The use of continuous milrinone therapy as bridge to transplant is safe in patients with short waiting times.

OBJECTIVE: The limited availability of donor organs creates a need for more effective management of heart disease when bridging a patient to cardiac transplant. Inotropic therapy is becoming more commonly used long term to maintain baseline function. The effectiveness and complications associated with their use have not been fully evaluated, and indications for mechanical versus medical therapy as a bridge have not been delineated. METHODS AND RESULTS: The purpose of this study is to evaluate the safety and efficacy of milrinone as a bridge to transplant. This was a retrospective study of 60 patients listed for a cardiac transplant and committed to home intravenous milrinone therapy. A subgroup of patients who eventually progressed to the use of a ventricular assist device were analyzed. Complications and survivals were analyzed for each group. Forty-six patients (76%) were successfully bridged to transplant with milrinone alone, and 14 patients' (24%) conditions deteriorated and required a left ventricular assist device (LVAD); 1-year survivals were 83% and 71%, respectively. The mean waiting time was 59.5 days (9-257 days) for patients receiving milrinone who did not require an LVAD and 112 days (24-270 days) for those whose conditions deteriorated to require an LVAD. CONCLUSIONS: This study suggests that chronic intravenous milrinone provides an adequate strategy as a bridge to transplant if the waiting time is short (<100 days), whereas an elective ventricular assist device implantation may be a safer strategy for patients expected to wait longer. These data provide the basis for a prospective evaluation of inotrope versus LVAD as a bridge to transplantation.

Pretreatment with high-dose statin, but not low-dose statin, ezetimibe, or the combination of low-dose statin and ezetimibe, limits infarct size in the rat.

Statins reduce infarct size by upregulating nitric oxide synthases and PGI2 production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F(1 alpha) levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F(1 alpha) levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.

The first year post-heart transplantation: use of immunosuppressive drugs and early complications.

A large number of heart transplants are performed annually in different transplant centers in the United States. This is partly because of the improved survival of patients who undergo cardiac transplantation, thus making it a more viable option in the management of end-stage heart failure. The survival benefit after heart transplantation is a result of newer immunosuppressive drug regimens and a better understanding of their effects and interactions. Several studies, mostly involving a small number of patients, describe use and comparison of the many distinct immunosuppressive drugs available to date. Interestingly, many transplant centers perform in-house typical induction treatment regimens because of their own experience and intra-institutional preference. This review summarizes current practices of immunosuppressive drug therapy in the first year post-heart transplant based on the available clinical evidence and discusses future options of heart transplant immunosuppressive drug therapies.

Pretreatment with statins may reduce cardiovascular morbidity and mortality after elective surgery and percutaneous coronary intervention: clinical evidence and possible underlying mechanisms.

After Murry et al (Circulation 1986;74:1124) described ischemic preconditioning in 1986, numerous pharmacologic agents with effects simulating ischemic preconditioning have been identified. With the exception of beta-blockers, most such agents have no proven clinical benefit in the setting of myocardial ischemia. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been consistently demonstrated to reduce myocardial injury, morbidity, and mortality in the clinical setting, both perioperatively and after percutaneous coronary intervention. Although the precise mechanism underlying their additional protective effect is not yet fully understood, it appears to be immediate in action and independent of cholesterol lowering. Experimental data from several animal models of ischemia and reperfusion have demonstrated an infarct size reduction with prior statin administration. At the cellular level, statins activate the phosphoinositol-3 kinase and Akt signaling cascade. Statins also increase expression and activity of endothelial nitric oxide synthase, inducible nitric oxide synthase, ecto-5'-nucleotidase, cyclooxygenase-2, and other prostaglandin synthesis pathway enzymes. However, when given by oral route to animals, relatively high dose of statins is needed to exert maximal protective effect. Understanding the underlying mechanism may enable to maximize the protective effect by using drug combination with synergistic activity and to avoid medications that may interfere with the protective effect of statins (ie, selective and nonselective cyclooxygenase-2 inhibition). Future clinical applications include preoperative and periprocedural risk reduction.

