Jose Ortiz

Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?

There are three US Food and Drug Administration–approved angiogenesis inhibitors for the treatment of cancer that specifically target vascular endothelial growth factor (VEGF) signaling. Bevacizumab (monoclonal antibody to VEGF) has been shown to confer a survival advantage when used in combination with cytotoxic chemotherapy in patients with colorectal cancer and non– small-cell lung cancer. 1,2 Sorafenib and sunitinib are orally bioavailable, small-molecule tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of the VEGF receptor (VEGFR) among other tyrosine kinase targets. Sorafenib has been shown to increase progression-free survival in patients with renal cell carcinoma. 3 Sunitinib has been shown to increase progressionfree survival in patients with renal cell carcinoma and GI stromal tumors. 4-6 A plethora of new small-molecule tyrosine kinase inhibitors are in preclinical development and early-phase clinical trials that target VEGFR with varying degrees of specificity, including AZD2171, which is the subject of a published report by Drevs et al

Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists?

Willem J. van Heeckeren, Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH Shyam Bhakta and Jose Ortiz, Division of Cardiology, Department of Medicine, CASE School of Medicine, Cleveland, OH Jeff Duerk, Departments of Radiology and Biomedical Engineering, CASE School of Medicine, Cleveland, OH Matthew M. Cooney, Afshin Dowlati, Keith McCrae, and Scot C. Remick, Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Developmental Therapeutics Program, CASE Comprehensive Cancer Center, University Hospitals of Cleveland, Cleveland, OH

Characterization of the excitable gap in a functionally determined reentrant circuit. Studies in the sterile pericarditis model of atrial flutter.

BACKGROUND Single premature beats were introduced in the reentrant circuit during stable atrial flutter in the canine sterile pericarditis model to test the hypotheses that (1) despite the fact that the reentrant circuit is functionally determined, there is a fully excitable gap; (2) the excitable gap in the reentrant circuit is not uniform; and (3) inhomogeneities of conduction in the reentrant circuit explain the effects of premature beats. METHODS AND RESULTS A multiplexing system was used to record 190 unipolar electrograms from the right atrial free wall during 18 atrial flutter episodes in 9 dogs. In all 18 episodes, premature stimuli captured the atrial flutter reentrant circuit. At the longest coupling intervals, the return cycle at the site closest to the pacing site did not prolong. As the coupling interval of the premature stimulus decreased, the return cycle then progressively increased, associated with changes in conduction in the reentrant circuit that were not uniform. The result was that coupling intervals associated with introduction of the premature beat also were not constant. The mean duration of the total (ie, fully plus partially) excitable gap was 12 +/- 4 ms in areas of slow conduction, and it was always shorter than the total excitable gap in other areas (22 +/- 6 ms, P < .001). The mean duration of the fully excitable gap based on analysis of the return cycle was 4 +/- 1 ms in the reentrant circuit. In 13 of 18 atrial flutter episodes, a premature stimulus terminated atrial flutter by causing block of the orthodromic wave front of the premature beat in an area of slow conduction. The mean coupling interval that caused orthodromic block was 113 +/- 5 ms (recorded at the site just proximal to the area of block), and it was always longer than the delivered stimulus coupling interval at the pacing site (96 +/- 8 ms, P < .001). CONCLUSIONS We conclude that in this functionally determined atrial flutter reentrant circuit in the canine sterile pericarditis model, (1) a fully excitable gap is present in at least part of the reentrant circuit; (2) the duration of the excitable gap in the reentrant circuit is shortest in areas of slow conduction; and (3) when a premature beat encounters the partially excitable gap of the reentrant circuit, it results in changes in conduction such that the coupling intervals are not uniform throughout in the reentrant circuit.

Mechanism of spontaneous termination of stable atrial flutter in the canine sterile pericarditis model.

