Cardiac work is related to creatine kinase energy supply in human heart failure: a cardiovascular magnetic resonance spectroscopy study.

BACKGROUND: It has been hypothesized that the supply of chemical energy may be insufficient to fuel normal mechanical pump function in heart failure (HF). The creatine kinase (CK) reaction serves as the heart's primary energy reserve, and the supply of adenosine triphosphate (ATP flux) it provides is reduced in human HF. However, the relationship between the CK energy supply and the mechanical energy expended has never been quantified in the human heart. This study tests whether reduced CK energy supply is associated with reduced mechanical work in HF patients. METHODS: Cardiac mechanical work and CK flux in W/kg, and mechanical efficiency were measured noninvasively at rest using cardiac pressure-volume loops, magnetic resonance imaging and phosphorus spectroscopy in 14 healthy subjects and 27 patients with mild-to-moderate HF. RESULTS: In HF, the resting CK flux (126 ± 46 vs. 179 ± 50 W/kg, p < 0.002), the average (6.8 ± 3.1 vs. 10.1 ± 1.5 W/kg, p  <0.001) and the peak (32 ± 14 vs. 48 ± 8 W/kg, p < 0.001) cardiac mechanical work-rates, as well as the cardiac mechanical efficiency (53% ± 16 vs. 79% ± 3, p < 0.001), were all reduced by a third compared to healthy subjects. In addition, cardiac CK flux correlated with the resting peak and average mechanical power (p < 0.01), and with mechanical efficiency (p = 0.002). CONCLUSION: These first noninvasive findings showing that cardiac mechanical work and efficiency in mild-to-moderate human HF decrease proportionately with CK ATP energy supply, are consistent with the energy deprivation hypothesis of HF. CK energy supply exceeds mechanical work at rest but lies within a range that may be limiting with moderate activity, and thus presents a promising target for HF treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00181259 .

Cardiac Complications of Cancer Therapy: Pathophysiology, Identification, Prevention, Treatment, and Future Directions.

PURPOSE OF REVIEW: Cardiotoxicity is an important complication of cancer therapy. With a significant improvement in the overall survival and prognosis of patients undergoing cancer therapy, cardiovascular toxicity of cancer therapy has become an important public health issue. Several well-established as well as newer anticancer therapies such as anthracyclines, trastuzumab, and other HER2 receptor blockers, antimetabolites, alkylating agents, tyrosine kinase inhibitors, angiogenesis inhibitors, checkpoint inhibitors, and thoracic irradiation are associated with significant cardiotoxicity. RECENT FINDINGS: Cardiovascular imaging employing radionuclide imaging, echocardiography, and magnetic resonance imaging is helpful in early detection of the cardiotoxicity and prevention of overt heart failure. These techniques also provide important tools for understanding the mechanism of cardiotoxicity of these modalities, which would help develop strategies for the prevention of cardiac morbidity and mortality related to the use of these agents. An understanding of the mechanism of the cardiotoxicity of cancer therapies can help prevent and treat their adverse cardiovascular consequences. Clinical implementation of algorithms based upon cardiac imaging and several non-imaging biomarkers can prevent cardiac morbidity and mortality associated with the use of cardiotoxic cancer therapies.

The lower the achieved blood pressure goal the better.

PURPOSE OF REVIEW: Hypertension is the eminent risk factor for renal and cardiovascular disease (CVD). Its management is a topic of public health priority. As either too high or too low blood pressure (BP) levels can have detrimental effects on health, optimal targets for BP continue to be controversial. The current manuscript will review relevant data published over the last year that add to this topic of controversy. RECENT FINDINGS: Recent studies confirm increased CVD-related risk with increasing SBP levels more than 140  mmHg among patients with hypertension and CVD as well as those over the age of 60 years. A SBP target less than 140  mmHg conveyed lessened risk of CVD-related events. There is some evidence suggesting that the ideal BP target lies between 120 and 140  mmHg. SUMMARY: Recent data support a target SBP of less than 140  mmHg among patients with hypertension or CVD, and achievement of this target might benefit those older than 60 years of age as well. Treating to SBPs below 120  mmHg may not result in further benefit. Data from randomized controlled trials specifically addressing the question whether lower BPs are associated with better outcomes are needed to further define ideal BP-target goals.

