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European Journal of Heart Failure 2006 8(2):115-121; doi:10.1016/j.ejheart.2005.07.012
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© 2006 European Society of Cardiology

Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy{star}

Dirk Westermanna, Björn C. Knollmannb, Paul Steendijkc, Susanne Rutschowa, Alexander Riada, Matthias Pauschingera, James D. Potterd, Heinz-Peter Schultheissa and Carsten Tschöpea,*

a Department of Cardiology and Pneumonology, Charite-Universiätsmedizin Berlin Campus Benjamin-Franklin, Hindenburgdamm 30 12220, Berlin, Germany
b Department of Pharmacology, Georgetown University Medical Center Washington, DC, U.S.A.
c Department of Cardiology, Leiden University Medical Center Leiden, The Netherlands
d Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine Miami, FL, U.S.A.

* Corresponding author. Tel: +49 30 8445 2349; fax: +49 30 78717823. E-mail address: ctschoepe{at}yahoo.com


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The cardiac troponin T I79N mutation, linked to familial hypertrophic cardiomyopathy, carries a high risk of sudden cardiac death even in the absence of significant cardiac hypertrophy. The pathology underlying this mechanism has not yet been identified.

Aims: To study the underlying mechanism of this phenomenon we characterized the left ventricular (LV) performance of transgenic mice carrying the human troponin T mutation I79N under basal and isoproterenol-induced stress conditions.

Methods and results: LV function was analyzed by recording pressure—volume loops using a microconductance catheter. Despite a hypercontractile systolic function under basal conditions TnT-I79N mice showed a diastolic dysfunction indicated by an increase in end-diastolic pressure—volume relationship (EDPVR), a load-independent factor of LV stiffness (0.06±0.01 vs. 0.02±0.01; P<0.05), when compared to mice expressing human wild-type troponin T (TnT-WT). TnT-I79N mutants developed severe diastolic heart failure and cardiac sudden death under isoproterenol stress. This was prevented after pretreatment with the L-type Ca2+ channel inhibitor diltiazem.

Conclusions: Diastolic dysfunction due to increased LV stiffness in TnT-I79N mice leads to severe primary diastolic heart failure and finally to cardiac sudden death, which can be prevented by diltiazem.

Key Words: Troponin T mutation • Diastole • Sudden death • Heart failure

Received January 28, 2005; Revised May 30, 2005; Accepted July 19, 2005


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Familial hypertrophic cardiomyopathy (FHC) is a disease caused by different genes encoding contractile proteins. More than 100 different defects in all 10 genes of the sarcomere have been demonstrated in FHC [1]. Most of them lead to a similar phenotype including cardiac hypertrophy, myocyte disarray, cardiac fibrosis and, most importantly, sudden cardiac death [2]. However, at least patients carrying troponin T mutations do not exhibit all of these classical hallmarks and often have little or no cardiac hypertrophy despite their high risk for sudden death [3,4].

It has been suggested that patients carrying the troponin T I79N mutation have an especially poor prognosis with a high incidence of sudden death in the young [4]. Previously, we have demonstrated that a murine model expressing the TnT-I79N mutations, like humans with this particular mutation, show little or no significant LV hypertrophy [5-7]. Although we observed an increased incidence of stress-induced ventricular arrhythmias in TnT-I79N mice [7], the ventricular tachyarrhythmias were not responsible for the increased incidence of sudden deaths in this model [5]. Thus, the mechanism responsible for the sudden cardiac deaths caused by the TnT-I79N mutation has not yet been clarified.

To address this question, we utilized a transgenic mouse model expressing the malignant human troponin T mutation I79N and determined LV pressure-volume function under basal conditions and after induction of isoproterenol stress. We found LV diastolic dysfunction under basal conditions reflected by increased LV stiffness leading to severe diastolic heart failure and sudden cardiac death after isoproterenol stress in TnT-I79N mice compared to mice expressing a human wild-type troponin T (TnT-WT) mutation. Severe diastolic heart failure and increased mortality in TnT-I79N mutants were prevented by pretreatment with the L-type Ca2+ channel inhibitor diltiazem.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals and treatment
The transgenic mouse model with the human troponin T mutation I79N and human wild-type troponin T was generated as described previously and maintained on the B6/SJL background [6]. TnT-I79N transgenic mice and TnT-WT mice of both genders, aged 5 to 7 months, were randomly selected for treatment by gavage with diltiazem (25 mg/kg/day) for 50 days at a dose shown to be beneficial in another murine FHC model [8], or with a placebo (n=8/group). Last treatment was given 1 h before cardiac characterization. The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985).

