The Burden of Iron Deficiency in Heart Failure: Therapeutic Approach

Heart failure (HF) is highlighted by its burdening symptom-limited exercise capacity and recurrent hospitalizations. Despite substantial advances regarding disease-modifying drugs in HF with reduced ejection fraction, additional therapeutic strategies to improve quality of life are invaluable. Currently, iron deficiency (ID) is overwhelmingly recognized in over 30% to 50% of patients with stable chronic HF, which worsens prognosis. The established pathophysiological mechanisms of progressive HF may be intertwined with increasing myocardial iron scarcity, wherein one begets the other. Most importantly, ID constitutes a novel target for symptom relief in carefully selected patients. In this regard, intravenous iron may be a safe and efficacious intervention, potentially reducing HF hospitalizations. We discuss the evidence and gaps in knowledge concerning iron therapy in HF and propose a practical, comprehensive, clinically oriented algorithm for timely adequate iron replenishment in different clinical scenarios. Finally, we further debate imperative decision-making before intervention and the drawbacks of such a strategy.     

Phospholamban: A Promising Therapeutic Target in Heart Failure?

Dilated cardiomyopathy and end-stage heart failure result in characteristic functional, biochemical and molecular alterations. Multiple defects in cardiac excitation-contraction coupling have been suggested to underlie disturbed myocardial function and progressive remodeling. Ca²⁺ uptake and release by the sarcoplasmic reticulum (SR) have been shown to be altered in various animal models and human conditions. This review will focus on SR Ca²⁺ ATPase and its regulatory protein, phospholamban, as potential therapeutic targets. We summarize structural and genetic approaches, which have helped to elucidate the physiological role of phospholamban as a principal regulator of cardiac contractility and -adrenergic stimulation in the heart. These findings are extended to the clinical arena, indicating a phospholamban/SR Ca²⁺ ATPase mismatch in human heart failure. Evidence is then provided, using genetically engineered mouse models, that SR dysfunction may play a key role in the onset and progression of heart failure. Phospholamban deficiency may prevent such left ventricular dysfunction and its progression to heart failure in some of the animal models with dilated cardiomyopathy. Based on these findings, we discuss the question of whether and how interfering with the phospholamban/SR Ca²⁺ ATPase interaction may be a promising therapeutic approach for heart failure.     

Mechanisms of Disease: Is Mitochondrial Function Altered in Heart Failure?

The human heart sustains an exceptional energy transfer rate, consuming more energy per gram weight than any other organ system. The healthy heart can rapidly adapt to changes in demand, while the failing heart cannot. Cardiac energy flux systems falter in the failing heart. The purpose of this review is to characterize the fundamental role of mitochondria in this energy transfer system and describe our local research on mitochondrial respiratory capacity in failing human hearts.     

Rheumatic Heart Disease in Pregnancy: New Strategies for an Old Disease?

RHD in pregnancy (RHD-P) is associated with an increased burden of maternal and perinatal morbidity and mortality. A sequellae of rheumatic fever resulting in heart valve damage if untreated, RHD is twice as common in women. In providing an historical overview, this commentary provides context for prevention and treatment in the 21 st century.Four underlying themes inform much of the literature on RHD-P: its association with inequities; often-complex care requirements; demands for integrated care models, and a life-course approach. While there have been some gains particularly in awareness, strengthened policies and funding strategies are required to sustain improvements in the RHD landscape and consequently improve outcomes.As the principal heart disease seen in pregnant women in endemic regions, it is unlikely that the Sustainable Development Goal 3 target of reduced global maternal mortality ratio can be met by 2030 if RHD is not better addressed for women and girls.     

Pulmonary Hypertension Due to Left Heart Disease—A Practical Approach to Diagnosis and Management

Pulmonary hypertension (PH) due to left heart disease (LHD) is a frequent complication of heart failure (HF) and is associated with exercise intolerance, poor quality of life, increased risk of hospitalisations, and reduced overall survival. Since the recent Sixth World Symposium on Pulmonary Hypertension in 2018, there have been significant changes in the hemodynamic definitions and clinical classification of PH-LHD. PH-LHD can be subdivided into (1) isolated postcapillary PH (IpcPH) and (2) combined precapillary and postcapillary PH (CpcPH). This categorisation of PH-LHD is important because CpcPH shares certain pathophysiologic, clinical, and hemodynamic characteristics with pulmonary arterial hypertension and is associated with worse outcomes compared with IpcPH. A systematic approach using clinical history and noninvasive investigations is required in the diagnosis of PH-LHD. Right heart catheterisation with and without provocative testing is performed in expert centres and is indicated in selected individuals. Although the definition of IpcPH and CpcPH is based on measurements made with right heart catheterisation, distinguishing between these two entities is not always necessary. Despite strong evidence for medical therapy in patients with pulmonary arterial hypertension, those options have limited benefit in PH-LHD. Expert PH centres in Canada have been established to provide ongoing care for the more complex patient subgroups.     

Electrolyte and Acid–Base Disturbances in End-Stage Liver Disease: A Physiopathological Approach

Electrolyte and acid–base disturbances are frequent in patients with end-stage liver disease; the underlying physiopathological mechanisms are often complex and represent a diagnostic and therapeutic challenge to the physician. Usually, these disorders do not develop in compensated cirrhotic patients, but with the onset of the classic complications of cirrhosis such as ascites, renal failure, spontaneous bacterial peritonitis and variceal bleeding, multiple electrolyte, and acid–base disturbances emerge. Hyponatremia parallels ascites formation and is a well-known trigger of hepatic encephalopathy; its management in this particular population poses a risky challenge due to the high susceptibility of cirrhotic patients to osmotic demyelination. Hypokalemia is common in the setting of cirrhosis: multiple potassium wasting mechanisms both inherent to the disease and resulting from its management make these patients particularly susceptible to potassium depletion even in the setting of normokalemia. Acid–base disturbances range from classical respiratory alkalosis to high anion gap metabolic acidosis, almost comprising the full acid–base spectrum. Because most electrolyte and acid–base disturbances are managed in terms of their underlying trigger factors, a systematic physiopathological approach to their diagnosis and treatment is required.     

Risk Scores for Predicting Outcomes in Valvular Heart Disease: How Useful?

Risk scoring tools have been developed from clinical databases to predict expected patient mortality from cardiac surgical procedures. The risk algorithms have been developed and validated from variables that have been demonstrated to be predictive of mortality. At least six risk models have been developed from different databases measuring outcomes of cardiac surgery. These algorithms have then been used to select very high risk patients for conventional aortic valve replacement (AVR) who would be appropriate candidates for transcatheter aortic valve implantation (TAVI). The two most common risk models used for TAVI selection are the logistic EuroSCORE (LES) and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) algorithms. Although both models are accurate in predicting mortality in low-risk patients, the LES has been clearly demonstrated to overpredict expected mortality by a factor of three in high-risk candidates for AVR. Various factors that also impact mortality but are not included in either algorithm include liver disease, frailty, porcelain aorta, and previous radiation. Despite these shortcomings, risk algorithms are effective models for predicting risk, with the STS-PROM being more accurate in high-risk patients. Ultimately, a new risk algorithm specific for TAVI will need to be developed once sufficient databases are developed.