Meta-analysis of published reports on the effect of statin treatment before percutaneous coronary intervention on periprocedural myonecrosis.

Myonecrosis, manifested by an increase in cardiac markers, may occur in up to 50% of patients undergoing elective percutaneous coronary intervention (PCI). The degree of periprocedural myonecrosis, measured by the peak creatine kinase-MB fraction, has been associated with incidence of adverse clinical outcomes. Therefore, strategies to decrease myonecrosis may translate into a decrease in mortality. We evaluated the efficacy of statin pretreatment in decreasing the incidence of myonecrosis after PCI on the basis of results of published studies. A systematic search of the PubMed database from its inception to October 2006 and from the references of identified studies was performed. Only studies with concurrent control groups were included. Information on baseline characteristics of included patients and clinical outcomes was independently extracted by 2 investigators. A random effects model was used to pool odds ratios of the incidence of periprocedural myonecrosis in statin-treated patients versus controls. A total of 9 trials was included in the analysis, 2 randomized trials (n = 604) and 7 retrospective cohort studies (n = 4,751), which assessed the impact of statin pretreatment on periprocedural myonecrosis. During this period, 196 of 2,149 patients (9%) in the statin-treated group compared with 455 of 2,602 (17.5%) in the control group (odds ratio 0.45, 95% confidence interval 0.33 to 0.62, p <0.01) developed myonecrosis. In conclusion, based on existing evidence, routine pretreatment with statins may decrease the risk of postprocedure myonecrosis. Large randomized controlled trials addressing the dose, duration, and type of statin on periprocedural myonecrosis are necessary before recommending routine use of statins to prevent myonecrosis in the elective PCI setting.

Late right ventricular perforation and hemothorax after transvenous defibrillator lead implantation.

A 53-year-old man with ischemic cardiomyopathy underwent prophylactic transvenous implantable cardioverter-defibrillator (ICD) placement. Nine days after the procedure, he had recurrent chest pain and left pleural effusion associated with a drop in hemoglobin. Hemothorax and right ventricular (RV) lead perforation were suspected on chest radiography and lead interrogation, and confirmed by thoracentesis and contrast computed tomography (CT) scanning, respectively. The CT-scan clearly demonstrated the RV lead tip projecting beyond the cardiac border into the anterior left pleural space. The perforated lead was removed in the operating room under transesophageal echocardiography guidance and a new transvenous lead was successfully placed a month later. This case highlights: 1) the importance of suspecting late RV perforation in patients with ICD implantation presenting with recurrent chest pain and/or pleural effusion; 2) the value of CT in its diagnosis; and 3) the need for a more careful management of this potentially life threatening complication.

Time to reperfusion in acute myocardial infarction. It is time to reduce it!

BACKGROUND AND OBJECTIVES: Mortality from ST-segment elevation myocardial infarction remains high, with most deaths occurring before hospital admission. Despite effective pre- and in-hospital reperfusion strategies becoming standard over the past 2 decades, time-to-admission and time-to-treatment remain prolonged. We reviewed temporal trends in these times in published clinical trials. METHODS: All major randomized clinical trials reporting on reperfusion strategies for acute myocardial infarction published between 1993 and 2003 were evaluated. Strategies included pre- and in-hospital thrombolysis, primary percutaneous coronary intervention (pPCI) with or without transfer, and "facilitated" PCI. We generated overall estimates of time-to-admission, time-to-treatment, door-to-balloon (DTB), and door-to-needle (DTN) times and evaluated temporal trends in the length of time-to-admission and time-to-treatment. RESULTS: In studies that evaluated only in-hospital thrombolysis, the time-to-admission was 149 +/- 45 minutes; the mean time-to-treatment was 181 +/- 29 minutes. In studies that considered only in-hospital pPCI (without transfer), the mean time-to-admission was 153 +/- 41 minutes; the mean time-to-treatment was 234 +/- 43 minutes. In studies that compared in-hospital pPCI with in-hospital thrombolytic therapy, the mean time-to-admission was 155 +/- 47 and 150 +/- 48 minutes, respectively. The DTN time was 65 +/- 10 minutes, whereas DTB time was 81 +/- 39 minutes. In other trials evaluating in-hospital thrombolysis and pPCI with transfer to a referral center, the time-to-admission in subjects treated with thrombolysis (n = 1345) was 127 +/- 32 minutes vs 131 +/- 36 minutes for pPCI (n = 1528). For in-hospital thrombolysis, time-to-treatment was 151 +/- 23 minutes vs 203 +/- 15 minutes for pPCI patients with transfer. The DTN time in the thrombolysis group was 44 +/- 28 minutes as compared with DTB time of 78 +/- 38 minutes in the pPCI group. Throughout the last decade, time-to-admission decreased significantly (P = .02) but time-to-treatment remained unchanged (P = .38) for patients undergoing thrombolysis. In the pPCI arm, time-to-admission remained unchanged (P = .11) but a insignificant trend toward reduction was demonstrated in time-to-treatment (P = .11). CONCLUSION: Time-to-admission and time-to-treatment for ST-segment elevation myocardial infarction are still prolonged. Resources should be directed to early recognition of the acute myocardial infarction, improved utilization of emergency services for transportation, and prehospital diagnosis and triaging. Ambulances equipped with wireless capability to transmit electrocardiograms to the on-call cardiologist seem to be promising tools to achieve earlier diagnosis and triaging with high diagnostic sensitivity and specificity.

