Diuretic therapy has become a mainstay of therapy in many patients with HF. This has been due to its effective, rapid improvement in hemodynamics with concurrent relief of congestive signs and symptoms. Diuretics have also been utilized to assist in the preservation of a “compensated-state.” In general, diuretic dosage requirements increase as HF and chronic renal disease progresses. Prior to CRT placement, diuretic optimization is individualized, with the primary goal being to maintain an optimal-stable volume status, while using the smallest possible dose in an effort to minimize longterm undesirable effects.

Unfortunately, the utilization of diuretics has been associated with a litany of deleterious consequences. Diuretics are known to predispose patients toward the development of hypotension, in part, secondary to the development of an unintentional and unfavorable hemodynamic profile and intravascular volume depletion. These medications have been associated with electrolyte abnormalities, such as hypokalemia and hypomagnesemia. These electrolyte disturbances have been correlated with a more favorable biochemical substrate for the development of cardiac arrhythmias. In addition, there is a greater risk for the development of renal dysfunction with diuretic use. This pathological cascade of escalating diuretic doses and increasing diuretic resistance may lead to a further injurious cycle of progressive renal disease and further upregulation of the renal-angiotensin and sympathetic nervous systems. This neurohormonal response then further exacerbates cardiovascular function as increasing circulating aldosterone is associated with an increase in myocardial fibrosis. Ultimately, the summation of these changes may lead to a more arrhythmogenic and maladaptive cardiac state. To date, the employment of diuretic therapy has been independently associated
with an increase in HF hospitalizations, progressive HF deaths, sudden cardiac deaths, and overall mortality.^6,7,8 We therefore recommend that the lowest dose of diuretic be used before and after CRT therapy as determined by best clinical judgment. Importantly, pharmacologic efforts should be focused on achieving target doses of angiotensin inhibitors (ACEi), beta blockers (BB), angiotensin receptor blockers (ARB), and aldosterone antagonist, aspirin, and statins as it is appropriate to a specific patient’s clinical profile.

Once a biventricular pacemaker is implanted, it typically allows for a significant attenuation of diuretic dose. Immediately post-CRT implantation, hemodynamic changes occur including an increase in stroke work, cardiac output, and systolic blood pressure along with a decrease in end-systolic volumes and pulmonary capillary wedge pressure.^9,10 In addition to the long-term biochemical and electromechanical cardiac restructuring frequently seen post-CRT, these shortterm hemodynamic shifts quickly result in an environment capable of supporting a new medical regimen.

One consequence of these changes is that the diuretic need is decreased with improved intracardiac filling pressures. These changes require a recalibration to match the decreased demand for diuresis and to avoid excessive intravascular volume loss. After CRT implantation, the previously “optimal” diuretic therapy dosage becomes, in effect, suboptimal and even potentially harmful. If the dose is not decreased, patients frequently will develop intravascular volume depletion, symptomatic hypotension, electrolyte disturbances, and prerenal azotemia.¹¹ Hence, post-CRT weaning of diuretic therapy is recommended. In some patients, this may allow implementation of higher doses of medications known to chronically improve mortality in HF patients.

For most patients with HF, BB use is an integral component of effective treatment. Bisoprolol, carvedilol, and metoprolol succinate have specifically been shown to improve outcomes in HF patients and are endorsed by the American Heart Association Guidelines for chronic HF. With BB, an improvement in functional class and ejection fraction has also been observed over an expected time-frame of months to years. Notably, with increasing doses of BB subsequent to CRT, patients on beta-blockade have demonstrably fewer hospitalizations and a lower mortality rate.

While the specific mechanisms of action responsible for these improved HF outcomes have yet to be completely elucidated, there are numerous cardiac structural, neurohormonal, and molecular changes associated with beta-blockade. The sympathetic nervous system is activated, in part, as a result of the failing heart’s increased adrenergic tone. This tone occurs initially as an intrinsic mechanism intended to improve cardiac function, but over time, this adaptive system degenerates and becomes maladaptive in part, leading to pathological remodeling. BB therapy in conjunction with CRT partially interrupts this maladaptive system and contributes to ventricular reverse remodeling. Structurally, this is seen with an increase in regional contractile functionality, a decrease in chamber size, and potentially with a longterm reduction in mechanical dyssynchrony and an improvement in ejection fraction. On a molecular level, there is mounting evidence of an antiapoptotic effect, a reduction in inflammatory cytokines, a decrease in the level of oxygen free radicals, an improved high-energy phosphate production, and a restoration of intracellular calcium management.^11,12 These alterations ultimately yield improvements in signal transduction. The final product of these molecular changes is a more capable, less dysfunctional myocyte milieu and ventricle.

