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Current practice guidelines support the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in patients with coronary artery disease (CAD) without heart failure (HF). However, a number of cited trials were performed prior to the era of prevalent statin use. Our objective was to evaluate the effectiveness of ACEi and ARBs in reducing cardiovascular events as well as the impact of statin therapy.We searched the MEDLINE and EMBASE databases for randomized-controlled trials (1/1/1980 - 8/31/2015) with ACEi or ARBs as the single intervention for patients with CAD without HF. We assessed the outcomes of non-fatal myocardial infarction (MI), stroke, cardiovascular mortality and all-cause mortality. The relationship between these outcomes and the percentages of patients on statin therapy was evaluated using meta-regression analysis.A total of ten ACEi trials and five ARB trials were included for analysis, with 78,761 patients followed for a mean of 36 months. Treatment with ACEi was associated with decreased non-fatal MI (RR 0.83; 95 % CI 0.75-0.91), stroke (RR 0.76; 95 % CI 0.68-0.86), cardiovascular mortality (RR 0.83; 95 % CI 0.72-0.95), and all-cause mortality (RR 0.86; 95 % CI 0.80-0.93). Treatment with ARBs was associated only with a decreased incidence of stroke (RR 0.92; 95 % CI 0.87-0.98). When adjusted for statin use, there was a trend towards an attenuated effect of ACEi in reducing cardiovascular mortality with increased use of statins (p-value = 0.063).In CAD patients without HF, ACEi, but not ARBs decreases the risk of non-fatal MI, cardiovascular mortality and all-cause mortality, while both ACEi and ARBs decrease the risk of stroke.

Antinuclear antibody (ANA) negative lupus is an important subset of the systemic lupus erythematosus (SLE) disease spectrum. Since the introduction of human cell line for ANA assay, the occurrence of true ANA-negative SLE has been a rare clinical phenomenon. The nature of cardiac involvement in ANA-negative SLE is not well understood, although any cardiac involvement, including valvular dysfunction, should be considered as a presenting manifestation of SLE irrespective of serology status. Early recognition and intervention appears to be associated with decreased morbidity. The following report describes our first case of ANA-negative SLE with an initial presentation of severe cardiac valvular dysfunction and heart failure. It also characterizes the spectrum of disease severity in ANA-negative SLE and demonstrates how aggressive SLE therapy can improve cardiac disease.

There is a 2.5-fold increased risk of incident heart failure (HF) among women living with human immunodeficiency virus (HIV) (WLWHIV) [(1)][1]. Whether HF outcomes differ by HIV status among women has not been established. Leveraging data from a large, current and established U.S. health care system

The health burden of type 2 diabetes mellitus continues to increase worldwide. A substantial portion of this burden is due to the development of cardiovascular disease in patients with diabetes. Recent failures of clinical trials of intensive glucose control to reduce macrovascular events, coupled with reports of potential harm of certain diabetic therapy, have led to increased scrutiny as new diabetic therapies are developed. Incretin peptides are a group of gastrointestinal proteins that regulate glucose metabolism through multiple mechanisms, and incretin-based therapies have been developed to treat type 2 diabetes. These agents include glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-IV (DPP-IV) inhibitors. In addition to effects on glucose homeostasis, growing evidence suggest that these peptides may also affect the cardiovascular system. In this review, we discuss recent findings concerning the potential, yet untested, benefits of incretin-based pharmacotherapy in the treatment of cardiovascular disease.

