Cavernous Malformation Hemorrhagic Presentation at Diagnosis Associated with Low 25-Hydroxy-Vitamin D Level.

BACKGROUND: Cavernous malformations (CM) are angiographically occult vascular malformations that may be incidental or present with intracerebral or spinal hemorrhage, seizures, or nonhemorrhagic focal neurologic deficit (FND). Recently in vitro data have suggested vitamin D may play a role in stabilizing CCM2 endothelial cells. Little is known about the effect of vitamin D in human CM disease. METHODS: Beginning in 2015, consecutive patients at our institution with radiologically confirmed CM were recruited to participate in a prospective clinical registry as well as 25-hydroxy-vitamin D study. A structured interview, survey, and examination were performed at baseline. Medical records and magnetic resonance imaging studies were reviewed and data collected included comorbid conditions, medication use, and location of CM. Standard definition of clinical hemorrhage, FND, and seizures was used. Univariate and multivariate logistic regression models were used, and OR, 95% CIs, and likelihood-ratio p values were calculated to determine the influence of the 25-hydroxy-vitamin D level on clinical presentation with hemorrhage. RESULTS: Of 213 patients enrolled in the clinical registry between January 2015 and October 2018, 70 participated in the vitamin D study (median age: 38.3 years; 51.4% female). Of the 70 participants, 30 (42.9%) presented with hemorrhage. 25-Hydroxy-vitamin D levels were performed within 1 year of symptoms in 64.1% of patients. Patients presenting with hemorrhage had a lower 25-hydroxy-vitamin D level compared to those presenting with seizure without hemorrhage, FND, or as an incidental finding (median 25.5 ng/mL; range 11-59 hemorrhage vs. median 31.0; range 14-60, no hemorrhage; p = 0.04). After adjusting for age, month of blood draw, and body mass index, 25-hydroxy-vitamin D remained a significant predictor of hemorrhagic presentation. Brainstem location also predicted hemorrhage at presentation. CONCLUSION: Low 25-hydroxy-vitamin D level was more common in patients with CM presenting with hemorrhage. This study supports the potential role of modifiable factor in the initial clinical presentation of CM. Further study is needed to determine the role of vitamin D on prospective hemorrhage risk and whether supplementation may be beneficial.

Effect of Continuous-Flow Left Ventricular Assist Device Support on Coronary Artery Endothelial Function in Ischemic and Nonischemic Cardiomyopathy.

BACKGROUND: The coronary vasculature encounters a reduction in pulsatility after implementing durable continuous-flow left ventricular assist device (CF-LVAD) circulatory support. Evidence exists that appropriate pulsatility is required to maintain endothelial cell homeostasis. We hypothesized that coronary artery endothelial function would be impaired after CF-LVAD intervention. METHODS AND RESULTS: Coronary arteries from patients with end-stage heart failure caused by ischemic cardiomyopathy (ICM; n=16) or non-ICM (n=22) cardiomyopathy were isolated from the left ventricular apical core, which was removed for the CF-LVAD implantation. In 11 of these patients, paired coronary arteries were obtained from an adjacent region of myocardium after the CF-LVAD intervention (n=6 ICM, 5 non-ICM). Vascular function was assessed ex vivo using isometric tension procedures in these patients and in 7 nonfailing donor controls. Maximal endothelium-dependent vasorelaxation to BK (bradykinin; 10-6-10-10 M) was blunted (P<0.05) in arteries from patients with ICM compared with non-ICM and donor controls, whereas responses to sodium nitroprusside (10-4-10-9 M) were similar among the groups. Contrary to our hypothesis, vasorelaxation responses to BK and sodium nitroprusside were similar before and 219±37 days after CF-LVAD support. Of these patients, an exploratory subgroup analysis revealed that BK-induced coronary artery vasorelaxation was greater (P<0.05) after (87±6%) versus before (54±14%) CF-LVAD intervention in ICM patients, whereas sodium nitroprusside-evoked responses were similar. CONCLUSIONS: Coronary artery endothelial function is not impaired by durable CF-LVAD support and in ICM patients appears to be improved. Investigating coronary endothelial function using in vivo approaches in a larger patient population is warranted.

Clinical and histopathological effects of heart failure drug therapy in advanced heart failure patients on chronic mechanical circulatory support.

AIMS: Adjuvant heart failure (HF) drug therapy in patients undergoing chronic mechanical circulatory support (MCS) is often used in conjunction with a continuous-flow left ventricular assist device (LVAD), but its potential impact is not well defined. The objective of the present study was to examine the effects of conventional HF drug therapy on myocardial structure and function, peripheral organ function and the incidence of adverse events in the setting of MCS. METHODS AND RESULTS: Patients with chronic HF requiring LVAD support were prospectively enrolled. Paired myocardial tissue samples were obtained prior to LVAD implantation and at transplantation for histopathology. The Meds group comprised patients treated with neurohormonal blocking therapy (concurrent beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and aldosterone antagonist), and the No Meds group comprised patients on none of these. Both the Meds (n = 37) and No Meds (n = 44) groups experienced significant improvements in cardiac structure and function over the 6 months following LVAD implantation. The degree of improvement was greater in the Meds group, including after adjustment for baseline differences. There were no differences between the two groups in arrhythmias, end-organ injury, or neurological events. In patients with high baseline pre-LVAD myocardial fibrosis, treatment with HF drug therapy was associated with a reduction in fibrosis. CONCLUSIONS: Clinical and histopathological evidence showed that adjuvant HF drug therapy was associated with additional favourable effects on the structure and function of the unloaded myocardium that extended beyond the beneficial effects attributed to LVAD-induced unloading alone. Adjuvant HF drug therapy did not influence the incidence of major post-LVAD adverse events during the follow-up period.