Conversely, if BB therapy is not carefully uptitrated and individualized to each patient, these drugs can potentially lead to a multitude of well-known adverse effects. After the initiation or recent uptitration of a BB, the optimal fluid balance of a given patient may be tipped askew as a result of increased fluid retention and a temporary decrease in contractile function. Fatigue, hypotension, lightheadedness, and dizziness may also occur. Lastly, bradycardia and heart block can develop. Many times, bradycardia is asymptomatic; however with increasing doses of BB, symptoms as well as insufficient heart rates or blood pressure can limit ideal doses of BB in HF patients. Prior to CRT placement, decreasing or even stopping therapy has sometimes been necessary, although the latter should occur only with persistent, severe symptoms, and after a close review and discontinuation of any other contributing drugs.

Overall, a need currently exists to improve the utilization of BB therapy in HF clinical practice, and CRT may help to improve reaching target doses as well as patient and physician compliance. In the large clinical trials demonstrating improved outcomes with CRT, the rates of BB use ranged from only approximately 30% to 60%.¹³ In an analysis of one of the landmark BB mortality trials, the top three given reasons for failure or hesitancy to uptitrate beta-blockade therapy were symptoms of worsening HF, bradycardia, and hypotension.¹³ CRT permits beta-blockade in many patients who previously were either unable to initiate therapy or to reach maximum goal dosage secondary to intolerance.¹⁴ Post-CRT, the precipitating conditions of intolerance are in part obviated. The hemodynamic profile is more conducive to the maintenance of an optimal intravascular volume status. Therefore, fluid retention associated with beta-blockade is less of an issue. The increase in systolic blood pressure commonly seen with CRT also decreases the chance of symptomatic drug-induced hypotension and allows for either initiation or uptitration of BB therapy. Lastly, CRT’s pacing activity eliminates the concerns of symptomatic bradycardia and heart block. Maximizing beta-blockade may also have its own prognostic incentive as evidence suggests synergistic effects of device and medical therapies including enhanced autonomic effects, improved reverse remodeling, and decreased hospitalization and mortality rates.^15,16

ACE inhibitor (ACEi) therapy is a cornerstone of HF management. Long-term use may stabilize or potentially improve myocardial function. HF patients on ACEI have reduced hospitalizations and mortality. The majority of patients
tolerate this class of drugs with careful titration. For those intolerant, angiotensin receptor blockers (ARB) are a reasonable alternative. In HF patients, valsartan and candesartan specifically have established noninferior outcomes relative to ACEi.⁶² Without ACEi or ARB therapy, the renin-angiotensinaldosterone system (RAAS) operates unopposed, thereby substantially contributing to the progression of HF. RAAS activation is associated with atrial remodeling, ventricular dilatation, hypertrophy, deleterious extracellular matrix changes, systolic dysfunction, and increasing arrhythmogenesis.¹⁷

CRT permits an increased cohort of HF patients to achieve optimal ACEi or ARB therapy. Intolerance has been a key barrier to this objective. Angiotensin suppression can predispose to hypotension, renal dysfunction, and potentially hyperkalemia. These adverse effects are noted limitations of therapy. In severe HF, high diuretic doses and unfavorable hemodynamics frequently contribute to suboptimal intravascular volume despite total body-volume overload. This further creates an environment conducive to limited, suboptimal medical management. Clinicians frequently find that hypotension occurs less frequently post-CRT. Significant dose-limiting azotemia appears lessened in clinical practice as well. These changes subsequent to CRT frequently lead to successful titration of drug therapy in many post-CRT HF patients. The medical optimization of pharmacologic therapy may also lead to improved patient outcomes in combination with the CRT.