BackgroundWe tested the hypotheses that spontaneous termination of stable atrial flutter is directly related to spontaneous beat-to-beat cycle length oscillations and that block of the circulating reentrant wave front occurs in an area of slow conduction. Methods and ResultsWe studied 30 episodes of spontaneous termination of stable atrial flutter induced by atrial stimulation in 11 conscious, nonsedated dogs with sterile pericarditis. Additionally, in 5 dogs, 14 episodes of spontaneous termination of stable atrial flutter were studied with a multisite mapping system to record simultaneously from 190 right atrial electrodes. In the conscious-state studies, atrial flutter cycle length oscillations began 6±1 (mean±SEM) beats before termination in 26 episodes, stable atrial flutter evolved into atrial fibrillation in 3 episodes, and no cycle length change occurred before termination in 1 episode. In the open-chest studies, in all instances, spontaneous oscillations began 7+1 beats before termination. The only consistent oscillation pattern occurred for the last two beats: a long cycle length (149±9 milliseconds) followed by a much shorter cycle length (110±6 milliseconds) (P<.01). Activation maps demonstrated that all cycle length oscillations were explained by changes of conduction in an area(s) of slow conduction in the reentrant circuit. In two instances, the last (short) cycle length was associated with disappearance of an area of slow conduction. In all episodes, the last circulating reentrant wave front blocked in an area of slow conduction in the reentrant circuit. Although not tested, during the last beat, the very early arrival of the circulating reentrant wave front at an area of slow conduction suggests an important role for refractoriness, with head and tail interactions, resulting in block. ConclusionsSpontaneous termination of stable atrial flutter in the sterile pericarditis model (1) is preceded by beat-to-beat cycle length oscillations that result from changes in conduction in areas of slow conduction in the reentrant circuit and (2) results from block of the circulating reentrant wave front in an area of slow conduction.

Mechanism of interruption of atrial flutter by moricizine. Electrophysiological and multiplexing studies in the canine sterile pericarditis model of atrial flutter.

BACKGROUND Moricizine is said to have potent effects on cardiac conduction but little or no effect on cardiac refractoriness. METHODS AND RESULTS The effects of moricizine (2 mg/kg IV) on induced atrial flutter were studied 2 to 4 days after the creation of sterile pericarditis in 11 dogs. Ten episodes of stable atrial flutter before and after the administration of moricizine were studied in 9 dogs in the conscious, nonsedated state, and 7 episodes were studied in 6 dogs in the anesthetized, open chest state. In the conscious state, the effects of moricizine on atrial excitability, atrial effective refractory period, and intra-atrial conduction times were studied by recording during overdrive pacing of sinus rhythm from epicardial electrodes placed at selected atrial sites. Moricizine prolonged the atrial flutter cycle length in all the episodes, from a mean of 133 +/- 9 to 172 +/- 27 milliseconds (P < .001), and then terminated 7 of the 10 episodes. Moricizine increased the atrial threshold of excitability from a mean of 2.3 +/- 1.4 to 3.3 +/- 2.2 mA (P < .01) and prolonged intra-atrial conduction times (measured from the sulcus terminalis to the posteroinferior left atrium) from a mean of 58 +/- 6 to 64 +/- 5 milliseconds (P < .005). Prolongation of the atrial effective refractory period from 166 +/- 20 to 174 +/- 24 milliseconds (P < .05) was observed only at the sulcus terminalis site. In the open chest studies, administration of moricizine prolonged the atrial flutter cycle length from a mean of 150 +/- 15 to 216 +/- 30 milliseconds (P < .001) and then terminated the atrial flutter in all 7 episodes. As demonstrated by simultaneous multisite mapping from 95 bipolar sites on the right atrial free wall, the atrial flutter cycle length prolongation was either due to further slowing of conduction in an area of slow conduction in the reentrant circuit of the atrial flutter (5 episodes) or further slowing of conduction in an area of slow conduction plus the development of a second area of slow conduction (2 episodes). The change in conduction times in the rest of the reentrant circuit was negligible (10.9 +/- 8.7% of the total change). In all 7 episodes, the last circulating reentrant wave front blocked in an area of slow conduction. CONCLUSIONS Moricizine (1) prolongs the atrial flutter cycle length, primarily by slowing conduction in an area of slow conduction in the reentrant circuit, (2) terminates atrial flutter by causing block of the circulating reentrant wave front in an area of slow conduction of the reentrant circuit, and (3) effectively interrupts otherwise stable atrial flutter in this canine model. The reason for these effects of moricizine are not readily explained by its effects on global atrial conduction times and refractoriness studied during sinus rhythm. Local changes in conduction in an area(s) of slow conduction are responsible for both cycle length prolongation and atrial flutter termination rather than the traditional wavelength concept of head-tail interaction.