Background Ibrutinib (IB), a nonselective Bruton's tyrosine kinase inhibitor, is associated with significantly improved disease control rates, progression free, and overall survival in several B-cell malignancies. Yet, IB's nonselective actions may result in a number of unintended adverse effects and complications that can lead to drug discontinuation. New or worsening hypertension (HTN) has been reported in 10-29% of those receiving IB within clinical trials. However, recent observational data suggest that this rate may be much higher in clinical practice and resistant to treatment. The management of IB-related HTN has not been previously well described. Furthermore, the relationship between IB-associated HTN and serious cardiovascular (CV) complications is unknown. Therefore, we sought to characterize the incidence, risk factors, management, and CV complications associated with IB-related HTN across long-term follow-up. Methods We performed a retrospective, single-center cohort study of all consecutive adult patients treated with IB for a hematologic malignancy from 2009-2016. Patient demographics, blood pressure (BP), antihypertensive therapy, cancer variables, and CV complications were collected throughout the duration of IB therapy. HTN was defined as systolic BP of ≥ 130 mmHg on 2 separate visits within 3 months. Worsened HTN was defined as an increase in HTN grade by Common Terminology Criteria for Adverse Events (CTCAE) or an increase an antihypertensive therapy. The composite of major adverse CV endpoint (MACE), including atrial fibrillation, ventricular arrhythmia, myocardial infarction, cerebrovascular accident, heart failure, and CV death, as stratified by HTN status was assessed. Univariate and multivariate Fine and Gray regression analyses accounting for competing risks of death and IB-discontinuation were preformed to determine the association between baseline covariates and outcomes, and survival analysis techniques were used to estimate the cumulative incidence of events. To assess whether any antihypertensive agent(s) was more effective in preventing IB-related HTN, the use of these agents at baseline was assessed by class, as protective factors against worsened HTN. Results Overall, 562 patients treated with IB were identified, a majority of which had CLL (73%) and were male (70%); mean age 64 ± 11 years. Sixty-two percent had preexisting HTN at the time of starting IB with 35% requiring at least one antihypertensive medication. During follow-up, 440 (78%) developed new or worsening HTN (figure 1A), with a mean increase in systolic BP of 5.2 mmHg (± 20.7). In those without baseline HTN, 72% developed new HTN while on IB, with a mean increase in systolic BP of 13.4 mmHg (± 20.1). Among patients with preexisting HTN, 82% saw worsening of their BP (mean increase in systolic BP of 4.1 mmHg (± 21.4)), including increased CTCAE grade in 77% and new antihypertensive medications in 46% of patients. Estrogen/progestin use [HR 3.47, 95% CI (1.25-9.64)] and history of diabetes [HR 1.66, 95% CI (1.03-2.66)] were risk factors for new, but not worsened HTN on multivariable analysis. MACE occurred in 19.1% of patients with new or worsened HTN, compared to 8.2% of patients with no HTN (figure 1B). In a multivariable model containing traditional HTN risk factors, new or worsened HTN was not significantly associated with MACE [HR 1.98, 95% CI (0.74-5.31)]. No specific class of antihypertensive agent was associated with the prevention of worsened HTN. Conclusion In this retrospective study, IB-therapy was associated with a substantial increase in the incidence and severity of HTN. Further research into the mechanisms, early detection strategies, optimal management, and clinical impacts of this complication are needed. Disclosures No relevant conflicts of interest to declare.

Radiotherapy (RT) is a standard treatment for cancer; however, RT is associated with an increase in atherosclerotic cardiovascular events (ASCVD). Whether the primary prevention ACC/AHA and USPSTF statin guidelines, using the pooled cohort risk equation (PCE), predict ASCVD after RT is unknown.

Ibrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor associated with dramatic improvements in outcomes of various B-cell hematologic malignancies and is now standard therapy. However, Ibrutinib is associated with a >4-fold increased risk of incident atrial arrhythmias. Recently, an alarming

Background— Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice. Methods and Results— This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms; P P P r =0.90; P P Conclusions— Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality.

