Roien Ahmadie

Utility of Tissue Doppler and Strain Rate Imaging in the Early Detection of Trastuzumab and Anthracycline Mediated Cardiomyopathy

BACKGROUND Trastuzumab provides considerable therapeutic benefits in the adjuvant setting of breast cancer. However, its use is limited by an elevated incidence of cardiotoxicity when used in combination with doxorubicin. Although Myocet (liposomal encapsulated doxorubicin) is less cardiotoxic, its cardiac safety profile with trastuzumab is not well known. The aim of this study was to determine if sensitive indices of left ventricular (LV) dysfunction, specifically Doppler tissue imaging (DTI), would be useful for addressing the early detection of trastuzumab and anthracycline-mediated cardiotoxicity. METHODS In an acute murine model, wild-type C57Bl/6 mice (n = 60) received one of the following drug regimens: (1) control, (2) doxorubicin, (3) Myocet, (4) trastuzumab, (5) doxorubicin plus trastuzumab, or (6) Myocet plus trastuzumab. DTI-derived peak endocardial systolic velocity, strain rate, and LV ejection fraction were measured serially for 5 days. On day 5, the hearts, lungs, and livers were removed for histopathologic and Western blot analyses. RESULTS Mice treated with Myocet plus trastuzumab demonstrated minimal cardiotoxicity compared with those treated with doxorubicin plus trastuzumab. Progressive LV dilatation and LV systolic dysfunction were observed by day 4 of treatment with doxorubicin plus trastuzumab, compared with preserved LV ejection fraction in the remaining groups. DTI parameters decreased within 24 hours in the doxorubicin alone and doxorubicin plus trastuzumab groups and predicted early mortality. The survival rate was only 20% at day 5 of the experiment in the doxorubicin plus trastuzumab group, whereas 100% of mice receiving trastuzumab, Myocet, or Myocet plus trastuzumab survived the 5 days. CONCLUSION DTI can detect early LV dysfunction prior to alterations in conventional echocardiographic indices and predicts early mortality in mice receiving doxorubicin plus trastuzumab.

Advancements in the field of intravaginal siRNA delivery

The vaginal tract is a suitable site for the administration of both local and systemic acting drugs. There are numerous vaginal products on the market such as those approved for contraception, treatment of yeast infection, hormonal replacement therapy, and feminine hygiene. Despite the potential in drug delivery, the vagina is a complex and dynamic organ that requires greater understanding. The recent discovery that injections of double stranded RNA (dsRNA) in Caenorhabditis elegans (C. elegans) results in potent gene specific silencing, was a major scientific revolution. This phenomenon known as RNA interference (RNAi), is believed to protect host genome against invasion by mobile genetic elements such as transposons and viruses. Gene silencing or RNAi has opened new potential opportunities to study the function of a gene in an organism. Furthermore, its therapeutic potential is being investigated in the field of sexually transmitted infections such as human immunodeficiency virus (HIV) and other diseases such as age-related macular degeneration (AMD), diabetes, hypercholesterolemia, respiratory disease, and cancer. This review will focus on the therapeutic potential of siRNA for the treatment and/or prevention of infectious diseases such as HIV, HPV, and HSV within the vaginal tract. Specifically, formulation design parameters to improve siRNA stability and therapeutic efficacy in the vaginal tract will be discussed along with challenges, advancements, and future directions of the field.

The utility of tissue Doppler imaging for the noninvasive determination of left ventricular filling pressures in patients with septic shock.

Background: Pulmonary artery wedge pressure (PAWP) is an important indicator of volume status in septic patients. Although it requires invasive pulmonary artery catheterization (PAC), a noninvasive method to assess PAWP would be clinically useful in this select patient population. Diastolic indices using transthoracic echocardiography (TTE) may provide an accurate estimate of PAWP. Objective: To determine whether echocardiographic Doppler assessment is accurate in estimating PAWP in patients with septic shock. Methods: A retrospective chart review was performed of 320 patients admitted with a diagnosis of septic shock from 2007-2008. Of the total patient population, 40 patients fulfilled the inclusion criteria, having undergone both TTE and PAC within 4 hours. Spectral Doppler indices including peak early (E) and late (A) transmitral velocities, E/A ratio, and E-wave deceleration time were measured. Tissue Doppler indices including S’, E’ and A’ velocities were determined. Pulmonary artery wedge pressure values measured invasively were compared to the dimensionless index of E/E’ in each patient. Results: The mean age was 68 ± 12 years with 28 males (70%). On echo assessment, 28% of patients had evidence of mild left ventricular diastolic dysfunction while 17% of patients had moderate diastolic dysfunction. Pulmonary artery wedge pressures ranged from 7 to 31 mm Hg with a mean of 18 ± 5 mm Hg. The mean E/E’ was 11 ± 8. Linear regression analysis between PAWP and E/E7apos; demonstrated a strong correlation (r = .84, P < .05). Conclusion: Tissue Doppler indices using TTE is a feasible and strong predictor of PAWP in patients with septic shock.