2.2. Surgical procedures and hemodynamic measurements
The animals were anesthetized (thiopental 125 µg/g i.p.), intubated and artificially ventilated. As recently described [9], a 1.4 F microconductance pressure catheter (ARIA SPR-719; Millar-Instruments, Inc., Texas, USA) was positioned in the LV for continuous registration of LV pressure-volume (PV) loops [10,11] in a closed-chest model. Calibration of the volume signal was obtained by hypertonic saline (10%) wash-in technique [12]. Indices of cardiac function were derived from PV data (Fig. 1) obtained both at steady state and during transient preload reduction by occlusion of the abdominal vena cava.


Figure 1
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  		Fig. 1 Representative PV loops of untreated TnT-WT and TnT-I79N and diltiazem-treated TnT-I79N and TnT-WT mice showing end-systolic and end-diastolic PV relationships. The black loop shows basal data. TnT-I79N and TnT-I79N diltiazem show increased systolic function and increased LV stiffness under basal conditions. After isoproterenol stress, diastolic heart failure is indicated by an increase in LVEDP and right shift (black arrows) of PV loop in TnT-I79N. Maintained cardiac function with normal LVEDP and no right shift in diltiazem-treated TnT-I79N.

 
Systolic function was quantified by LV end-systolic pressure (LVP), dP/dt max as an index of LV contractility, ejection fraction (EF), end-systolic volume (ESV), stroke volume (SV), cardiac index (CI), and heart rate (HR). LV inotropy was determined by the slope of the end-systolic pressure-volume relationship (ESPVR) [13]. The absolute ratios of peak rate of pressure rise and fall (dP/dt max:min) were measured to determine any disparity between systolic and diastolic kinetics [14].

Diastolic function was measured by LV end-diastolic pressure (LVEDP), dP/dt min, Tau, and EDPVR, an indicator for LV stiffness, determined from an exponential fit to the end-diastolic pressure-volume points [10,11].

To test stress tolerance we administered isoproterenol (0.25 mg/kg i.p.) to the mice after the basal hemodynamic measurement. Sixty seconds after injection we performed hemodynamic measurements to obtain PV loops during isoproterenol stress. PV signals were followed for 5 min.

2.3. Histochemical quantification of collagen content by Sirius Red staining
Total collagen content of the Sirius Red (Polyscience, Inc., Warrington, PA, USA) stained sections was measured under circularly polarized light as recently reported [15] and was quantified by digital image analysis [16]. Representative slides of Sirius Red stained myocardial sections of TnT-I79N, TnT-WT, TnT-I79N diltiazem, and TnT-WT diltiazem are illustrated in Fig. 2.


Figure 2
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  		Fig. 2 Sirius Red staining (original magnification x100) in representative heart sections of a) TnT-WT, b) TnT-I79N, c) TnT-WT diltiazem, and d) TnT-I79N diltiazem without significant differences in total collagen content.

 
2.4. Statistical analysis
Data are presented as mean±S.E.M. Statistical analysis was performed by 2-way ANOVA, followed by Student's t-tests. Differences were considered significant at P<0.05. Survival analysis was performed using Fisher's exact test.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Basal LV function
Under basal conditions, systolic function was enhanced in TnT-I79N compared to TnT-WT mice. The dP/dt max (+39%), stroke volume (+46%), cardiac index (+45%), and EF (+32%) were significantly higher in TnT-I79N though LV pressure, end-systolic volume, ESPVR, and heart rate did not differ compared to TnT-WT (Table 1).


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  		Table 1 Hemodynamic parameters under basal conditions

 
The load-dependent markers for diastolic function like LV end-diastolic pressure, dP/dt min, and Tau were unchanged in TnT-I79N compared to TnT-WT. However, EDPVR, the load-independent marker for diastolic function, was increased by 200%, indicating an impaired diastolic function in the TnT-I79N mouse model (Table 1).Baseline LV function in diltiazem-treated TnT-I79N mice was not significantly different from that of non-treated TnT-I79N animals (Table 1). Also, like the placebo-treated TnT-I79N mice, the diltiazem-treated TnT-I79N animals showed significantly increased diastolic stiffness (+160%) and enhanced systolic function with increased dP/dt max (+18%), stroke volume (+48%), cardiac index (+44%), and EF (+29%) when compared to TnT-WT mice (Table 1). TnT-WT treated with diltiazem were not significantly different in any parameter compared to TnT-WT.