Background: Data from randomized-controlled trials regarding the efficacy of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in patients with coronary artery disease (CAD) but no evidence of heart failure are inconclusive. Current ACC/AHA guidelines support their use in this population. The variation in efficacy of ACEi and ARBs in improving cardiovascular (CV) outcomes may be related to the rising use of statin therapy in the past two decades. Methods: We conducted literature review of randomized-controlled trials with ACEi or ARBs as the single intervention, focusing on studies involving patients with CAD including patients with left ventricular dysfunction but no clinical symptoms of heart failure. The MEDLINE database was searched for publications between 1/1/1980 and 12/31/2012 with searched terms including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, coronary artery disease, cardiovascular events, and myocardial infarction. Of the 1553 potentially relevant publications, 19 (14 ACEi and 5 ARB) met the inclusion criteria for a total of 99,631 randomized patients followed for a mean of 38 months. We evaluated the endpoints of CV mortality, all-cause mortality, non-fatal MI, and stroke. The relationship between endpoints across the 19 trials and the percentage of patients on statins in each trial (with available data) were evaluated using meta-regression analysis, expressed as highest standardized regression coefficient, Beta. Results: ACEi and ARB therapy across the 19 trials was associated with decreased CV mortality (OR 0.85; 95% CI 0.78-0.93) and all-cause mortality (OR 0.92; 95% CI 0.86-0.98). When adjusted for the percentage of statin, 46% of patients in the cohort, there was a significant linear decrease in the odds of CV mortality reduction with ACEi and ARB therapy (Beta = 0.01; p = 0.034). Conclusion: In patients with CAD and no evidence of heart failure, the additive benefits of ACEi and ARBs in decreasing CV mortality are blunted by statin therapy. The exact mechanism(s) for this result is unclear and further investigation is warranted. The modification of current ACC/AHA practice guidelines should be considered.

Background: Patients presenting with chest pain and evidence of functional ischemia by myocardial perfusion imaging (MPI), but lacking commensurate angiographic disease pose a diagnostic and therapeutic dilemma. They are often dismissed as having ‘false-positive MPI’. Moreover, a majority of the available long-term outcome data for it has been derived from homogenous female populations. In this study, we sought to evaluate the long-term outcomes of this presentation in a multiethnic male-predominant cohort. Materials and Methods: We retrospectively identified 47 patients who presented to our institution between 2002 and 2005 with chest pain and evidence of ischemia on MPI, but with no significant angiographic disease on subsequent cardiac catheterization (cases). The occurrence of adverse cardiovascular outcomes (chest pain, congestive heart failure, acute myocardial infarction and stroke) postindex coronary angiogram was tracked. Similar data was collected for 37 patients who also presented with chest pain, but normal MPI over the same period (controls). Overall average follow-up was over 22 months. Results: Fifty-three percent (26/47) of the cases had one or more of the adverse outcomes as compared with 22% (8/37) of controls (P < 0.01). Of these, 13 (50.0%) and 3 (37.5%) were males, respectively. Conclusions: Ischemia on MPI is predictive of long-term adverse cardiovascular outcomes despite normal (‘false-negative’) coronary angiography. This appears to be gender-neutral.Keywords: Cardiac syndrome X, multiethnic, male-predominant

Fusobacterium necrophorum, an obligate, anaerobic, filamentous, gram-negative rod, is thought to be a normal inhabitant of the mucous membranes in human beings. Fusobacterium species have been implicated in cases of Lemierre syndrome and other pathologic conditions. Their reported association with infective endocarditis is extremely rare. We describe the case of a previously healthy 34-year-old man who emergently presented with flu-like symptoms and dyspnea on exertion. He had recently undergone a dental procedure. Empiric antibiotic therapy was initiated. Blood cultures were positive for metronidazole-resistant F. necrophorum. A transesophageal echocardiogram revealed 2 mobile vegetations on the mitral valve. Despite the antibiotic therapy, the patient's respiratory status worsened and, after 3 weeks, he died. On the basis of the organism's pathophysiology and the patient's recent dental procedure, the oral cavity was the likely source of the bacteremia. Our patient's case underscores the importance of recognizing Fusobacterium bacteremia as a possible cause of endocarditis. To our knowledge, this is the first reported case of monomicrobial F. necrophorum endocarditis to have presented in a patient after the 2nd decade of life. In addition, it is apparently only the 4th report of F. necrophorum mitral valve endocarditis with case results derived from modern culture techniques.

Summary Background Spontaneous coronary artery dissection is a rare cause of acute coronary syndromes; and one quarter of these patients present during the post-partum period. Furthermore, ventricular fibrillation is a rare presentation of this disease entity. Case A 32-year-old woman presented 3 days post Cesarean-section delivery with chest pain, ischemic electrocardiogram changes, and ventricular fibrillation arrest. The patient was taken for cardiac catheterization and found to have a left anterior coronary artery dissection necessitating 6 stents to restore flow to the vessel. Conclusion We report the first case of survival after ventricular fibrillation arrest of a woman presenting with spontaneous coronary dissection in the post-partum period. Our case underscores the importance of recognizing ventricular fibrillation as a first presenting sign of spontaneous coronary artery dissection in the post-partum period.

