Konstantinos Charitakis

Vascular Toxicities of Cancer Therapies The Old and the New – An Evolving Avenue

Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called targeted therapies. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of effects off their intended cancer tissue or molecular targets. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. In addition, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for the cardiotoxicity of 5-fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutic agents. Classical chemotherapeutic agents such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis and may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as they pertain to clinical practice, and to the conceptualization of cardiovascular diseases, as well. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.

Hospital Volume Outcomes After Septal Myectomy and Alcohol Septal Ablation for Treatment of Obstructive Hypertrophic Cardiomyopathy: US Nationwide Inpatient Database, 2003-2011

IMPORTANCE Previous data on septal myectomy (SM) and alcohol septal ablation (ASA) in obstructive hypertrophic cardiomyopathy have been limited to small, nonrandomized, single-center studies. Use of septal reduction therapy and the effect of institutional experience on procedural outcomes nationally are unknown. OBJECTIVE To examine in-hospital outcomes after SM and ASA stratified by hospital volume within a large, national inpatient database. DESIGN, SETTING, AND PARTICIPANTS This study analyzed all patients who were hospitalized for SM or ASA in a nationwide inpatient database from January 1, 2003, through December 31, 2011. MAIN OUTCOMES AND MEASURES Rates of adverse in-hospital events (death, stroke, bleeding, acute renal failure, and need for permanent pacemaker) were examined. Multivariate logistic regression analysis was performed to compare overall outcomes after each procedure based on tertiles of hospital volume of SM and ASA. RESULTS Of 71 888 761 discharge records reviewed, a total of 11 248 patients underwent septal reduction procedures, of whom 6386 (56.8%) underwent SM and 4862 (43.2%) underwent ASA. A total of 59.9% of institutions performed 10 SM procedures or fewer, whereas 66.9% of institutions performed 10 ASA procedures or fewer during the study period. Incidence of in-hospital death (15.6%, 9.6%, and 3.8%; P < .001), need for permanent pacemaker (10.0%, 13.8%, and 8.9%; P < .001), and bleeding complications (3.3%, 3.8%, and 1.7%; P < .001) after SM was lower in higher-volume centers when stratified by first, second, and third tertiles of hospital volume, respectively. Similarly, there was a lower incidence of death (2.3%, 0.8%, and 0.6%; P = .02) and acute renal failure (6.2%, 7.6%, and 2.4%; P < .001) after ASA in higher-volume centers. The lowest tertile of SM volume among hospitals was an independent predictor of in-hospital all-cause mortality (adjusted odds ratio, 3.11; 95% CI, 1.98-4.89) and bleeding (adjusted odds ratio, 3.77; 95% CI, 2.12-6.70), whereas being in the lowest tertile of ASA by volume was not independently associated with an increased risk of adverse postprocedural events. CONCLUSIONS AND RELEVANCE In US hospitals from 2003 through 2011, most centers that provide septal reduction therapy performed few SM and ASA procedures, which is below the threshold recommended by the 2011 American College of Cardiology Foundation/American Heart Association Task Force Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy. Low SM volume was associated with worse outcomes, including higher mortality, longer length of stay, and higher costs. More efforts are needed to encourage referral of patients to centers of excellence for septal reduction therapy.

Temporal Trends and Outcomes of Patients Undergoing Percutaneous Coronary Interventions for Cardiogenic Shock in the Setting of Acute Myocardial Infarction: A Report From the CathPCI Registry

OBJECTIVES The purpose of this study was to examine the temporal trends in demographics, clinical characteristics, management strategies, and in-hospital outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (CS-AMI) who underwent percutaneous coronary intervention (PCI) from the Cath-PCI Registry (2005 to 2013). BACKGROUND The authors examined contemporary use and outcomes of PCI in patients with CS-AMI. METHODS The authors used the Cath-PCI Registry to evaluate 56,497 patients (January 2005 to December 2013) undergoing PCI for CS-AMI. Temporal trends in clinical variables and outcomes were assessed. RESULTS Compared with cases performed from 2005 to 2006, CS-AMI patients receiving PCI from 2011 to 2013 were more likely to have diabetes, hypertension, dyslipidemia, previous PCI, dialysis, but less likely to have chronic lung disease, peripheral vascular disease, or heart failure within 2 weeks (p < 0.01). Between 2005 and 2006 to 2011 and 2013, intra-aortic balloon pump use decreased (49.5% to 44.9%; p < 0.01), drug-eluting stent use declined (65% to 46%; p < 0.01), and the use of bivalirudin increased (12.6% to 45.6%). Adjusted in-hospital mortality; increased (27.6% in 2005 to 2006 vs. 30.6% in 2011 to 2013, adjusted odds ratio: 1.09, 95% confidence interval: 1.005 to .173; p = 0.04) for patients who were managed with an early invasive strategy (<24 h from symptoms). CONCLUSIONS Our study shows that despite the evolution of medical technology and use of contemporary therapeutic measures, in-hospital mortality in CS-AMI patients who are managed invasively continues to rise. Additional research and targeted efforts are indicated to improve outcomes in this high-risk cohort.