3.2. LV function during isoproterenol stress
Heart rate, LV pressure, and dP/dt max increased equally in TnT-I79N and TnT-WT mice responding to beta-adrenergic receptor stimulation with isoproterenol. Whereas the TnT-WT mice showed a normal physiological reduction in end-systolic volume (–21%) and essentially unchanged LV end-diastolic pressure (+5%), the TnT-I79N mutants showed an abnormal increase in end-systolic volume (+51%) and LV end-diastolic pressure (+120%), accompanied by a reduction in EF (–40%) and ESPVR (–44%). Together, these data indicate acute heart failure, which resulted in cardiac decompensation and sudden death in all TnT-I79N animals (Table 2).


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  		Table 2 Hemodynamic parameters and mortality after induction of isoproterenol stress

 
In contrast to the untreated TnT-I79N mice, the diltiazem-treated TnT-I79N mice did not show evidence for diastolic heart failure during isoproterenol stress. For example, their LV end-diastolic pressure (–60%) and EF (+58%) responded to isoproterenol injection in a fashion similar to those of TnT-WT mice (Table 2). Again, cardiac parameters of TnT-WT treated with diltiazem were not significantly different from those of TnT-WT mice treated with placebo.

3.3. Mortality
None of the TnT-WT and TnT-WT diltiazem mice evidenced cardiac sudden death after isoproterenol stress (0/8 TnT-WT and 0/8 TnT-WT diltiazem), but all TnT-I79N mice died within 5 min (8/8 TnT-I79N). During this period, LV end-diastolic pressure increased further, leading to an overall decline in LV function, hypotension, bradycardia, and finally sudden death. The mortality of diltiazem-treated TnT-I79N mice was significantly reduced compared with untreated TnT-I79N mice (2/8 TnT-I79N diltiazem, Table 2, P<0.01 by Fisher's exact test).

3.4. Total collagen content
Collagen content of ventricular myocardium was quantified by digital image analysis as illustrated by representative tissue cross-sections in Fig. 2. No significant differences in total collagen content were observed between TnT-WT 0.0128%+0.001% area fraction and TnT-I79N mice 0.021%+0.01%. Diltiazem treatment had no significant effect on collagen content TnT-WT diltiazem 0.0104%+0.005% and TnT-I79N diltiazem 0.019%+0.008%.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study demonstrates in vivo that the FHC animal model with the cardiac troponin T mutation TnT-I79N shows an isolated LV diastolic dysfunction characterized by an increase in LV stiffness under basal conditions (see Table 1 and Fig. 1). The diastolic dysfunction occurs in the absence of significant myocardial fibrosis or hypertrophy (Fig. 2). During isoproterenol stress, TnT-I79N mice developed severe diastolic heart failure leading to LV decompensation and sudden cardiac death (Fig. 1 and Table 2). This was prevented by pretreatment with diltiazem (Fig. 1 ).

4.1. Basal LV function in TnT-I79N model
LV function with higher dP/dt max and EF is a clear indicator of enhanced systolic LV function in TnT-I79N mice. Similar findings of enhanced systolic LV function were also obtained in other animal models of FHC [8]. LV diastolic function of TnT-I79N mice also differed from that of TnT-WT mice. Although almost all load-dependent diastolic indices, like LV end-diastolic pressure or Tau, were normal, we found an increase in LV stiffness. LV stiffness, obtained by micro-conductance technique, is the most precise marker for an exact load-independent evaluation of diastolic properties in vivo [17]. Heart rate was not significantly changed by treatment with diltiazem and did not alter any parameter compared to the non-treated groups.

These data confirm previous studies with TnT-I79N mice demonstrating impaired relaxation in isolated perfused hearts, yet normal load-dependent diastolic indices by echocardiography [5]. Also, in agreement with these results, Pak et al. [18] reported an increase in LV stiffness in patients with FHC, demonstrating a diastolic but not a systolic LV dysfunction.

