Case Presentation: Our patient is an 88-year-old female who presented with abdominal pain, nausea, and vomiting. Her medical comorbidities included hypertension, diabetes, CAD, heart failure with preserved ejection fraction, paroxysmal atrial fibrillation, hypothyroidism and a history of cerebrovascular accident without any residual deficits. Her prescription regimen included amlodipine, furosemide, isosorbide mononitrate, levothyroxine, metformin, omeprazole and ranolazine. Physical examination was remarkable for bradycardia and decreased breath sounds in the left lower lung field. Laboratory studies were significant for a serum potassium of 6.8 mEq/L and a serum creatinine of 1.6 mg/dL. She was given insulin with dextrose, sodium polystyrene, calcium gluconate and fluids. Her bradycardia and renal function worsened over next 24 hours. Ranolazine was discontinued. Metabolic derangements were treated appropriately. After 48 hours from presentation, potassium and renal function returned to baseline and her heart rate improved to a range of 60-100 bpm. She was discharged home and Ranolazine treatment was not continued upon discharge.

Discussion: Ranolazine works by inhibiting the slow inactivating component of the cardiac sodium channel during repolarization. This reduces myocyte dysfunction in the ischemic heart, and improves coronary vascular compliance and resistance. A review of the 5 major Ranolazine trials (MARISA, CARISA, ERICA, MERLIN-TIMI 36 and RAN080) observed that bradycardia is seen in less than 2% of patients.BRASH syndrome, an acronym for; bradycardia, renal failure, atrioventricular (AV) nodal blockage, shock and hyperkalemia, is a recently coined term for the aforementioned constellation of findings. It has typically been described in patients on AV nodal blocking agents. Dehydration, gastroenteritis and poor oral intake have been implicated as the inciting factors, leading to hypotension and pre-renal azotemia. The acute renal injury causes hyperkalemia, which in turn hinders AV node activity, when combined with any agent able to induce bradycardia. Bradycardia leads to further kidney hypoperfusion which worsens renal dysfunction and hyperkalemia. This results in a vicious cycle of bradycardia, renal failure and hyperkalemia. Often clinicians associate hyperkalemia as the sole cause of the bradycardia. The distinction between bradycardia purely due to hyperkalemia versus that induced by hyperkalemia in synergy with medications, is an important one. In pure hyperkalemic bradycardia, serum potassium levels are higher and ECG changes are common, including broad QRS complexes and peaked T waves. The absence of such findings in a patient with hyperkalemia and severe junctional bradycardia, favors an additional etiology of the bradycardia. The synergism of hyperkalemia with negative dromotropic agents, resulting in bradycardia, is well-defined with multiple case reports highlighting such findings in patients on verapamil. We propose that ranolazine can produce a similar effect, thereby leading to a syndrome analogous to BRASH.

Conclusions: In summary, our case illustrates an association between ranolazine, and renal failure induced hyperkalemia, leading to conduction delays in the myocardium. Though further studies are warranted, we suspect that this is a variant of the recently described BRASH syndrome. We propose that in cases such as ours, along with treatment of the hyperkalemia, medication review and removal of any offending agent should be considered.

IMAGE 1: FIGURE 1 – EKG ON ADMISSION – WITH PULSE RATE OF 40 BPM, (NOTE THE ABSENCE OF PEAKED T-WAVES)