The Multidisciplinary Heart Team in Cardiovascular Medicine: Current Role and Future Challenges.

Cardiovascular multidisciplinary heart teams (MDHTs) have evolved significantly over the past decade. These teams play a central role in the treatment of a wide array of cardiovascular diseases affecting interventional cardiology, cardiac surgery, interventional imaging, advanced heart failure, adult congenital heart disease, cardio-oncology, and cardio-obstetrics. To meet the specific needs of both patients and heart programs, the composition and function of cardiovascular MDHTs have had to adapt and evolve. Although lessons have been learned from multidisciplinary cancer care, best practices for the operation of cardiovascular MDHTs have yet to be defined, and the evidence base supporting their effectiveness is limited. This expert panel review discusses the history and evolution of cardiovascular MDHTs, their composition and role in treating patients across a broad spectrum of disciplines, basic tenets for successful operation, and the future challenges facing them.

The j-point phenomenon in aggressive therapy of hypertension: new insights.

In the era of aggressive control of cardiovascular risk factors such as hypertension, the mantra of "lower is better" has taken a strong foothold. Although there is clear epidemiologic evidence that lower blood pressure improves specific organ-related outcomes, this rule does not apply to all patients and definitely not all target organs. The concept of J-curve or adverse outcomes at lower blood pressure has been proposed for more than three decades but has recently come under increasing scrutiny. Specifically, a relationship between adverse cardiovascular outcomes and low diastolic blood pressure has been observed in multiple clinical trials. In this article we review the advances in understanding of the J-curve phenomenon and include a discussion on specific populations that might be at higher risk due to the J-curve relationship.

Evaluation for Heart Transplantation and LVAD Implantation: JACC Council Perspectives.

Timely referrals for transplantation and left ventricular assist device implantation play a key role in favorable outcomes in patients with advanced heart failure. Nonetheless, evaluation usually occurs at advanced heart failure centers and is obscured from referring physicians. The purposes of this review are to explain the decision-making process for candidacy for advanced therapies and to describe the potential impact of the new organ allocation algorithm on center decision making. The document first addresses the signs of advanced heart failure, specifically focusing on the importance of the syndrome of low cardiac output as a key feature of advanced heart failure, and then summarizes the evaluation as a 3-step process addressing the following questions: 1) Is transplantation or durable assist device placement indicated? 2) Are there contraindications to either intervention? 3) How can one choose between transplantation and left ventricular assist device implantation if advanced therapies are indicated and not contraindicated?

Long-term Safety of Minimally Invasive Left Ventricular Assist Device Discontinuation for Myocardial Recovery.

BACKGROUND: Left ventricular assist devices (LVADs) play important roles in advanced heart failure (HF) management. In patients who experience myocardial recovery, the LVAD is often explanted via a resternotomy, which may negatively impact the newly recovered heart. We describe a case-series of LVAD discontinuation using a minimally invasive approach, focusing on thromboembolic phenomenon and infection rates in long-term follow-up. METHODS: Our study is a single-center, retrospective case series of patients with myocardial recovery after mechanical unloading with an LVAD. Patients underwent outflow graft ligation through a minimally invasive approach with driveline excision. Postdiscontinuation, patients obtained serial transthoracic echocardiograms for a minimum of 6 months and followed with our heart failure specialist. RESULTS: All 7 recovery patients had nonischemic cardiomyopathy and included 4 women (57%). Mean age was 44.3 ± 15.6 years. Median LVAD support duration was 454 (interquartile range, 326 to 1096) days. Intensive care unit length of stay and total length of stay were 3.4 ± 1.9 days and 6.3 ± 2.3 days, respectively. Blood transfusion rate was 0.86 ± 1.1 units. At a median follow-up of 874 (interquartile range, 864 to 1007) days, no patients developed thromboembolic phenomena despite use of aspirin only for prophylaxis. One patient experienced driveline infection, who had persistent driveline infection before procedure. CONCLUSIONS: This minimally invasive approach for LVAD discontinuation through outflow graft ligation, driveline removal, and LVAD stoppage in setting of myocardial recovery avoids resternotomy risks. Despite leaving the LVAD in situ, there was no risk of thromboembolism or infection associated with residual hardware.