Unfortunately, CRT utilization still has a 20% to 30% “nonresponders” rate. The meaning of the term itself is currently debatable. There is not yet an established definition of a nonresponder. Both echocardiographic measures (ejection fraction, mitral regurgitation, ventricular dimensions and volumes), as well as clinical measures (NYHA class, quality of life score, 6-minute walking distance, functional capacity) have been utilized to assess response. A lack of improvement in the chosen parameter has led to the term “nonresponder” in prior CRT studies. Yet, a firm correlation between clinical and echocardiographic improvement does not always exist because an HF patient may clinically improve with no significant change in their echocardiogram or vice-versa. It is also important to note that clinical and imaging improvements do not necessarily occur simultaneously. Current efforts are ongoing to standardize the nonresponder designation.

Nonresponse evaluation should occur if worsening HF and ongoing pathologic ventricular remodeling continue within the first few months post-CRT, or if there is no abatement in symptoms in the first 6 months after implantation. Delineating a potentially correctable cause of nonresponse is an important component of post-CRT management. Volume abnormalities, ongoing coronary ischemia, device placement issues, and suboptimal device programming can all contribute to lack of response. Lastly, once all identifiable causes are excluded, a selected nonresponder population will inevitably remain with progressive disease. This “true nonresponder” group will require further intervention.

Volume abnormalities may inhibit CRT’s beneficial effects. Congestion or intravascular volume depletion can result in maladaptive filling pressures. Clinical decompensation and detrimental remodeling may follow. Avoidance of suboptimal hemodynamics is necessary to maximize CRT response. An evaluation for prerenal azotemia is warranted in nonresponders as well. Post-CRT, over-diuresis can occur without diuretic dose titration. Measures to minimize congestion including fluid and salt restriction, daily weight assessment, and medication compliance should be continued. A limitation of clinical practice is the occasional lack of correlation between current volume assessment measures and true volume status. Ongoing studies are investigating whether implantable continuous hemodynamic monitoring devices will lead to improved patient outcomes. This may be a useful adjunctive tool for the HF caregiver in the future.

Other reasons for poor CRT responses may include ongoing ischemia and lead placement. A CRT nonresponder should be evaluated for ischemia amenable to revascularization. Interventions should be performed on target coronary lesions. While this typically is done at an earlier point in HF management, CRT nonresponse should prompt reassessment in suitable patients. In addition, impaired global perfusion reserve is also thought to trigger intermittent ischemia. SPECT and MR imaging have associated significant nonviability with diminished CRT response.^{18,19,20,21,22,23} CRT can improve metabolism and perfusion, although these effects may augment function as well in nonischemic cardiomyopathy patients.²⁴ As a separate concern, LV lead placement in scarred myocardium may prevent resynchronization.²⁵

CRT implantation is associated with early and late complications. Ramifications can prohibit placement, impede response, or prompt corrective interventions. Greater than 90% of CRT devices are successfully implanted (initially) at experienced centers. Placement failure is most commonly caused by technical difficulties implanting the LV lead. Anatomical factors are typically responsible with tortuous venous anatomy precluding access being one of the primary causes. Retrograde venography and noninvasive venous imaging usually allows suitable selection. Additional technical difficulties are frequently encountered as enlarged right atrium distorts the coronary sinus ostium. A resultant inability to either cannulate or support the guiding catheter may occur in up to 4% of cases.²⁶ Prior studies have reported a 0.4% to 4% incidence of coronary sinus dissection. As the venous system is a low-pressure system, this usually does not have significant long term sequela, as perforation is very uncommon. Suboptimal lead placement can also lead to
nonresponse or worsening dyssynchrony. Implant in anterior location or nondyssynchronous region heightens the probability of this complication.²⁷

Other problems may arise post-implantation. These may include: 1) CRT nonresponse, with proper lead placement and suitable pacing capture thresholds, 2) lead dislodgement as has been reported in 4% to 12% of patients, 3) phrenic nerve stimulation secondary to lead proximity and inappropriate pacing output. This complication may be seen in 1.6% to 12% of patients and may develop as a consequence of postural changes.²⁸

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