Background: PAH Problem Idiopathic pulmonary arterial hypertension is a rare disease with about 2–3 newly diagnosed cases per million people per year in Europe and the US. Medical therapy is targeted at reduction of pulmonary pressure and resistance. Approved therapies such as endothelin antagonists or prostenoids are complex and expensive. Prior to treatment, the patient’s pulmonary vasodilator response to prostacyclin or nitric oxide is assessed during invasive monitoring.

       Typically, less than 15-25% of the patients show a significant (>= 20%) lowering of the pulmonary arterial (PA) pressure during the acute test. Often, close monitoring of PA pressure is needed to achieve and maintain optimal therapy that chronically lowers the PA pressure without also causing symptomatic systemic hypotension. Currently, this monitoring is done either invasively by repeated catheterizations or non-invasively by Doppler-echocardiography estimation of right ventricular systolic pressure. Use of the Chronicle^® IHM (Implantable Hemodynamic Monitor) system in this patient population has the potential to allow more precise titration of drugs by providing data continuously during rest and exercise, and when drugs and doses are modified.

Figure 1.

llustration of the Chronicle IHM, the RV lead with pressure transducer and the external pressure reference devices. Also shown are the variables measured by the IHM system.

Device Description
       The Chronicle^® IHM (Figure 1) is a system consisting of the IHM, the pressure sensing lead, the External Pressure Reference (EPR, the Interactive Remote Monitor (Figure 2), the Model 9790 Programmer with customized software, and the CareLink Information Network. The IHM and lead are implanted to monitor hemodynamic information, primarily right ventricular pressure, heart rate and activity. The  investigational system is intended to assist in the medical management of patients diagnosed with pulmonary arterial hypertension. Other applications under investigation include continuous monitoring of intra-cardiac pressure in patients with advanced heart failure, as these patients are at risk of hospitalization largely due to inappropriate changes in fluid volume status.

Figure 2.

Illustration of the remote monitor device the PAH patients have in their home for routine transmission of the data stored in the IHM to the Web-based Information Network.

       The Chronicle^® IHM system acquires and stores hemodynamic trend data that can be retrieved transtelephonically for analysis from an ambulatory patient. Data can be stored for up to two months when samples are obtained at a frequency sufficient to provide clinically useful continuous hemodynamic measurements. Information made available through the device includes right ventricular diastolic and systolic pressure, right ventricular dP/dt (maximum positive and maximum negative slopes), pulse pressure, pre-ejection interval, systolic time interval and estimates of pulmonary artery mean and diastolic pressures, core temperatures, activity counts from an activity crystal and heart rate from a unipolar right ventricular intracardiac electrogram. The IHM system allows correlation of heart rate and activity with the hemodynamic information to distinguish hemodynamic status at rest versus exercise and normal rates versus arrhythmias.
       The IHM system is also capable of real-time display of hemodynamic information, and thus will provide improved patient follow-up and treatment without subjecting the patient to multiple invasive procedures.
       The hemodynamic data is stored within a large internal memory as trends, histograms, or as a snapshot of hemodynamic status. The trend data can be averaged at programmable intervals ranging from seconds to days. The IHM system is capable of event- and patient-triggered activation, to provide higher resolution snapshots of specific events. Temporary higher resolution recording can be activated manually by application of a magnet to the implant site or by programmed criteria. In addition, real-time telemetry or stored data can be obtained from the implanted IHM system by a standard programmer for analysis and display.
       The IHM system functions using a single transvenous ventricular unipolar pressure sensing lead implanted in the right ventricle (Figure 3). The tip electrode and sensor, located near the distal end of the lead, provide the means of collecting information on heart rate via intracardiac electrogram and right ventricular pressure.

Figure 3.

X-ray illustration showing the right ventricular pressure lead positioned in the right ventricle in the distal tip in the high inter-ventricular septum.

       A Programmer provides the user with an interface to the implanted device and the EPR, and was used during all implants and scheduled follow-ups. The Model 9790 Programmer is used for all implants. The EPR measures and records the barometric pressure, and is kept with or near the patient. When connected to the Programmer, barometric changes stored in the EPR are used to correct the barometric changes in the stored hemodynamic pressure within the IHM. The Programmer provides a means by which to alter settings of the IHM, to receive data via telemetry, to display, and to generate printed reports. The Programmer can also be used as a diagnostic tool in that it can place the IHM in modes that check the proper functionality of the sensor.
The Chronicle^® Information Network is a web-based application that allows the viewing of short- or long-term data files. Data can be loaded to this application by floppy diskette generated by the Programmer at the investigative center or by the Interactive Remote Monitor, from the clinic or the patient's home, respectively. The application allows the clinic staff to review chronic pressure data from implant to the current date, review a summary of the most recently transmitted data, add notes to the trend data and print reports of this data. The Interactive Remote Monitor is a tool that can be used by the patient to send data stored by the IHM and the EPR via a phone line to the Information Network. The Interactive Remote Monitor has a slot for the EPR and a telemetry head, which is used to collect data from the implanted monitor.

Pulmonary Hypertension Case Review
       A 42-year-old female was treated for six years with intravenous epoprostenol that reduced her Doppler-echocardiographically-estimated RV systolic pressure (RVSP) from 91 mmHg to approximately 40 mmHg at a peak dose of 57 ng/kg/minute. The baseline non-invasive echo data corresponded closely to right-heart catheterization. Her WHO Class (Figure 4) improved from IV to II. Because of side effects and inconvenience, she wished to attempt transition to the oral endothelin antagonist, bosentan. Bosentan was initiated, and epoprostenol was slowly tapered off over 13 months, during which she remained WHO Class II; her RVSP near the end of this transition was 46 mmHg. However, she developed progressive dyspnea several weeks after discontinuation of epoprostenol therapy, and her RVSP increased to 86 mmHg. The patient declined re-initiation of epoprostenol, but agreed to a trial of subcutaneous treprostinil infusions, and also consented to the Chronicle® implantation.

Figure 4. WHO Classification of functional status of patients with pulmonary hypertension.

- Class Description I. Patients with pulmonary hypertension in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest pain or pre-syncope. II. Patients with pulmonary hypertension who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain or pre-syncope. III. Patients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain or pre-syncope. IV. Patients with pulmonary hypertension who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity.

       The patient’s baseline hemodynamic data and peak responses during an acute vasodilator (epoprostenol) challenge study are shown in Table 1. The PA mean pressure dropped from 67 mmHg to 43 mmHg at the peak of the drug infusion. PA resistance dropped from 29.9 to 10.3 Units/m2. Over 12 weeks of therapy, treprostinil was gradually increased to a dose of 22.5 ng/kg/minute while continuing the bosentan and calcium-channel-blocker (Diltiazem). Symptoms again improved to WHO Class II. Chronicle^® measurements showed progressive improvement (decreases) in the patient’s pulmonary hemodynamics with the mean PA pressure decreasing from 81 to 61 mmHg (Table 2, Figure 5) at a dose of 22.5 ng/kg/minute. Dose increases were continued to 45 ng/kg/minute with further decrease in pressure. Addition of sildenafil and withdrawal of bosentan during continued monitoring are also being considered.

Figure 5.

Illustration of six-month plots of continuous IHM data collected in a PAH patient undergoing up-titration of Bosentan. Plots show median (black line) and 6 to 94th percentiles (red lines) for the variables from every six-minute storage interval. Vertical lines are annotations of incremental doses of Bosentan.