0.23 Calsequestrin 1.34 ± 0.58 1.16 ± 0.25 1.30 ± 0.44

/Ca2+ exchanger 1.69 ± 0.76 1.14 ± 0.14 1.46 ± 0.84

AR = adrenergic receptor; GRK2 = G protein-coupled receptor kinase 2; mRNA = messenger ribonucleic acid; SERCA2a = sarcoplasmic reticulum Ca2+ adenosine

AR= adrenergic receptor, GRK2+ G protein-coupled receptor kinase 2; mRNA = messenger ribonucleic acid; SERCA 2a =

**Table 1.** Relative Abundance of Contractile Regulatory Protein mRNAs in Endomyocardial Biopsy Specimens Relative

At present, it is reported that the patients with non-ischemic DCM have an impairment of coronary microcirculation and their coronary flow reserve is diminished [36, 37]. Skalidis EI, et al. investigated the association between LV contractile reserve and coronary flow reserve [38]. They studied 14 patients with idiopathic DCM and 11 control subjects. A significant correlation between coronary flow reserve and the corresponding contractile reserve in the vascular territory was reported. Interstingly, Otasevic P, et al. reported the relation of myo‐ cardial histomorphometric features in endomyocardial biopsy specimens and LV contractile reserve assessed by dobutamine stress echocardiography [39]. It was revealed that myocyte diameter and interstitial fibrosis strongly correlated with change in the wall motion score index, followed by the change in LV ejection fraction. Recently, Yamada S, et al. invetigated the association between myocardial blood volume and LV contractile reserve in 21 DCM patients using myocardial contrast echocardiography [40]. Myocardial blood volume was not correlated with any parameters of resting LV function, but significantly correlated with percent increase in LV ejection fraction during dobutamine stress testing. They speculated in their paper that myocardial histomorphometric features in DCM conceivably cause the reduction

to the Corresponding Amount of Glyceraldehyde-3-Phosphate Dehydrogenase mRNA [25]

in myocardial blood volume, being related to the depressed contractile reserve.

Na<sup>+</sup>

triphosphatase 2a.

sarcoplasmic reticulum Ca2+ adenosine triphosphate 2a.

**4.5. Latest findings about contractile reserve**

Data are means ± SD. \* p<0.05 vs. group I.

Data are means ± SD. \*p <0.05 vs. group I.

#### **4.4. Molecular biological significance and contractile reserve**

Recently, we reported that dobutamine stress testing is a useful diagnostic tool for evaluating adrenergic myocardial contractile reserve. This residual contractile reserve is related to alterd myocardial expression of ß1-adrenergic receptor, SERCA2a, and phospholamban genes in DCM [25]. In this study, 46 asymptomatic or mildly-symptomatic DCM patients were enrolled and classified into 3 groups based on baseline LV ejection fraction and ΔLV dP/dtmax (Figure 5). The amounts of ß1-adrenergic receptor, SERCA2a, and phospholamban mRNA were significantly smaller in group IIa and IIb than in group I (Table 1). This result indicated that impaired contractile reserve by dobutamine stress testing may be associated with molecular remodeling caused by the overactivation of sympathetic nerve system.

Patients were classified into 3 groups: group I (orange with black circles), ∆LV dP/dtmax >100% (LV ejection fraction [LVEF] >25%); group IIa (orange circles), ∆LV dP/dtmax ≤100% and LVEF >25%; and group IIb (brown triangles), ∆LV dP/dtmax ≤100% and LVEF ≤25%. [25]

**Figure 5.** Relation between baseline LV ejection fraction and LV dP/dtmax


Data are means ± SD. \* p<0.05 vs. group I.

Kasama S, et al. evaluated the LV response using dobutamine gated blood pool scintigraphy in 22 DCM patients [20]. In the good response group to 15 µg/kg/min dobutamine (the presence of contractile reserve; echocardiographic LV ejection fraction >5% improvement), LV systolic function was significantly improved after 1 year of ß-blocker therapy. Cardiac sympathetic nerve activity and New York Heart Association functional class also improved with cardiac reverse remodeling. In addition, they investigated contractile reserve using 99mTc-tetrofosmin quantitative gated single photon emission computed tomography (SPECT) and the similar

Recently, we reported that dobutamine stress testing is a useful diagnostic tool for evaluating adrenergic myocardial contractile reserve. This residual contractile reserve is related to alterd myocardial expression of ß1-adrenergic receptor, SERCA2a, and phospholamban genes in DCM [25]. In this study, 46 asymptomatic or mildly-symptomatic DCM patients were enrolled and classified into 3 groups based on baseline LV ejection fraction and ΔLV dP/dtmax (Figure 5). The amounts of ß1-adrenergic receptor, SERCA2a, and phospholamban mRNA were significantly smaller in group IIa and IIb than in group I (Table 1). This result indicated that impaired contractile reserve by dobutamine stress testing may be associated with molecular

Patients were classified into 3 groups: group I (orange with black circles), ∆LV dP/dtmax >100% (LV ejection fraction [LVEF] >25%); group IIa (orange circles), ∆LV dP/dtmax ≤100% and LVEF >25%; and group IIb (brown triangles), ∆LV

findings were shown [21].

54 Cardiomyopathies

dP/dtmax ≤100% and LVEF ≤25%. [25]

**Figure 5.** Relation between baseline LV ejection fraction and LV dP/dtmax

**4.4. Molecular biological significance and contractile reserve**

remodeling caused by the overactivation of sympathetic nerve system.

AR= adrenergic receptor, GRK2+ G protein-coupled receptor kinase 2; mRNA = messenger ribonucleic acid; SERCA 2a = sarcoplasmic reticulum Ca2+ adenosine triphosphate 2a.

**Table 1.** Relative Abundance of Contractile Regulatory Protein mRNAs in Endomyocardial Biopsy Specimens Relative to the Corresponding Amount of Glyceraldehyde-3-Phosphate Dehydrogenase mRNA [25]

#### **4.5. Latest findings about contractile reserve**

At present, it is reported that the patients with non-ischemic DCM have an impairment of coronary microcirculation and their coronary flow reserve is diminished [36, 37]. Skalidis EI, et al. investigated the association between LV contractile reserve and coronary flow reserve [38]. They studied 14 patients with idiopathic DCM and 11 control subjects. A significant correlation between coronary flow reserve and the corresponding contractile reserve in the vascular territory was reported. Interstingly, Otasevic P, et al. reported the relation of myo‐ cardial histomorphometric features in endomyocardial biopsy specimens and LV contractile reserve assessed by dobutamine stress echocardiography [39]. It was revealed that myocyte diameter and interstitial fibrosis strongly correlated with change in the wall motion score index, followed by the change in LV ejection fraction. Recently, Yamada S, et al. invetigated the association between myocardial blood volume and LV contractile reserve in 21 DCM patients using myocardial contrast echocardiography [40]. Myocardial blood volume was not correlated with any parameters of resting LV function, but significantly correlated with percent increase in LV ejection fraction during dobutamine stress testing. They speculated in their paper that myocardial histomorphometric features in DCM conceivably cause the reduction in myocardial blood volume, being related to the depressed contractile reserve.