Clinical utility of cardiac magnetic resonance imaging in Churg–Strauss syndrome: case report and review of the literature

We describe a case of an individual with Churg–Strauss syndrome who presented with a cerebrovascular accident (CVA) secondary to left ventricular intracavitary thrombi. Noninvasive cardiovascular imaging using transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) was used to identify the cardioembolic source of CVA. The clinical utility of CMR in the management of patients with Churg–Strauss syndrome is reviewed.

Acute severe mitral regurgitation: consideration of papillary muscle architecture

We present a case of an individual who presented with acute severe mitral regurgitation in the setting of an inferior ST elevation myocardial infarction. Both transthoracic and transesophageal echocardiography demonstrated a posteriorly directed eccentric jet of severe mitral regurgitation with flail anterior mitral valve leaflet attached presumably to the anterior papillary muscle. Intraoperative findings demonstrated rupture of the postero-medial papillary muscle attached via chords to the anterior mitral valve leaflet. This case serves to remind us that both the anterior and posterior leaflets of the mitral valve are attached to both papillary muscle heads. The direction and eccentricity of the mitral regurgitant jet on echocardiography helps to locate the leaflet involved, but not necessarily the coexisting papillary muscle pathology.

The Role of Tissue Doppler Imaging in the Noninvasive Detection of Chronic Rejection after Heterotopic Cardiac Transplantation in Rats

Background: Chronic rejection is a risk factor for the development of cardiac allograft vasculopathy (CAV) in heart transplant recipients. A useful animal model to study the role of immunosuppressive strategies in the prevention of chronic rejection involves heterotopic abdominal cardiac transplantation in rats. The detection of rejection and concurrent CAV traditionally involves subjective serial palpation of the graft from a scale of 0 to 4, with 4 indicating vigorous beats. Recent advances in murine echocardiography, in particular Tissue Doppler imaging (TDI), may allow for objective in vivo monitoring of chronic rejection in this transplant model. Objective: The objective of this study was to compare the diagnostic accuracy of murine echocardiography as compared to the abdominal palpation heart score for the noninvasive detection of chronic cardiac graft rejection. Methods: In an animal model of heterotopic cardiac transplantation, 18 male Fischer and Lewis rats were used as donors and recipients, respectively. Abdominal palpation and murine transthoracic echocardiography were performed to assess in vivo function of the transplanted heart. Left ventricular (LV) structure and function and TDI indices, including endocardial velocity (Vendo) and strain rate (SR), were evaluated in the ectopic heart. Graft tissues were processed for histological examination and graded for chronic rejection. Results: Abdominal palpation scores were obtained in all 18 rats; score 1 (n = 5); score 2 (n = 4); score 3 (n = 6); and score 4 (n = 3). The mean LV ejection fraction was significantly (P <0.01) lower in score 3 and 4 grafts as compared to score 1 grafts. There was no correlation between the abdominal palpation score and LV systolic function. There was a significant relationship between decreasing Vendo or SR values and increasing grades of rejection (r = 0.65, P <0.05 and r = 0.75, P < 0.05, respectively). Conclusion: TDI of the transplanted heart in rats is feasible, reproducible, and more sensitive than palpation for the detection of chronic rejection.

Chiari Network Endocarditis: Not Just an Innocent Bystander

A Chiaris network, noted in approximately 2% of the general population, is a congenital remnant of the sinus venosum valve present in the right atrium. We report a case of a 67‐year‐old male who presented with acute infective endocarditis of the tricuspid valve due to coagulase‐negative Staphylococci. Despite appropriate antimicrobial therapy for 2 weeks, the patient remained febrile with septic emboli to the pulmonary vasculature. Repeat transthoracic echocardiography (TTE) revealed persistent vegetations adherent to the tricuspid valve, extending onto the Chiari network, necessitating surgical intervention.