Noncompaction of ventricular myocardium associated with hypertrophic cardiomyopathy and polycystic kidney disease.

Noncompaction of ventricular myocardium (NVM), a relatively new diagnostic entity, is described as an arrest in the process of compaction of myocardial fibers, which results in a prominent trabecular network and deep intertrabecular recesses. Its coexistence with other cardiac anomalies like hypertrophic obstructive cardiomyopathy (HOCM) or polycystic kidney disease (PKD) had been reported in the past. We report the first case with all 3 different inherent conditions (NVM, HOCM, and PKD) manifesting in 1 patient. A 37-year-old man was referred for evaluation of a heart murmur. His medical history was positive for paroxysmal atrial fibrillation. Physical examination revealed a grade 3/6 systolic murmur loudest along the left sternal border accentuating on Valsalva maneuver. Echocardiography revealed HOCM. Cardiac magnetic resonance confirmed the presence of HOCM with the incidental finding of NVM and PKD. This case raises the possibility of genetic mutation common to these 3 clinical entities or 2 different gene mutations existing in the same individual.

Hypothyroidism and renal function in patients with systolic heart failure.

The extent to which hypothyroidism affects renal function in patients with heart failure remains incompletely explored, despite the known adverse prognostic implications of renal dysfunction in these patients.In a pilot retrospective study, we evaluated 75 patients (age, >or=18 yr) with left ventricular ejection fractions <0.40. Forty-five patients had normal thyroid function (thyroid-stimulating hormone [TSH], 0.35-5.5 micro IU/mL) and 30 had hypothyroidism. The group with hypothyroidism was subdivided into 17 patients who had controlled hypothyroidism (TSH, 0.35-5.5 micro IU/mL) and 13 who had uncontrolled hypothyroidism (TSH, >5.5 micro IU/mL). Renal function, measured in terms of glomerular filtration rate, was analyzed once in each patient, and the populations were statistically compared, with P <0.05 conferring statistical significance.Baseline characteristics in all groups were similar. Mean glomerular filtration rate was better in patients with normal thyroid function than those with hypothyroidism (75.45 +/- 31.48 vs 63.95 +/- 21.43 mL/min/1.73 m2; P=0.032). There was no significant difference between patients with controlled hypothyroidism (66.89 +/- 24.18 mL/min/1.73 m2) and those with normal thyroid function (P=0.131). In patients with uncontrolled hypothyroidism, mean glomerular filtration rate (60.2 +/- 17.4 mL/min/1.73 m2) was significantly worse than in patients with normal thyroid function (P=0.015).We found that heart-failure patients with insufficiently treated hypothyroidism have worse renal function than do patients whose thyroid function is normal or whose hypothyroidism is effectively treated. Larger studies will be needed in order to evaluate this conclusion further. We recommend that hypothyroidism in heart-failure patients be strictly controlled, lest it affect prognosis adversely.