Venoarterial ECMO for Adults: JACC Scientific Expert Panel.

Venoarterial extracorporeal membrane oxygenation (ECMO) is a rescue therapy that can stabilize patients with hemodynamic compromise, with or without respiratory failure, for days or weeks. In cardiology, the main indications for ECMO include cardiac arrest, cardiogenic shock, post-cardiotomy shock, refractory ventricular tachycardia, and acute management of complications of invasive procedures. The fundamental premise underlying ECMO is that it is a bridge-to recovery, to a more durable bridge, to definitive treatment, or to decision. As a very resource- and effort-intensive intervention, ECMO should not be used on unsalvageable patients. As the use of this technology continues to evolve rapidly, it is important to understand the indications and contraindications; the logistics of ECMO initiation, management, and weaning; the general infrastructure of the program (including the challenges associated with transferring patients supported by ECMO); and ethical considerations, areas of uncertainty, and future directions.

Fatigability, Exercise Intolerance, and Abnormal Skeletal Muscle Energetics in Heart Failure.

BACKGROUND: Among central and peripheral factors contributing to exercise intolerance (EI) in heart failure (HF), the extent to which skeletal muscle (SM) energy metabolic abnormalities occur and contribute to EI and increased fatigability in HF patients with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively) are not known. An energetic plantar flexion exercise fatigability test and magnetic resonance spectroscopy were used to probe the mechanistic in vivo relationships among SM high-energy phosphate concentrations, mitochondrial function, and EI in HFrEF and HFpEF patients and in healthy controls. METHODS AND RESULTS: Resting SM high-energy phosphate concentrations and ATP flux rates were normal in HFrEF and HFpEF patients. Fatigue occurred at similar SM energetic levels in all subjects, consistent with a common SM energetic limit. Importantly, HFrEF New York Heart Association class II-III patients with EI and high fatigability exhibited significantly faster rates of exercise-induced high-energy phosphate decline than did HFrEF patients with low fatigability (New York Heart Association class I), despite similar left ventricular ejection fractions. HFpEF patients exhibited severe EI, the most rapid rates of high-energy phosphate depletion during exercise, and impaired maximal oxidative capacity. CONCLUSIONS: Symptomatic fatigue during plantar flexion exercise occurs at a common energetic limit in all subjects. HFrEF and HFpEF patients with EI and increased fatigability manifest early, rapid exercise-induced declines in SM high-energy phosphates and reduced oxidative capacity compared with healthy and low-fatigability HF patients, suggesting that SM metabolism is a potentially important target for future HF treatment strategies.

Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death.

Morbidity and mortality from heart failure (HF) are high, and current risk stratification approaches for predicting HF progression are imperfect. Adenosine triphosphate (ATP) is required for normal cardiac contraction, and abnormalities in creatine kinase (CK) energy metabolism, the primary myocardial energy reserve reaction, have been observed in experimental and clinical HF. However, the prognostic value of abnormalities in ATP production rates through CK in human HF has not been investigated. Fifty-eight HF patients with nonischemic cardiomyopathy underwent ³¹P magnetic resonance spectroscopy (MRS) to quantify cardiac high-energy phosphates and the rate of ATP synthesis through CK (CK flux) and were prospectively followed for a median of 4.7 years. Multiple-event analysis (MEA) was performed for HF-related events including all-cause and cardiac death, HF hospitalization, cardiac transplantation, and ventricular-assist device placement. Among baseline demographic, clinical, and metabolic parameters, MEA identified four independent predictors of HF events: New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), African-American race, and CK flux. Reduced myocardial CK flux was a significant predictor of HF outcomes, even after correction for NYHA class, LVEF, and race. For each increase in CK flux of 1 µmol g⁻¹ s⁻¹, risk of HF-related composite outcomes decreased by 32 to 39%. These findings suggest that reduced CK flux may be a potential HF treatment target. Newer imaging strategies, including noninvasive ³¹P MRS that detect altered ATP kinetics, could thus complement risk stratification in HF and add value in conditions involving other tissues with high energy demands, including skeletal muscle and brain.

