**5. Impact of dobutamine-induced MA**

#### **5.1. Prognosis**

The occurrence of dobutamine-induced MA was a clinical predictor of poor prognosis in ambulatory patients with IDCM in sinus rhythm. Although there was no significant dif‐ ference in LVEF between patients who manifested only pacing-induced MA and those who developed both pacing- and dobutamine-induced MA, the probability of event-free survival in the latter group was significantly lower than that in the former. Multivariate analysis also revealed that the occurrence of dobutamine-induced MA was a significant independent predictor of cardiac events.

#### **5.2. Mechanisms**

**Univariate analysis**

**(n = 72) (n = 18 )**

Plasma BNP (pg/mL) 123 ± 238 228 ± 162 0.0013 eGFR (mL min–1 1.73 m–2) 74 ± 17 68 ± 18 0.089 Plasma norepinephrine (pg/mL) 521 ± 452 524 ± 292 0.32

*E*/*E*' 15.6 ± 8.6 24.2 ± 8.4 0.227 PAWP (mmHg) 11.5 ± 5.3 13.7 ± 6.6 0.044 Cardiac index (L min–1 m–2) 3.02 ± 0.57 3.13 ± 0.64 0.85 LVEDVI (mL m–2) 73 ± 52 115 ± 79 0.02 LVESVI (mL m–2) 43 ± 36 84 ± 62 0.018 LVEF (%) 38.2 ± 8.7 32.8 ± 6.8 0.003 Heart rate (bpm) 76 ± 17 75 ± 14 0.34 LVEDP (mmHg) 12 ± 8 15 ± 9 0.019 LVSP (mmHg) 119 ± 19 116 ± 23 0.62 LV *dP/dt* max (mmHg/s) 1114 ± 263 1160 ± 263 0.73

T1/2 (ms) 39 ± 7 44 ± 4.7 0.0086

Plasma BNP (pg/mL) 0.0021 1.002 (1.0004–1.0038) 0.014 *T*1/2 (ms) 0.076 1.079 (1.0033–1.161) 0.041

The occurrence of dobutamine-induced MA was a clinical predictor of poor prognosis in ambulatory patients with IDCM in sinus rhythm. Although there was no significant dif‐

**Multivariate analysis**

**β OR ( 95% CI )** *P*

1.4 4.05 (1.35–12.2) 0.013

*P*

**Parameter Event-free group Cardiac-event group**

**Table 3.** Univariate of predictors of cardiac events.

**Parameter**

Dobutamine-induced MA (group D/groups P and N)

**Table 4.** Multivariate analysis of predictors of cardiac events.

**5. Impact of dobutamine-induced MA**

**5.1. Prognosis**

100 Cardiomyopathies

Three general mechanisms have been proposed to account for the development of MA: alteration of action potential duration, impaired ventricular relaxation, and abnormal intra‐ cellular Ca2+-handling.[7] The low relative ratio of phospholamban to SERCA reduces the inhibition of SERCA and increases Ca2+-uptake; this enhances relaxation and contraction in the human atrium. However, humans lacking phospholamban develop lethal IDCM.[8] SERCA2a and ryanodine receptor 2 mRNA levels were similar in all three of our groups, whereas the relative ratio of SERCA to phospholamban was significantly higher in patients with pacingand dobutamine-induced MA than in those with only pacing-induced MA or with no MA. These results suggest that an imbalance between phospholamban and SERCA mRNA levels in the abundant Ca2+-handling proteins is associated with dobutamine-induced MA. Kobaya‐ shi et al. reported that the amounts of mRNAs for the β1-adrenergic receptor and SERCA2a in the myocardium were smaller in asymptomatic or mildly symptomatic IDCM patients with reduced adrenergic myocardial contractile reserve than in those with preserved adrenergic contractile reserves.[9] The occurrence of dobutamine-induced MA in our patients in the present study might also reflect abnormal β1-adrenergic receptor signaling in the myocardium. However, steady-state mRNA levels do not necessarily reflect the corresponding protein levels, in particular because both mRNA and protein synthesis or degradation may be altered in the failing heart.[10, 11] Further studies are needed to elucidate these issues.

In patients with heart failure, dobutamine-induced MA is highly prevalent[6] and mechanical and visible T-wave alternans is detectable under tachycardia or catecholamine exposure.[4, 12] Dobutamine-induced MA may be attributed various factors, including an increase in the heart rate as a result of dobutamine infusion, impaired LV contraction, the influence of preload, and abnormal Ca2+ under pathophysiological conditions. Dobutamine is a β-stimulator that increases both heart rate and LV contraction. The increase in heart rate, but not that in LV contraction, is likely to be a trigger for the occurrence of dobutamine-induced MA. Therefore, the increased occurrence of dopamine-induced MA in heart failure patients might be related to their poor myocardial contractile reserve.
