Long‐term effects of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger inhibition with ORM‐11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction

Primeßnig, Uwe; Bracic, T; Levijoki, Jouko; Otsomaa, Leena; Pollesello, Piero; Falcke, Martin; Pieske, Burkert; Heinzel, Frank R.

doi:10.1002/ejhf.1619

Cited by 23 publications

(35 citation statements)

References 28 publications

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“…Considering the promising results, future trials are needed to evaluate the feasibility of such treatment also in humans. 272 Acute heart failure Epidemiology Several precipitating factors may lead to acute HF, namely, arrhythmia, respiratory infections, and other non-CV factors. 273 Worsening HF may develop in an outpatient or an inpatient setting, with a similar drastic increase in event rates.…”

Section: Treatment: Lack Of Favourable Resultsmentioning

confidence: 99%

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Heart failure in the last year: progress and perspective

et al. 2020

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Research about heart failure (HF) has made major progress in the last years. We give here an update on the most recent findings. Landmark trials have established new treatments for HF with reduced ejection fraction. Sacubitril/valsartan was superior to enalapril in PARADIGM‐HF trial, and its initiation during hospitalization for acute HF or early after discharge can now be considered. More recently, new therapeutic pathways have been developed. In the DAPA‐HF and EMPEROR‐Reduced trials, dapagliflozin and empagliflozin reduced the risk of the primary composite endpoint, compared with placebo [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.65–0.85; P < 0.001 and HR 0.75; 95% CI 0.65–0.86; P < 0.001, respectively]. Second, vericiguat, an oral soluble guanylate cyclase stimulator, reduced the composite endpoint of cardiovascular death or HF hospitalization vs. placebo (HR 0.90; 95% CI 0.82–0.98; P = 0.02). On the other hand, both the diagnosis and treatment of HF with preserved ejection fraction, as well as management of advanced HF and acute HF, remain challenging. A better phenotyping of patients with HF would be helpful for prognostic stratification and treatment selection. Further aspects, such as the use of devices, treatment of arrhythmias, and percutaneous treatment of valvular heart disease in patients with HF, are also discussed and reviewed in this article.

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Section: Treatment: Lack Of Favourable Resultsmentioning

confidence: 99%

“…Novel specific Na + /Ca 2+ exchanger inhibitor ORM‐11035 is able to reduce cardiac remodelling and diastolic dysfunction with no effects on systemic blood pressure in rats. Considering the promising results, future trials are needed to evaluate the feasibility of such treatment also in humans 272 …”

Section: Heart Failure With Preserved Ejection Fractionmentioning

confidence: 99%

Heart failure in the last year: progress and perspective

et al. 2020

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“…However, increased forward-mode activity also leads to a positive net charge shift (1 Ca 2+ outwards, 3 Na + inwards), which has been associated with an increased frequency of triggered, arrhythmic Ca 2+ release events in patients with AF [30]. Recent data linked increased reverse mode NCX activity in ventricular cardiomyocytes to cardiac remodeling and diastolic dysfunction in a rat model of HFpEF (following partial nephrectomy) [31]. In contrast, in atrial cardiomyocytes, increased forward mode NCX was a potential contributor to the amelioration of structural remodeling (e.g.…”

Section: Discussionmentioning

confidence: 99%

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

Bode

Semmler

Wakula

et al. 2021

Cardiovasc Diabetol

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Background Sodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. Methods 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable. Results Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. Conclusion The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

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“…A reduction of cardiac remodelling may be a therapeutic goal in HF with preserved ejection fraction (HFpEF) 7 . Yamanaka et al 8 .…”

Section: Cardiac Remodellingmentioning

confidence: 99%