Meningococcal serotype Y myopericarditis

Involvement of the pericardium in meningococcal disease is a well-recognized but rare complication. Isolated meningococcal pericarditis is defined as purulent pericarditis without clinical evidence of meningococcemia. Neisseria meningitidis serotypes C, B, and W135 have been previously described to cause pericarditis. This is the 1st case report of isolated meningococcal myopericarditis due to N. meningitidis serotype Y.

Stress Echocardiography: Abnormal Tissue Doppler Imaging in the Absence of Cardiac Allograft Vasculopathy in Heart Transplant Recipients

Background: The most significant predictor of long‐term survival in heart transplant patients is the development of accelerated cardiac allograft vasculopathy (CAV). Several studies have demonstrated the usefulness of dobutamine stress echocardiography (DSE) for screening CAV, by detecting regional wall motion abnormalities. Tissue Doppler imaging (TDI)‐derived indices during DSE allow for the early detection of ischemic heart disease (IHD), prior to a reduction in regional or global systolic function. These indices include a reduction in annular systolic velocity (S′), a decrease in early diastolic annular velocity (E′), and prolongation of time to E′. In cardiac transplant patients, the application of these TDI abnormalities during DSE remains unknown. Objective: The objective of this study was to evaluate the pattern of (TDI‐derived indices of systolic and diastolic function during DSE in cardiac transplant patients without evidence of CAV. Methods: A retrospective evaluation of 30 patients (mean age 54 ± 11 years) who had both DSE and coronary angiography was performed. The control group consisted of 15 patients referred to rule out coronary artery disease while the study group consisted of 15 cardiac transplant patients referred for routine annual follow‐up. During each stage of DSE, tissue Doppler measurements of systolic (S′), early (E′), and late (A′) diastolic velocities of the lateral annulus were taken. Results: All 30 patients had normal DSE based on systolic regional function and normal coronary angiograms with no stenosis >50%. There was no difference in hemodynamic parameters during the DSE at baseline and with stress. Despite normal coronaries, cardiac transplant patients demonstrated lower S′, E′, and A′ velocities at peak stress compared to the control patients. Conclusion: Dobutamine‐induced augmentation of TDI velocities of the lateral annulus, normally observed in the absence of ischemia in nontransplanted adults, is reduced in cardiac transplant recipients.

A High-Lipid Diet Potentiates Left Ventricular Dysfunction in Nitric Oxide Synthase 3-Deficient Mice after Chronic Pressure Overload

A high-lipid diet (HLD) may lead to adverse left ventricular (LV) remodeling and endothelial dysfunction in conditions of hemodynamic stress. Although congenital absence of nitric oxide synthase 3 (NOS3) leads to adverse LV remodeling after transverse aortic constriction (TAC), the effects of a HLD in this state remains unknown. Wild-type (WT) and NOS3 knockout mice (NOS3(-/-)) were randomized into the following 4 groups: 1) WT + low-lipid diet (LLD) (10% of energy); 2) WT + HLD (60% of energy); 3) NOS3(-/-) + LLD; and 4) NOS3(-/-) + HLD for a total of 12 wk. After 1 wk of randomization, TAC was performed on all groups. Serial echocardiography revealed a decrease in LV ejection fraction (LVEF) in WT and NOS3(-/-) mice fed the HLD compared with those fed the LLD diet at 12 wk post-TAC. Mice fed the NOS3(-/-) + HLD diet had a lower LVEF compared with mice in the other 3 groups (P < 0.05). There was greater myocyte hypertrophy, interstitial fibrosis, and percentage change in plasma cholesterol concentrations in the NOS3(-/-) + HLD group 12 wk post-TAC compared with the other 3 groups. Although high molecular weight fibroblast growth factor-2, a marker of cardiac hypertrophy, was more upregulated in the NOS3(-/-) + HLD group than in the other groups, markers of the renin-angiotensin system did not differ among them. A HLD potentiates LV dysfunction in NOS3(-/-) mice in a chronic pressure overload state.