The Use of Low-Dose Intermittent Levosimendan Infusion Therapy as Bridge-to-Left Ventricular Assist Device in Advanced Chronic Heart Failure Secondary to Isolated Cardiac Sarcoidosis.

Heart failure (HF) is a progressive condition that usually involves a debilitating late course with poor health-related quality of life and increasing mortality rate. In this report, we demonstrate the efficacy and safety of intermittent levosimendan infusion as a bridging therapy to left ventricular assist device use in a patient suffering from cardiac sarcoidosis who failed to respond to optimized medical therapy. Levosimendan was administered in an outpatient infusion-therapy facility every 2 weeks as a single intravenous infusion over 6 h at dose and rate of 0.2 μg/kg/min not proceeded by a bolus. The primary observation we are reporting is the efficacy of this approach reflected on serum concentrations of N-terminal brain natriuretic propeptide and creatinine levels. Secondary observation comprised patient-reported outcomes and clinical events including hospitalization (s). Copyright:

INTRODUCTION

Advanced heart failure (HF) is characterized by frequent episodes of cardiac decompensation, requiring a prolonged hospital stay and a significant compromise in patients' quality of life. The rising prevalence of these late stages of HF remains a challenge for patients, physicians, and health-care systems. Advanced HF is associated with substantial morbidity, mortality, and high health-care expenditure.[1]

A limited number of options are available to help control the disease and slow its progression in patients who are not responding to the guidelines-recommended therapeutic approach. Moreover, advanced therapies are not widely available for patients with late-stage HF, such as mechanical circulatory support and heart transplant. As a result, there is an increased need for newer therapies.[2]

Intermittent use of inotropic infusions to induce periods of hemodynamic relief has been reportedly tried. However, the results about the efficacy of this approach remain inconsistent.[23] Levosimendan, an inodilator, with a unique mechanism of action is proposed to offer patients with advanced HF both hemodynamic-status improvement and long-term morbidity benefit. Levosimendan is a calcium sensitizer, facilitating calcium binding to troponin C without increasing the levels of intracellular calcium, thus improving myocardial contractility without increasing oxygen consumption. Furthermore, levosimendan has a vasodilator effect which is mediated by its action on the Adenosine Triphosphate (ATP)-dependent potassium channels in cardiac mitochondria as well as on smooth muscle vasculature.[3]

In this report, we present a case of advanced HF, decompensated. The patient was hospitalized but did not improve despite intensive medical therapy for HF. She was managed by intermittent levosimendan infusions with clinical improvement which led to successful left ventricular assist device (LVAD) implantation.

CASE PRESENTATION

A 54-year-old lady presented to the emergency department complaining of severe breathlessness (dyspnea with NYHA IV) as well as productive cough of frothy yellow sputum. She also described orthopnea and paroxysmal nocturnal dyspnea. She also reported poor appetite, lethargy, and dizzy spells. Her past medical history is significant for presumed idiopathic dilated cardiomyopathy (DCM) which was later proven to be isolated cardiac sarcoidosis (CS) on heart tissue biopsy.

Relevant clinical data include ejection fraction (EF) 20%–25%, severe functional mitral regurgitation, history of cardiac resynchronization therapy defibrillator insertion in 2018, and hypothyroidism on thyroid hormone supplement. She underwent coronary evaluation by angiogram in 2016, which ruled out ischemic origin as the cause of her disease.

She is a lifelong nonsmoker and does not consume alcohol. Preadmission medications include bisoprolol 6.25 mg once a day (O.D.), eplerenone 12.5 mg O.D, valsartan 40 mg O.D, and bumetanide 2 mg twice daily (BID). Sacubitril/valsartan was tried twice; however, it was discontinued due to intolerance. Despite required adjustments of medication being carried out periodically, the patient continued to require hospitalization over the past 3 months with congestive cardiac failure. On average, she spent 13 days in the hospital each time.

On clinical examination, her recorded vital signs were temperature 37.3°C, blood pressure 82/51: mmHg, oxygen saturation: 91% on room air, weight: 86.5 kg with a gain of 5.5 kg above her baseline weight, body mass index (BMI) of 37 kg/m2, raised jugular venous pressure, and bilateral ankle pitting edema. Furthermore, systemic examinations were remarkable for bilateral infrascapular rales and Grade IV pansystolic murmur over the mitral area. Laboratory tests revealed deterioration in renal function with serum creatinine at 219 μmol/L (serum creatinine baseline was 112 μmol/L, serum potassium: 5 mEq/L, and urea: 17 mg/dL). Expectedly, N-terminal brain natriuretic propeptide (NT pro-BNP) was markedly elevated at 40,879 pg/mL. Chest X-ray showed evidence of pulmonary congestion, and electrocardiograph showed paced rhythm.