Mitochondrial function in heart failure: The impact of ischemic and non-ischemic etiology.

BACKGROUND: Although cardiac mitochondrial dysfunction is associated with heart failure (HF), this is a complex syndrome with two predominant etiologies, ischemic HF (iHF) and non-ischemic HF (niHF), and the exact impact of mitochondrial dysfunction in these two distinct forms of HF is unknown. METHODS AND RESULTS: To determine the impact of HF etiology on mitochondrial function, respiration was measured in permeabilized cardiac muscle fibers from patients with iHF (n=17), niHF (n=18), and healthy donor hearts (HdH). Oxidative phosphorylation capacity (OXPHOS), assessed as state 3 respiration, fell progressively from HdH to niHF, to iHF (Complex I+II: 54±1; 34±4; 27±3pmol·s(-1)·mg(-1)) as did citrate synthase activity (CSA: 206±18; 129±6; 82±6nmol·mg(-1)·min(-1)). Although still significantly lower than HdH, normalization of OXPHOS by CSA negated the difference in mass specific OXPHOS between iHF and niHF. Interestingly, Complex I state 2 respiration increased progressively from HdH, to niHF, to iHF, whether or not normalized for CSA (0.6±0.2; 1.1±0.3; 2.3±0.3; pmol·mg(-1)·CSA), such that the respiratory control ratio (RCR), fell in the same manner across groups. Finally, both the total free radical levels (60±6; 46±4AU) and level of mitochondrial derived superoxide (1.0±0.2; 0.7±0.1AU) were greater in iHF compared to niHF, respectively. CONCLUSIONS: Thus, the HF-related attenuation in OXPHOS actually appears to be independent of etiology when the lower mitochondrial content of iHF is taken into account. However, these findings provide evidence of deleterious intrinsic mitochondrial changes in iHF, compared to niHF, including greater proton leak, attenuated OXPHOS efficiency, and augmented free radical levels.

Recovery Versus Remission: Clinical Insights.

Adverse myocardial remodeling can be reversed by medical, surgical, and device therapies leading to reduced heart failure (HF) morbidity and mortality and significant improvements in the structure and function of the failing heart. The growing population of HF patients who experience a degree of myocardial improvement should be better studied in terms of long-term outcomes and underlying biology to more clearly define the difference between recovery and remission. These investigations should also be focused in determining whether in chronic HF patients complete myocardial recovery is achievable at a meaningful rate and help us better understand, predict, and manipulate cardiac recovery.

Myocardial Structural and Functional Response After Long-Term Mechanical Unloading With Continuous Flow Left Ventricular Assist Device: Axial Versus Centrifugal Flow.

OBJECTIVES: The aim of this study was to assess the impact of continuous-flow left ventricular assist device (LVAD) type-axial flow (AX) versus centrifugal flow (CR)-on myocardial structural and functional response following mechanical unloading. BACKGROUND: The use of continuous-flow LVADs is increasing steadily as a therapeutic option for patients with end-stage heart failure who are not responsive to medical therapy. Whether the type of mechanical unloading influences the myocardial response is yet to be determined. METHODS: A total of 133 consecutive patients with end-stage heart failure implanted with continuous-flow LVADs (AX, n = 107 [HeartMate II Thoratec Corporation, Pleasanton, California]; CR, n = 26 [HeartWare, HeartWare International, Framingham, Massachusetts]) were prospectively studied. Echocardiograms were obtained pre-LVAD implantation and then serially at 1, 2, 3, 4, 6, 9, and 12 months post-implantation. RESULTS: The 2 pump types led to similar degrees of mechanical unloading as assessed by invasive hemodynamic status and frequency of aortic valve opening. Myocardial structural and functional parameters showed significant improvement post-LVAD in both AX and CR groups. Left ventricular ejection fraction increased significantly from a mean of 18% to 28% and 26% post-LVAD in the AX and CR groups, respectively. Left ventricular end-systolic volume index and left ventricular end-diastolic volume index decreased significantly as early as 30 days post-implantation in the 2 groups. The degree of myocardial structural or functional response between patients in the AX or CR groups appeared to be comparable. CONCLUSIONS: Long-term mechanical unloading induced by AX and CR LVADs, while operating within their routine clinical range, seems to exert comparable effects on myocardial structural and functional parameters.

Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning.

This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery.

Elevated resting heart rate in heart transplant recipients: innocent bystander or adverse prognostic indicator?

BACKGROUND: The elevated baseline heart rate (HR) of a heart transplant recipient has previously been considered inconsequential. However, we hypothesized that a resting HR above 100 beats per minute (bpm) may be associated with morbidity and mortality. METHODS: The U.T.A.H. Cardiac Transplant Program studied patients who received a heart transplant between 2000 and 2011. Outpatient HR values for each patient were averaged during the first year post-transplant. The study cohort was divided into two groups: the tachycardic (TC) (HR > 100 bpm) and the non-TC group (HR ≤ 100 bpm) in which mortality, incidence of rejection, and cardiac allograft vasculopathy were compared. RESULTS: Three hundred and ten patients were included as follows: 73 in the TC and 237 in the non-TC group. The TC group had a higher risk of a 10-yr all-cause mortality (p = 0.004) and cardiovascular mortality (p = 0.044). After adjustment for donor and recipient characteristics in multivariable logistic regression analysis, the hazard ratio was 3.9, (p = 0.03, CI: 1.2-13.2) and 2.6 (p = 0.02, CI: 1.2-5.5) for cardiovascular mortality and all-cause mortality, respectively. CONCLUSION: Heart transplant recipients with elevated resting HR appear to have higher mortality than those with lower resting HR. Whether pharmacologically lowering the HR would result in better outcomes warrants further investigation.