Myocardial Stunning Following Combined Modality Combretastatin-Based Chemotherapy: Two Case Reports and Review of the Literature

Myocardial stunning, known as stress cardiomyopathy, broken‐heart syndrome, transient left ventricular apical ballooning, and Takotsubo cardiomyopathy, has been reported after many extracardiac stressors, but not following chemotherapy. We report 2 cases with characteristic electrocardiographic and echocardiographic features following combined modality therapy with combretastatin, a vascular‐disrupting agent being studied for treatment of anaplastic thyroid cancer. In 1 patient, an ECG performed per protocol 18 hours after drug initiation showed deep, symmetric T‐wave inversions in limb leads I and aVL and precordial leads V2 through V6. Echocardiography showed mildly reduced overall left ventricular systolic function with akinesis of the entire apex. The patient had mild elevations of troponin I. Coronary angiography revealed no epicardial coronary artery disease. The electrocardiographic and echocardiographic abnormalities resolved after several weeks. The patient remains stable from a cardiovascular standpoint and has not had a recurrence during follow‐up. An electrocardiogram performed per protocol in a second patient showed deep, symmetric T‐wave inversions throughout the precordial leads and a prolonged QT interval. Echocardiography showed mildly reduced left ventricular function with hypokinesis of the apical‐septal wall. Acute coronary syndrome was ruled out, and both the electrocardiographic and echocardiographic changes resolved at follow‐up. Although the patient remained pain‐free without recurrence of anginal symptoms during long‐term follow‐up, the patient developed progressive malignancy and died. Copyright

Atrial defibrillation using temporary epicardial defibrillation stainless steel wire electrodes : studies in the canine sterile pericarditis model

OBJECTIVES This study sought to determine whether temporary epicardial wire electrodes can be used safely and effectively to defibrillate the atria with low energy shocks in the absence of anesthesia. BACKGROUND Atrial fibrillation after open heart surgery is a significant clinical problem. METHODS Twelve dogs with sterile pericarditis were studied. In the first group (6 dogs, bilateral thoracotomy group), a wire electrode, insulated except for the distal 6 cm, was placed on the epicardial free wall of each atrium. Each end of the bare wire was then sutured to the parietal pericardium. In the second group (6 dogs, median sternotomy group), the wire electrodes were kept in place by a double loop of Prolene placed around the distal tip of the bare wire and sewn to the overlying parietal pericardium. In the bilateral thoracotomy group, atrial defibrillation thresholds (defined as < 90% and > 10% successful defibrillation of 20 shocks at a given delivered energy) were obtained in anesthetized dogs using the wire electrodes with the chest closed and open and using two transvenously placed catheters with coil electrodes in the distal 6 cm (one in the coronary sinus and the other in the right atrial appendage) with the chest open. In the median sternotomy group, thresholds were obtained in minimally sedated animals without reopening the chest. A 25% increase above threshold shock was also used to determine a new percent success. After 4 days, the wire electrodes were removed by pulling on the external ends. At the time of removal, blood pressure and heart rate were monitored for 30 min, after which dogs were killed and their hearts sent for histopathologic study. For all dogs, chest radiographs were obtained postoperatively and on study days. RESULTS Atrial defibrillation using the wire electrodes was successful in all dogs at a mean (+/- SE) voltage of 112 +/- 9 V, with an energy level of 0.46 +/- 0.07 J and an impedance of 59.3 +/- 5 ohms. The mean percent success at the atrial defibrillation threshold was 36 +/- 5%. The 25% increase in defibrillation voltage improved the mean percent success to 73% (mean energy 0.66 +/- 0.19 J). No clinical or hemodynamic complications were observed during shock delivery, and no ventricular arrhythmias were induced during the shocks. No complications followed wire electrode removal. Histopathologic analysis showed no structural damage. CONCLUSIONS The atrial defibrillation threshold obtained using temporary epicardial wire electrodes for atrial defibrillation is < 1 J in dogs. Atrial defibrillation using temporary epicardial wire electrodes can be performed safely, quickly and reliably without the need for anesthesia or antiarrhythmic agents. The wire electrodes can be removed without adverse hemodynamic or structural consequences. These data provide a basis for testing atrial defibrillation using epicardial wire electrodes in patients after open heart surgery.

Successful atrial defibrillation with very-low-energy shocks by means of temporary epicardial wire electrodes