The patient was admitted to the coronary care unit with an impression of acute decompensated HF and cardiorenal syndrome. Intravenous (IV) furosemide was commenced, along with intravenous dobutamine and milrinone infusions. We recorded three episodes of nonsustained ventricular tachycardia during this admission, most likely related to inotropes.

Transthoracic echocardiography was repeated and the findings were consistent with a diagnosis of severe DCM, with further deterioration in left ventricular (LV) systolic function (EF 10%–15%) and severe functional mitral regurgitation [Figures 1 and 2].

Figure 1

Transthoracic echocardiography showing severe dilated cardiomyopathy (ejection fraction: 10%–15%)

Figure 2

Transthoracic echocardiography showing severe dilated cardiomyopathy and severe functional mitral regurgitation

During her hospital stay, the patient was dependent on furosemide infusion. Notably, it has been challenging to wean her off the furosemide and she failed to lose weight despite the diuretic. However, her renal function was slowly recovering but never reached her baseline. LV assist device was thought to be a reasonable option at this stage. However, with the described hemodynamics and clinical state, BMI of 30 kg/m2, and taking into account the fact that optimum tolerated medical therapy was already reached, the opinion from an advanced HF specialist was that the patient is not a candidate for LVAD.

Clinically, the patient at this point was bed bound and unable to perform day-to-day activities while dependent on furosemide infusion. Palliative and hospice care were planned which included turning off the defibrillator.

A trial of levosimendan was made as a last resort with the aim of gradually weaning the patient off the furosemide infusion. Continuous IV infusion of levosimendan 0.1 μg/kg/min over 24 h was started through the peripherally inserted central catheter line. Clinical improvement was apparent in 24 h both subjectively and objectively, as the patient clinically looked well and her shortness of breath reportedly improved. The furosemide infusion was switched over to IV boluses. The patient's condition continued to improve dramatically on subsequent days. Urine output improved and the patient was able to walk within the ward with no reported dyspnea. Her renal function continued to improve touching her baseline for the first time since her admission. Figure 3 illustrates the trend of renal function before and after levosimendan infusion.

Figure 3

Trend of renal function before and after levosimendan infusion

Clinical improvement correlated with body weight reduction to 81 kg. The patient was discharged in a stable clinical condition after 31 days of hospital stay; her weight on discharge was 81 kg and creatinine was 111 μmol/L.

In view of the patient's condition with advanced HF, recurrent admissions with acute decompensated HF and not being an ideal candidate for LVADs or heart transplantation, she was scheduled to get intermittent levosimendan infusions every 2 weeks as a bridging therapy with the aim of proceeding to LVAD. Levosimendan was administered in an outpatient infusion-therapy facility every 2 weeks as a single intravenous infusion over 6 h at dose and rate of 0.2 (μg/kg/min) not proceeded by a bolus. During this therapy, NT pro-BNP and creatinine levels were monitored. Our patient received five infusions before she was accepted for LVAD therapy. Overall, there was a consistent reduction in postinfusion NT-proBNP level over time. Moreover, the new baseline NT-proBNP was approximately 12,000 pg/mL. Creatinine also showed a significant reduction post infusion.

Our patient did not require hospitalization for acute decompensated HF during the course of treatment with intermittent levosimendan infusions. Her medications were uptitrated; valsartan dose was increased to 40 mg O.D. and eplerenone was increased to 25 mg O.D. No adverse reactions or side effects to levosimendan infusions were identified. Her weight remained static at 80 kg.

The short form (36) health survey (SF-36) was used to assess the quality of life. There was a dramatic improvement in different health domains, notably energy, pain, and emotional well-being. The patient reported 75% improvement in overall health after starting the intermittent levosimendan infusions. She successfully underwent LVAD insertion.