The J-curve between blood pressure and coronary artery disease or essential hypertension: exactly how essential?

The topic of the J-curve relationship between blood pressure and coronary artery disease (CAD) has been the subject of much controversy for the past decades. An inverse relationship between diastolic pressure and adverse cardiac ischemic events (i.e., the lower the diastolic pressure the greater the risk of coronary heart disease and adverse outcomes) has been observed in numerous studies. This effect is even more pronounced in patients with underlying CAD. Indeed, a J-shaped relationship between diastolic pressure and coronary events was documented in treated patients with CAD in most large trials that scrutinized this relationship. In contrast to any other vascular bed, the coronary circulation receives its perfusion mostly during diastole; hence, an excessive decrease in diastolic pressure can significantly hamper perfusion. This adverse effect of too low a diastolic pressure on coronary heart disease leaves the practicing physician with the disturbing possibility that, in patients at risk, lowering blood pressure to levels that prevent stroke or renal disease might actually precipitate myocardial ischemia. However, these concerns should not deter physicians from pursuing a more aggressive control of hypertension, because currently blood pressure is brought to recommended target levels in only approximately one-third of patients.

Potentiation of Doxorubicin cardiotoxicity by iron loading in a rodent model.

OBJECTIVES: The role of iron toward doxorubicin (DOX) cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. BACKGROUND: Doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially life-threatening cardiotoxicity. Doxorubicin cardiotoxicity is thought to be mediated through free-radical injury. METHODS: Male Sprague Dawley rats fed iron-rich chow (n = 8) and regular chow (n = 8) were treated with DOX or saline (4 animals in each arm). Cardiotoxicity was assessed using mortality, weight changes, Tc-99m annexin-V imaging, histopathology, and immunohistochemistry. RESULTS: Animals fed iron-rich chow showed significantly higher DOX cardiotoxicity as evidenced by greater weight loss (107 +/- 14 g vs. 55 +/- 10 g weight loss, p < 0.05), higher annexin uptake (0.14 +/- 0.01% vs. 0.08 +/- 0.01% injected dose/g of myocardium, p < 0.05), more severe myocyte injury on electron microscopy, and significantly higher cleaved caspase-3 staining compared with regular chow fed rats given DOX. Feeding iron-rich chow alone did not result in any cardiotoxicity. CONCLUSIONS: Dietary iron loading resulted in a substantially increased DOX cardiotoxicity in rats. Body iron stores as well as its bioavailability in tissue may be important independent predictors of susceptibility to DOX cardiotoxicity in man. Further clinical studies are warranted.

Beta-blockers for primary prevention in hypertension: era bygone?

Beta-blockers are used commonly worldwide in clinical practice for lowering blood pressure. Most of the agents in this class are efficacious in reducing blood pressure, although they vary widely in their pharmacokinetic and pharmacodynamic properties. This variability may confer significant differences in clinical benefits associated with use of specific agents. Although commonly used in managing hypertension, the role of beta-blockers for primary prevention in uncomplicated hypertension has been controversial. Evidence from recent trials suggest relatively poor efficacy toward primary prevention and worse outcomes for certain end points, when compared with other blood pressure-lowering agents, Recently updated National Institute for Health and Clinical Excellence guidelines for England and Wales reflect this concern and have changed the indication for beta-blockers for blood pressure control from primary agents to use as an add-on agent in patients requiring multiple therapy. In this review, considering the extended debate on this topic, we discuss the general properties of beta-blockers and evidence from clinical trials supporting or refuting their use in various clinical scenarios. Newer beta-blockers have additional properties which may be beneficial. Although, whether these additional benefits will help in primary prevention is not clear.