Management of hypertension in chronic heart failure.

Chronic heart failure (CHF) is associated with frequent hospitalizations and high mortality. It affects more than 5 million individuals in the USA, and another 660,000 new cases are diagnosed each year; overall, heart failure (HF) now accounts for 7% of all deaths from cardiovascular disease. Hypertension (HTN) increases the risk of development of HF and it precedes it in 75% of cases. HF patients are nearly evenly divided between those with reduced left ventricular (LV) function or systolic dysfunction and those with preserved LV systolic function or diastolic dysfunction. The management of HTN in patients with CHF is challenging. Drugs such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor blockers, hydralazine and nitrates, which have shown mortality benefit in CHF and exert antihypertensive effects, should be used as first-line agents to control HTN in CHF. In addition, antihypertensive drugs such as alpha-receptor blockers that can increase mortality in HF should be avoided. The dihydropyridine group of calcium channel blockers are good antihypertensive medications with a neutral effect on mortality in patients with CHF. These may be used in CHF patients with refractory HTN. In patients with HF with reduced ejection fraction, HTN is treated differently in comparison to patients with HF with normal ejection fraction. This article reviews the treatment of essential HTN in patients at risk for developing HF, in the presence of HF and the latest developments in treatment that might benefit both HTN and HF management.

The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation.

Statins activate phosphatidylinositol-3-kinase, which activates ecto-5'-nucleotidase and phosphorylates 3-phosphoinositide-dependent kinase-1 (PDK-1). Phosphorylated (P-)PDK-1 phosphorylates Akt, which phosphorylates endothelial nitric oxide synthase (eNOS). We asked if the blockade of adenosine receptors (A(1), A(2A), A(2B), or A(3) receptors) could attenuate the induction of Akt and eNOS by atorvastatin (ATV) and whether ERK1/2 is involved in the ATV regulation of Akt and eNOS. In protocol 1, mice received intraperitoneal ATV, theophylline (TH), ATV + TH, or vehicle. In protocol 2, mice received intraperitoneal injections of ATV, U0126 (an ERK1/2 inhibitor), ATV + U0126, or vehicle; 8 h later, hearts were assessed by immunoblot analysis. In protocol 3, mice received intraperitoneal ATV alone or with 8-sulfophenyltheophylline (SPT); 1, 3, and 6 h after injection, hearts were assessed by immunoblot analysis. In protocol 4, mice received intraperitoneal ATV alone or with SPT, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), alloxazine, or MRS-1523; 3 h after injection, hearts were assessed by immunoblot analysis. ATV increased P-ERK, P-PDK-1, Ser(473) P-Akt, Thr(308) P-Akt, and P-eNOS levels. TH blocked ATV-induced increases in P-ERK, Ser(473) P-Akt, Thr(308) P-Akt, and P-eNOS levels without affecting the induction of P-PDK-1 by ATV. U0126 blocked the ATV induction of Ser(473) P-Akt and Thr(308) P-Akt while attenuating the induction of P-eNOS. A detectable increase in P-ERK, Ser(473) P-Akt and P-eNOS was seen 3 and 6 h after injection but not at 1 h. DPCPX, CSC, and alloxazine partially blocked the ATV induction of P-ERK, Ser(473) P-Akt, and P-eNOS. In conclusion, blockade of adenosine A(1), A(2A), and A(2B) receptors but not A(3) receptors inhibited the induction of Akt and eNOS by statins. Adenosine was required for ERK1/2 activation by statins, which resulted in Akt and eNOS phosphorylation.

An unusual electrocardiogram artifact: what is its source?

A diabetic female presented with nausea and vomiting. Her electrocardiogram showed sinus rhythm with two artifactual spikes, not synchronized with the cardiac rhythm. The patient had an implanted gastric electrical stimulation system for treating her diabetic gastroparesis. Recent DC shock for ventricular fibrillation during coronary angiography caused malfunction of the gastric pacemaker.