Sustained atrial fibrillation is very common after cardiac surgical procedures. We hypothesized that atrial defibrillation could be accomplished consistently and safely by means of low-energy shocks delivered by temporary stainless steel wire electrodes placed at the time of the operation. Sterile pericarditis was created in five mongrel dogs (20.9 +/- 2.1 kg), and pairs of standard temporary stainless steel wire electrodes were placed on the right atrial appendage, on Bachmanns bundle, and on the right ventricular apex for pacing, sensing, and recording. Temporary stainless steel wire electrodes, insulated except for the distal 6 cm and used to deliver defibrillation shocks, were placed adjacent to both atrial free walls and secured to the pericardium. All electrodes were brought out through the skin, and the sternotomy was closed. Dogs were tested in the conscious state on postoperative day 2. Sustained atrial fibrillation was induced by rapid atrial pacing. A customized software program was used to control the defibrillator, which delivered R wave-synchronous biphasic shocks to the atria through the temporary defibrillation electrodes. The shock intensity began at 50 volts and was increased by 10-volt increments until atrial fibrillation was terminated. Atrial fibrillation was terminated in all dogs at 112 +/- 7 volts, with an energy of 0.42 +/- 0.07 joule and an impedance of 67.8 +/- 4 ohms (all values mean +/- standard error of the mean). The mean percent success for atrial defibrillation at this minimal threshold was 49%. Thus at low-threshold voltages atrial fibrillation could be terminated with every other shock. A 25% increase in the minimal threshold voltage improved the conversion rate to 73% (mean energy 0.66 +/- 0.19 joule and mean impedance of 67 +/- 3.8 ohms). No complications were detected with the use of the electrodes or after their removal on the seventh postoperative day. One instance of electrode migration on the right atrial free wall was detected by roentgenography, but this did not adversely affect atrial defibrillation threshold. No ventricular arrhythmias or hemodynamic complications were noted during shock delivery. We conclude that successful conversion of atrial fibrillation to sinus rhythm can be achieved consistently with shock energies below 0.5 joule delivered with temporary epicardial defibrillation wire electrodes in this canine pericarditis model. These results suggest that this approach to the management of sustained atrial tachyarrhythmias has considerable promise in the management of atrial fibrillation in patients who have had cardiac operations.

Magnetic resonance reveals long-term sequelae of apical ballooning syndrome

BACKGROUND The presence of small areas of necrosis has been occasionally reported immediately following apical ballooning syndrome (ABS). However, their persistence at later stages and impact on long-term prognosis are currently unknown. METHODS Twenty consecutive patients admitted for ABS between 2004 and 2007 were prospectively evaluated. Demographic, clinical, angiographic, and echocardiographic data were collected during hospital admission. At a mean of 11+/-9 months follow-up, a contrast enhanced cardiac magnetic resonance (ce-CMR) study was performed in 17 cases. The presence of hyperenhancement on ce-CMR images, reflecting irreversible myocardial damage, was recorded by two independent observers. RESULTS Two of 3 patients with hyperenhancement on ce-CMR images presented in worse condition, including pulmonary edema or cardiogenic shock, compared to just 2 of 14 patients without hyperenhancement (p=0.052). Segmental wall motion substantially improved in both of those cases; the third patient continued to have hypokinesis in a segment showing hyperenhancement. Segmental wall motion also significantly improved in all patients with no hyperenhancement. At a mean of 20+/-12 months follow-up, no deaths or major adverse cardiac events were documented among patients with or without hyperenhancement. CONCLUSIONS Despite segmental wall motion recovery, an area of irreversible myocardial damage can sometimes be identified long after ABS. However, in this limited series of patients, the presence of scar, even when presenting with heart failure and a higher troponin release, was not associated with adverse long-term outcomes as compared to patients with intact myocardium.

Epidemiology, Clinical Features, and Outcome of Infective Endocarditis due to Abiotrophia Species and Granulicatella Species: Report of 76 Cases, 2000–2015

Background Infective endocarditis (IE) caused by Abiotrophia (ABI) and Granulicatella (GRA) species is poorly studied. This work aims to describe and compare the main features of ABI and GRA IE. Methods We performed a retrospective study of 12 IE institutional cases of GRA or ABI and of 64 cases published in the literature (overall, 38 ABI and 38 GRA IE cases). Results ABI/GRA IE represented 1.51% of IE cases in our institution between 2000 and 2015, compared to 0.88% of HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella)-related IE and 16.62% of Viridans group streptococci (VGS) IE. Institutional ABI/GRA IE case characteristics were comparable to that of VGS, but periannular complications were more frequent (P = .008). Congenital heart disease was reported in 4 (10.5%) ABI and in 11 (28.9%) GRA cases (P = .04). Mitral valve was more frequently involved in ABI than in GRA (P < .001). Patient sex, prosthetic IE, aortic involvement, penicillin susceptibility, and surgical treatment were comparable between the genera. New-onset heart failure was the most frequent complication without genera differences (P = .21). Five (13.2%) ABI patients and 2 (5.3%) GRA patients died (P = .23). Factors associated with higher mortality were age (P = .02) and new-onset heart failure (P = .02). The genus (GRA vs ABI) was not associated with higher mortality (P = .23). Conclusions GRA/ABI IE was more prevalent than HACEK IE and approximately one-tenth as prevalent as VGS; periannular complications were more frequent. GRA and ABI genera IE presented similar clinical features and outcomes. Overall mortality was low, and related to age and development of heart failure.