The renal inward rectifying potassium channel Kir1.1 plays key roles in regulating electrolyte homeostasis and blood pressure. Loss-of-function mutations in the channel cause a life-threatening salt and water balance disorder in infants called antenatal Bartter syndrome (ABS). Of more than 30 ABS mutations identified, approximately half are located in the intracellular domain of the channel. The mechanisms underlying channel dysfunction for most of these mutations are unknown. By mapping intracellular mutations onto an atomic model of Kir1.1, we found that several of these are localized to a phylogenetically ancient immunoglobulin (Ig)-like domain (IgLD) that has not been characterized previously, prompting us to examine this structure in detail. The IgLD is assembled from two beta-pleated sheets packed face-to-face, creating a beta-sheet interface or core, populated by highly conserved side chains. Thermodynamic calculations on computationally mutated channels suggest that IgLD core residues are among the most important residues for determining cytoplasmic domain stability. Consistent with this notion, we show that two ABS mutations (A198T and Y314C) located within the IgLD core impair channel biosynthesis and trafficking in mammalian cells. A fraction of core mutant channels reach the cell surface, but are electrically silent due to closure of the helix-bundle gate. Compensatory mutation-induced rescue of channel function revealed that IgLD core mutants fail to rectify. Our study sheds new light on the pathogenesis of ABS and establishes the IgLD as an essential structure within the Kir channel family.

Case Report A 65-year-old male with a biventricular implantable cardioverter defibrillator (ICD) placed 1 month prior presented from an outside hospital with chest pain and shortness of breath. Echocardiography showed a perforation of his right ventricular (RV) free wall by the ICD lead complicated by a moderate pericardial effusion (Figure 1; Video 1). The RV lead was noted to be in the pericardial space, suggesting lead migration/ perforation (Figure 2). A pericardial window was placed, and pericardiocentesis was performed via a subxiphoid approach with removal of approximately 1,500 cc of bloody fluid. The RV lead was unscrewed under fluoroscopy and repositioned, lead parameters were confirmed, and the device was returned to the pocket. The patient tolerated the procedure well. Follow-up transthoracic echocardiogram (Figure 3) revealed resolution of the pericardial effusion and the pericardial drain was removed. The patient was discharged home after recovery. Delayed lead perforation is defined as migration and perforation at least one month after implantation. A rare complication, the incidence has been reported at 0.1–0.8% in permanent pacemaker and 0.6–5.2% in ICD implantations, respectively.1,2 The pathophysiology is unclear, however two mechanisms have been proposed. The first involves direct mechanical lead perforation of the myocardium during implantation, while the second proposes an excessive immune response of the visceral pericardium leading to post-implantation pericarditis. Both mechanisms would suggest potential association with the level of tissue injury incurred at the time of device implantation, supporting efficacy to cautious monitoring. Importantly, the clinical presentation of these patients ranges from no symptoms to cardiac tamponade.3 Early recognition and appropriate treatment of complicating pericardial effusions are essential, with pericardiocentesis and/ or pericardial window if necessary. The most commonly employed therapeutic approach is surgical removal, although successful percutaneous lead extraction with stand-by cardiothoracic surgery has been widely reported. Additionally, lead repositioning without extraction, as with our patient, has been reported.

Left coronary cusp perforation is an extremely rare consequence of blunt chest trauma. A 22-year-old male presented after a motor vehicle accident with dyspnea. Transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) showed moderate to severe aortic regurgitation with prolapsing right coronary cusp. In the operating room he was found to have a left coronary cusp tear near the annulus and an enlarged right cusp. The patient recovered well after successful aortic valve replacement with a mechanical valve. Traumatic aortic regurgitation with left cusp perforation is serious and surgical intervention may be lifesaving if performed timely.

Data from randomized-controlled trials of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) in patients with coronary artery disease (CAD) but no clinical evidence of heart failure are inconclusive. This study was undertaken to more clearly define the role of