Typical causes of increased LV stiffness are changes in the extracellular matrix regulation, leading to fibrosis [17], hypertrophy or dysregulations in the contractile apparatus of the cardiomyocytes [19]. However, we found no increased cardiac fibrosis in this model demonstrated by unchanged content of total collagen in Sirius Red staining (Table 1 and Fig. 2). No hypertrophy had been identified in this model [20]. In contrast, Ca2+ myofilament sensitivity in this animal model is shown to be enhanced [6,7,20]. Therefore, we analyzed the ratio of dP/dt max:min, a parameter that corrects diastolic function for differences in systolic function. An imbalance in this ratio was only seen in FHC animal models [14]. Compared to TnT-WT, we found an altered ratio in TnT-I79N. These data suggest that the single mutation of the troponin T complex leads to a relative impairment of diastolic LV function even though systolic function is enhanced. Perhaps this finding is a consequence of increased myofilament Ca2+ sensitivity induced by I79N mutation [6], which would be expected to delay diastolic detachment of Ca2+ from the troponin complex, thereby slowing myofilament detachment. Consistent with this idea, the rate of intracellular Ca2+ decay during myocyte relaxation was found to be slower in TnT-I79N compared to TnT-WT myocytes [7]. This could also provide an explanation for our finding of increased stiffness in the TnT-I79N mice (Table 1). However, under basal conditions, diastolic dysfunction was mild and could only be detected with the load-independent measurement of LV stiffness by conductance technique, but not with conventional load-dependent parameters like Tau, LV end diastolic pressure and dP/dt min.

In summary, diastolic dysfunction as well as systolic hypercontractility are directly caused by the troponin T mutation even in the absence of classical hallmarks of FHC [21] such as cardiac hypertrophy and fibrosis.

4.2. LV function in the TnT-I79N model under isoproterenol stress
The importance of the increased LV stiffness under baseline condition is demonstrated by the increased survival rate after induction of isoproterenol stress. After application of isoproterenol, TnT-WT mice developed the expected increase in systolic function without changes in LV end-diastolic pressure, indicating an adequate contractile reserve. In contrast, despite an increase in contractility, the contractile reserve was not able to cope with the isoproterenol-induced systemic vasodilatation in the TnT-I79N model, leading to acute heart failure. This heart failure was characterized by nearly unaltered contractility in the beginning, but increased LVEDP and decreased stroke volume and EF. Therefore, we conclude that a hemodynamic-dependent mechanism is responsible for sudden cardiac death in the TnT-I79N animals, which secondarily resulted in bradyarrhythmias and heart block and, finally, cardiac death.

Though we previously [7] showed ventricular tachycardia in TnT-I79N mice during isoproterenol stress both in vivo and ex vivo, the ventricular tachycardia was never sustained. TnT-I79N mice surprisingly died with bradyarrhythmias and heart block present on ECG [5]. Here we demonstrate that the isoproterenol administration induced a decline in LV diastolic function leading to death from acute heart failure (Fig. 1 and Table 2). Previously, we have shown that when isoproterenol was applied to ventricular myocytes isolated from TnT-I79N hearts, it caused a significant increase in diastolic intracellular Ca2+ concentrations [7]. It is intriguing to speculate that this rise in diastolic Ca2+, together with the increased myofilament Ca2+ sensitivity of I79N-mutant myofilaments [6], was responsible for the isoproterenol-induced diastolic dysfunction. In particular, since based on the shape of the PV loops (Fig. 1), we could rule out major LV outflow obstructions as cause of death.

Interestingly, treatment with diltiazem in the current study prevented isoproterenol-induced acute heart failure and sudden death (Table 2). There are several potential explanations for the beneficial effect of diltiazem: Acute inhibition of L-type Ca2+ current, which is significantly increased in the presence of isoproterenol, would reduce the Ca2+ influx into the myocytes and thereby could have prevented the isoproterenol-induced increase in diastolic Ca2+ observed in TnT-I79N myocytes [7]. Theoretically, a negatively chronotropic effect of diltiazem could have contributed to improved diastolic function, although unlikely a major effect here, since diltiazem did not significantly reduce the heart rate (Table 2). Furthermore, chronic administration of diltiazem has been shown to normalize Ca2+ storage proteins in another murine FHC model [8], although no data exist on whether Ca2+ storage proteins are altered in TnT-I79N mice. Finally, it remains to be seen whether the beneficial effect of diltiazem for the TnT-I79N mutation can be demonstrated also for other FHC-linked TnT mutations.

In conclusion, our study demonstrates that in animals with the TnT mutation I79N, primary diastolic heart failure leads to sudden cardiac death. This sudden cardiac death can be prevented by diltiazem.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} This work was in part supported by funds from the National Institutes of Health (HL071670-01 to B.C.K., HL42325 and HL67415 to J.D.P.). Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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