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.

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.

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.

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.

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.

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.

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.

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.

Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study.

Background The incidence and management of trastuzumab-mediated cardiotoxicity outside of clinical trials has not been well described. Objective and methods The aim of the study was to retrospectively evaluate the incidence of cardiac dysfunction, characterize its natural history, and identify the degree of reversibility using cardiac MRI, in a population of HER-2 positive breast cancer patients receiving trastuzumab in the adjuvant setting. Results Out of 152 patients (mean age 52 +/- 10 years), 36 (24%) developed trastuzumab mediated cardiomyopathy, the majority asymptomatic. Factors that predicted the development of trastuzumab mediated cardiac dysfunction were a pre-existing history of hypertension, smoking history, and a family history of coronary artery disease. Within 3 months of treatment with trastuzumab, there was a difference in LVEF between the normal cohort and those patients who developed LV systolic dysfunction (61 +/- 5% vs. 51 +/- 8%, P < 0.01). During the 6-month-followup, 34/36 patients demonstrated subepicardial linear delayed enhancement of the lateral wall of the left ventricle on cardiac MRI, suggesting trastuzumab induced myocarditis. Conclusion Approximately 1 in 4 women may develop LV systolic dysfunction after treatment with adjuvant trastuzumab, necessitating careful patient selection and close serial monitoring using noninvasive cardiac imaging.

Chiari network endocarditis: not just an innocent bystander.

A Chiari's 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.

Clinical utility of tissue Doppler imaging in patients with acute myocardial infarction complicated by cardiogenic shock.

BACKGROUND: Echocardiography is widely used in the management of patients with cardiogenic shock (CS). Left ventricular ejection fraction (EF) has been shown to be an independent predictor of survival in CS. Tissue Doppler Imaging (TDI) is a sensitive echocardiographic technique that allows for the early quantitative assessment of regional left ventricular dysfunction. TDI derived indices, including systolic velocity (S'), early (E') and late (A') diastolic velocities of the lateral mitral annulus, are reduced in heart failure patients (EF < 30%) and portend a poor prognosis. In CS patients, the application of TDI prior to revascularization remains unknown. OBJECTIVE: To characterize TDI derived indices in CS patients as compared to patients with chronic CHF. METHODS: Between 2006 and 2007, 100 patients were retrospectively evaluated who underwent echocardiography for assessment of LV systolic function. This population included: Group I) 50 patients (30 males, 57 +/- 13 years) with chronic CHF as controls; and Group II) 50 patients (29 males, 58 +/- 10 years) with CS. Spectral Doppler indices including peak early (E) and late (A) transmitral velocities, E/A ratio, and E-wave deceleration time were determined. Tissue Doppler indices including S', E' and A' velocities of the lateral annulus were measured. RESULTS: Of the entire cohort, the mean LVEF was 25 +/- 5%. Cardiogenic shock patients demonstrated significantly lower lateral S', E' and a higher E/E' ratio (p < 0.01), as compared to CHF patients. The in-hospital mortality in the CHF cohort was 5% as compared to the CS group with an in hospital mortality of 40%. In the subset of CS patients (n = 30) who survived, the mean S' at presentation was higher as compared to those patients who died in hospital (3.5 +/- 0.5 vs. 1.8 +/- 0.5 cm/s). CONCLUSION: Despite similar reduction in LV systolic function, CS patients have reduced myocardial velocities and higher filling pressures using TDI, as compared to CHF patients. Whether TDI could be a reliable tool to determine CS patients with the best chance of recovery following revascularization is yet to be determined.

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.