Inherited disposition to cardiac myxoma development

Carney complex is a genetic condition in which affected individuals develop benign tumours in various tissues, including the heart. Most individuals with Carney complex have a mutation in the PRKAR1A gene, which encodes the regulatory R1α subunit of protein kinase A — a significant component of the cyclic-AMP signalling pathway. Genetically engineered mutant Prkar1a mouse models show an increased propensity to develop tumours, and have established a role for R1α in initiating tumour formation and, potentially, in maintaining cell proliferation. Ongoing investigations are exploring the intersection of R1α-dependent cell signalling with other gene products such as perinatal myosin, mutation of which can also cause cardiac myxomas.

Rate of percutaneous coronary intervention for the management of acute coronary syndromes and stable coronary artery disease in the United States (2007 to 2011).

Although the benefit of percutaneous coronary interventions (PCIs) for patients presenting with acute coronary syndromes (ACS) has been established in numerous studies, the role of PCI in stable coronary artery disease (CAD) remains controversial. With the publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluations trial and the appropriate use criteria for coronary artery revascularization, we sought to examine the impact of these treatment strategies and guidelines on the current practice of PCI in United States. We conducted a serial cross-sectional study with time trends of patients undergoing PCI for ACS and stable CAD from 2007 to 2011. The annual rate of all PCI decreased by 27.7% from 10,785 procedures per million adults per year in 2007 to 2008 to 7,801 procedures per million adults per year in 2010 to 2011 (p=0.03). Although there was no statistically significant decrease in the PCI utilization for ACS from 2007 to 2011, PCI utilization for stable CAD decreased by 51.7% (from 2,056 procedures per million adults per year in 2008 to 992 procedures per million adults per year in 2011, p=0.02). Hospitals with a higher volume of PCI experienced a more significant decrease. Decrease in PCI utilization for stable CAD was statistically significant for patients with Medicare and private insurance/health maintenance organization (44.5%, p=0.03 and 59.5%, p=0.007, respectively). In conclusion, the rate of PCI decreased substantially starting from 2009 in the United States. Most of the decrease was attributed to the reduction in PCI utilization for stable CAD.

SCAI expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologıa Intervencionista)

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients.

SCAI Expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologıa interve: Management of Cancer Patients in the Cath Lab

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients.

Novel Antiplatelet Therapies

Advances in antiplatelet therapy have significantly improved outcomes in patients with ischemic heart disease. Thienopyridines remain a cornerstone of therapy along with aspirin. Recently, concerns have been raised about the use of clopidogrel due to its pharmacokinetic and pharmacogenetic interpatient variability. A third-generation thienopyridine, prasugrel, overcomes some of these problems by improving inhibition of platelet aggregation, but increasing the risk of peri-procedural bleeding. Other novel antiplatelet agents, such as ticagrelor, have shown improved efficacy in recent trials and require further investigations. The field of pharmacotherapy continues to rapidly evolve as newer agents, such as thrombin receptor antagonists, along with older agents, such as cilostazol and glycoprotein IIb/IIIa inhibitors, are being explored.

Degenerating Heart Valves Fill Them up With Filamin

The intellect is always fooled by the heart. — - La Rochefoucauld Myxoid valvular heart dystrophies are a frequent cause of valvular diseases. They affect approximately 3% of the population and are the most common cause of isolated mitral regurgitations that require surgical repair.1,2 These valvular diseases are a heterogeneous group of disorders and include isolated nonsyndromic valvular diseases, such as idiopathic mitral valve prolapse and the X-linked myxomatous valvular dystrophy (XMVD), and syndromic entities, such as Marfan syndrome. In this issue of Circulation , Kyndt et al3 report their surprising finding that specific mutations in filamin A (FLNA) , a gene previously associated primarily with neurological and skeletal disorders, actually cause XMVD. Article p 40 XMVD is a rare form of inherited nonsyndromic valvular dystrophy that was identified more than 30 years ago by Monteleone and Fagan.4 Initial reports suggested that only men could be affected, but a subsequent study revealed that the disease has heterogeneous presentations and that women can have milder manifestations.5 Histologically, the valves classically display abnormalities of myxomatous degeneration, with fragmentation of collagen bundles within the valve fibrosa and accumulation of proteoglycan and secondary calcification. The clinical spectrum of XMVD ranges from isolated mild valve defects to severe multivalvular lesions, but XMVD usually affects the mitral and/or aortic valve. The result is mitral valve prolapse and mitral and/or aortic regurgitation. Affected individuals are usually asymptomatic until valvular lesions progress to significant hemodynamic impairment and heart failure. Complications can include endocarditis, spontaneous chordal rupture, and sudden death.5,6 Mutations of fibrillin and collagen genes have been correlated with syndromic cases of myxoid valvular heart dystrophies (eg, as part of Marfan and Ehlers–Danlos syndromes),7,8 but until now, no specific gene had been identified for nonsyndromic valvular dystrophies. Idiopathic mitral valve prolapse exhibits …

Trends in hospital treatments for peripheral arterial disease in the United States and association between payer status and quality of care/outcomes, 2007–2011

This study sought to identify the temporal trends of presenting diagnoses and vascular procedures performed for peripheral arterial disease (PAD) along with the rates of procedures and in‐hospital outcomes by payer status.