DISCUSSION

In this clinical case, we presented a case of HF that progressed to an advanced stage of the disease despite guidelines-recommended drug and device therapy. Beyond these recommended therapies, specific treatments for those who fail these therapeutic measures are limited. The more sophisticated therapies such as LV-assisted device and heart transplant are not widely available worldwide. Thus, new therapeutic approaches to provide a period of hemodynamic stability and better quality of life in patients with advanced chronic HF are crucially needed.[1]

The use of intermittent inotropic infusion to patients with advanced HF to improve patients' quality of life as well as providing a period of hemodynamic stability has been always an attractive approach to many clinical researchers across the globe.[2] However, meta-analysis has shown that the use of conventional adrenergic and phosphodiesterase inhibitor inotropes failed to improve the clinical outcomes in this subset of population.

Furthermore, the majority resulted in increased mortality despite some favorable effects on hemodynamics as well as symptomatic improvements.[34] Introduction of inodilator like levosimendan, 20 years ago, has offered a new option in the treatment of HF. It is the most studied inotrope in HF and it is considered to be the only inotrope associated with a survival benefit and has also been linked with a reduced risk of progression of HF and the need for hospitalization.[356] This is primarily due to its unique mechanism of action.

We demonstrated the safety and efficacy of intermittent use of levosimendan infusion in the setting of advanced chronic HF. Levosimendan was associated with a noticeable clinical advantage in this group of patients. Our clinical case showed that this approach led to a reduction in the BNP levels and possibly stabilizing it. This has translated into clinical improvement of our patient as she never needed admission with acute decompensated HF and her quality of life has improved dramatically.

This result was consistent with the data reported in randomized studies. For instance, the LION-HEART study showed the superiority of levosemindan over placebo in reducing BNP levels and inhospital admissions rate.[7] Furthermore, LevoRep study demonstrated that this approach was associated with improvement, although not significant, in health-related quality of life in 19% of patients in the Levosimendan group compared to 15.8% of patients in the placebo group.[8] Low blood pressure and deranged renal function were important obstacles in uptitrating patient anti-failure medications. However, this was not an issue during the intermittent infusion approach, as levosimendan improves creatinine within 24 h of the infusion. Thus, valsartan was increased to 40 mg. Importantly, levosimendan was a very safe and well-tolerated drug.

These findings can be explained by the unique mechanism of action of levosimendan as a calcium sensitizer. It increases the sensitivity of troponin C to a given concentration of calcium within the cardiomyocytes without increasing myocardial oxygen consumption. Moreover, levosimendan exerts cardioprotective effects through action on potassium-dependent ATP channels on cardiac mitochondria.[29] As a result, it reduces cardiomyocyte apoptosis and exerts beneficial effects on remodeling. All the above mechanisms have been shown to increase cardiac output and reduce pulmonary capillary wedge pressure.

Our patient was proven histologically to have isolated cardiac sarcoid (ICS), which is defined as “the absence of active or inactive disease on18F-fluorodeoxyglucosis positron emission tomography computed tomography in any extracardiac organs, including the thoracic lymph nodes and no clinical evidence of skin or eye disease. It is a rare and challenging disease that carries a poor prognosis. The true prevalence of ICS is not known, but it ranges from 27% to 54%. Patients with ICS appear to present with more advanced HF and a higher rate of arrhythmias such as ventricular tachycardia as compared with patients with systemic sarcoidosis with CS. For instance, Kandolin et al. reported that 82% of patients with ICS had impaired LV systolic function at presentation.

The most common echocardiographic findings suggestive of cardiac sarcoid include regional wall motion abnormalities, thinning of the basal septum, and cardiac dysfunction. However, these findings are not specific for the diagnosis of CS. About 30% of patients present with a clinical picture resembling DCM. On presentation, our patient was labeled with idiopathic DCM as she, unfortunately, did not have a cardiac magnetic resonance imaging. The optimal strategy for HF management secondary to ICS has not been well studied.

While patients with systemic sarcoidosis and CS who are managed with prednisone may experience improvements in LV systolic function, patients with ICS do not exhibit a similar response. Advanced therapies such as LVAD and cardiac transplantation may be appropriate options in end-stage HF associated with ICS. Although the recurrence of CS following heart transplantation has rarely been reported, it remains a theoretical possibility.[10]

CONCLUSION

Intermittent levosimendan infusion is a safe and feasible approach in patients with advanced chronic HF who fail conventional treatments and are not suitable candidates for LVAD/heart transplant. However, larger randomized controlled trials are needed to corroborate our findings.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.