Mitochondria as a Therapeutic Target in Heart Failure Bayeva, Marina, PhD; Gheorghiade, Mihai, MD; Ardehali, Hossein, MD, PhD
Journal of the American College of Cardiology,
02/2013, Letnik:
61, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Heart failure is a pressing public health problem with no curative treatment currently available. The existing therapies provide symptomatic relief, but are unable to reverse molecular changes that ...occur in cardiomyocytes. The mechanisms of heart failure are complex and multiple, but mitochondrial dysfunction appears to be a critical factor in the development of this disease. Thus, it is important to focus research efforts on targeting mitochondrial dysfunction in the failing heart to revive the myocardium and its contractile function. This review highlights the 3 promising areas for the development of heart failure therapies, including mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial iron handling. Moreover, the translational potential of compounds targeting these pathways is discussed.
Endothelial Dysfunction, Arterial Stiffness, and Heart Failure Marti, Catherine N., MD; Gheorghiade, Mihai, MD; Kalogeropoulos, Andreas P., MD, PhD ...
Journal of the American College of Cardiology,
10/2012, Letnik:
60, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Outcomes for heart failure (HF) patients remain suboptimal. No known therapy improves mortality in acute HF and HF with preserved ejection fraction; the most recent HF trial results have been ...negative or neutral. Improvement in surrogate markers has not necessarily translated into better outcomes. To translate breakthroughs with potential therapies into clinical benefit, a better understanding of the pathophysiology establishing the foundation of benefit is necessary. Vascular function plays a central role in the development and progression of HF. Endothelial function and nitric oxide availability affect myocardial function, systemic and pulmonary hemodynamics, and coronary and renal circulation. Arterial stiffness modulates ventricular loading conditions and diastolic function, key components of HF with preserved ejection. Endothelial function and arterial stiffness may therefore serve as important physiological targets for new HF therapies and facilitate patient selection for improved application of existing agents.
Acute Heart Failure Syndromes Gheorghiade, Mihai, MD, FACC; Pang, Peter S., MD
Journal of the American College of Cardiology,
02/2009, Letnik:
53, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Heart failure resulting in hospitalization represents a significant and growing health care burden. Heterogeneity characterizes this group in terms of mode of presentation, pathophysiology, and ...prognosis. The vast majority of patients symptomatically improve during hospitalization; however, their early post-discharge rehospitalization and mortality rates continue to be high. Worsening signs and symptoms, neurohormonal, and renal abnormalities occurring soon after discharge may contribute to these high post-discharge event rates. Currently available assessment modalities combined with recent advances in cardiovascular therapies provide present-day opportunities to improve post-discharge outcomes. Further investigation into pathophysiologic targets and novel approaches to clinical trial design are needed. Improving post-discharge outcomes is the single most important goal in the management of acute heart failure syndromes.
Despite available therapy, mortality and readmission rates within 60-90 days of discharge for patients hospitalized with heart failure (HF) approach 15% and 30%, respectively. This early ...postdischarge period has been termed the 'vulnerable phase' and accounts for a disproportionate amount of the >US$30 billion spent annually on HF care in the USA. The pathophysiology underlying these early adverse events is likely associated with persistently elevated filling pressures at time of discharge and subsequent acute or subacute worsening of postdischarge haemodynamics. Despite limited proven strategies to reduce early adverse events, hospitals in the USA face penalties for 30-day readmission rates that exceed current expectations, and an urgent need exists for novel approaches to improve early postdischarge outcomes. The objective of this Review is to describe the early postdischarge problem among patients hospitalized for HF, the associated patient profile and pathophysiology, and the limitations of current postdischarge treatment strategies. We also identify therapeutic targets and outline a progressive management approach that should be considered by clinicians for reducing early postdischarge morbidity and mortality. Although these strategies require prospective validation, they are practical, affordable, and have the potential to improve patient outcomes substantially after HF hospitalization.
Heart failure is associated with activation of thrombin-related pathways, which predicts a poor prognosis. We hypothesized that treatment with rivaroxaban, a factor Xa inhibitor, could reduce ...thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease.
In this double-blind, randomized trial, 5022 patients who had chronic heart failure, a left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.5 mg twice daily or placebo in addition to standard care after treatment for an episode of worsening heart failure. The primary efficacy outcome was the composite of death from any cause, myocardial infarction, or stroke. The principal safety outcome was fatal bleeding or bleeding into a critical space with a potential for causing permanent disability.
Over a median follow-up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2507 patients assigned to rivaroxaban and in 658 (26.2%) of 2515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval CI, 0.84 to 1.05; P=0.27). No significant difference in all-cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P=0.48).
Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation. (Funded by Janssen Research and Development; COMMANDER HF ClinicalTrials.gov number, NCT01877915 .).
Abstract Little is known about specific modes of death in patients with heart failure with preserved ejection fraction (HFpEF). Herein, the authors critically appraise the current state of data and ...offer potential future directions. They conducted a systematic review of 1,608 published HFpEF papers from January 1, 1985, to December 31, 2015, which yielded 8 randomized clinical trials and 24 epidemiological studies with mode-of-death data. Noncardiovascular modes of death represent an important competing risk in HFpEF. Although sudden death accounted for ∼25% to 30% of deaths in trials, its definition is nonspecific; it is unclear what proportion represents arrhythmic deaths. Moving forward, reporting and definitions of modes of death must be standardized and tailored to the HFpEF population. Broad-scale systematic autopsies and long-term rhythm monitoring may clarify the underlying pathology and mechanisms driving mortal events. There is an unmet need for a longitudinal multicenter, global registry of patients with HFpEF to map its natural history.
Patients with acute heart failure syndromes (AHFS) typically present with signs and symptoms of systemic and pulmonary congestion at admission. However, elevated left ventricular (LV) filling ...pressures (hemodynamic congestion) may be present days or weeks before systemic and pulmonary congestion develop, resulting in hospital admission. This “hemodynamic congestion,” with or without clinical congestion, may have deleterious effects including subendocardial ischemia, alterations in LV geometry resulting in secondary mitral insufficiency, and impaired cardiac venous drainage from coronary veins resulting in diastolic dysfunction. It is possible that these hemodynamic abnormalities in addition to neurohormonal activation may contribute to LV remodeling and heart failure progression. Approximately 50% of patients admitted for AHFS are discharged with persistent symptoms and/or minimal or no weight loss in spite of the fact that the main reason for admission was clinical congestion. Accordingly, the assessment and management of pulmonary and systemic congestion in these patients require reevaluation.
Summary Background Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high ...treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide. Methods In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m2 intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov , number NCT00278525. Findings Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04–∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted. Interpretation Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed. Funding None
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